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1
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Dutuze MF, Clark SD, Del Piero F, Christofferson RC. Preliminary evidence that Bunyamwera virus causes severe disease characterized by systemic vascular and multiorgan necrosis in an immunocompromised mouse model. J Gen Virol 2024; 105:002040. [PMID: 39503743 PMCID: PMC11539936 DOI: 10.1099/jgv.0.002040] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2024] [Accepted: 10/15/2024] [Indexed: 11/08/2024] Open
Abstract
Bunyamwera virus (BUNV) is the prototypical member of the Bunyamwera serogroup within the Orthobunyvirus genus. BUNV is transmitted by mosquito vectors of the genera Culex, Aedes and Anopheles and has historically circulated in East Africa, though the transmission has been observed in Argentina. BUNV has been identified as an agent of human and animal disease and has also been misdiagnosed as other agents. BUNV is often thought to be an agent of mild febrile illness in humans, though it can cause abortions in ruminants and neurological disease in horses. Joint pain and gastritis have also been attributed to BUNV. There are limited data concerning the possible spectrum of disease and extent of pathogenesis of BUNV infection, and there are currently no therapeutics or vaccines available. Furthermore, options for animal models for Orthobunyaviruses in general - of which BUNV is the prototypical member - are limited. Eight mice deficient in the type I interferon response were infected with BUNV, and all developed overt disease. All mice developed detectable viraemia and clinical signs, including weight loss, hunched posture and lethargy. Three of the eight mice developed severe diseases, including vascular necrosis and necrosis in the liver, lungs, reproductive organs, bone marrow and spleen, as well as haemorrhages (n=1) and severe diffuse facial oedema (n=3), reminiscent of the pathology of Schmallenberg and the Arenaviruses Lassa and Lujo viruses. Thus, BUNV infection of IRF3/7 DKO mice could serve as a BSL-2 model for severe diseases of higher-risk group viruses, which often must be studied at BSL-4. Additionally, our results suggest that BUNV may have the ability to cause severe disease in immunocompromised hosts. Thus, further investigation into the potential spectrum of pathogenesis due to BUNV is important to prioritize for outbreak response, diagnostics and the development of countermeasures.
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Affiliation(s)
- M. Fausta Dutuze
- Rwanda Institute for Conservation Agriculture, Kigali, Rwanda
- Department of Pathobiological Sciences, School of Veterinary Medicine, Louisiana State University, Baton Rouge, Louisiana 70803, USA
| | - Samantha D. Clark
- Department of Pathobiological Sciences, School of Veterinary Medicine, Louisiana State University, Baton Rouge, Louisiana 70803, USA
| | - Fabio Del Piero
- Department of Pathobiological Sciences, School of Veterinary Medicine, Louisiana State University, Baton Rouge, Louisiana 70803, USA
| | - Rebecca C. Christofferson
- Department of Pathobiological Sciences, School of Veterinary Medicine, Louisiana State University, Baton Rouge, Louisiana 70803, USA
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2
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Chan YT, Cheok YY, Cheong HC, Tang TF, Sulaiman S, Hassan J, Looi CY, Tan KK, AbuBakar S, Wong WF. Immune Recognition versus Immune Evasion Systems in Zika Virus Infection. Biomedicines 2023; 11:biomedicines11020642. [PMID: 36831177 PMCID: PMC9952926 DOI: 10.3390/biomedicines11020642] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2022] [Revised: 01/17/2023] [Accepted: 01/19/2023] [Indexed: 02/22/2023] Open
Abstract
The reemergence of the Zika virus (ZIKV) infection in recent years has posed a serious threat to global health. Despite being asymptomatic or mildly symptomatic in a majority of infected individuals, ZIKV infection can result in severe manifestations including neurological complications in adults and congenital abnormalities in newborns. In a human host, ZIKV is primarily recognized by RIG-like receptors and Toll-like receptors that elicit anti-viral immunity through the secretion of type I interferon (IFN) to limit viral survival, replication, and pathogenesis. Intriguingly, ZIKV evades its host immune system through various immune evasion strategies, including suppressing the innate immune receptors and signaling pathways, mutation of viral structural and non-structural proteins, RNA modulation, or alteration of cellular pathways. Here, we present an overview of ZIKV recognition by the host immune system and the evasion strategies employed by ZIKV. Characterization of the host-viral interaction and viral disease mechanism provide a platform for the rational design of novel prophylactic and therapeutic strategies against ZIKV infection.
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Affiliation(s)
- Yee Teng Chan
- Department of Medical Microbiology, Faculty of Medicine, University of Malaya, Kuala Lumpur 50603, Malaysia
| | - Yi Ying Cheok
- Department of Medical Microbiology, Faculty of Medicine, University of Malaya, Kuala Lumpur 50603, Malaysia
| | - Heng Choon Cheong
- Department of Medical Microbiology, Faculty of Medicine, University of Malaya, Kuala Lumpur 50603, Malaysia
| | - Ting Fang Tang
- Department of Medical Microbiology, Faculty of Medicine, University of Malaya, Kuala Lumpur 50603, Malaysia
| | - Sofiah Sulaiman
- Department of Obstetrics and Gynecology, Faculty of Medicine, University of Malaya, Kuala Lumpur 50603, Malaysia
| | - Jamiyah Hassan
- Department of Obstetrics and Gynecology, Faculty of Medicine, University of Malaya, Kuala Lumpur 50603, Malaysia
| | - Chung Yeng Looi
- School of Biosciences, Faculty of Health & Medical Sciences, Taylor’s University, 1, Jalan Taylors, Subang Jaya 47500, Malaysia
| | - Kim-Kee Tan
- Tropical Infectious Diseases Research and Education Centre (TIDREC), Higher Education Center of Excellence (HICoE), University of Malaya, Kuala Lumpur 50603, Malaysia
| | - Sazaly AbuBakar
- Tropical Infectious Diseases Research and Education Centre (TIDREC), Higher Education Center of Excellence (HICoE), University of Malaya, Kuala Lumpur 50603, Malaysia
| | - Won Fen Wong
- Department of Medical Microbiology, Faculty of Medicine, University of Malaya, Kuala Lumpur 50603, Malaysia
- Correspondence: ; Tel.: +60-(3)-7967-6672
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Use of Envelope Domain III Protein for the Detection of IgG Type Antibodies Specific to Zika Virus by Indirect ELISA. Diagnostics (Basel) 2023; 13:diagnostics13030462. [PMID: 36766567 PMCID: PMC9913938 DOI: 10.3390/diagnostics13030462] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2022] [Revised: 12/19/2022] [Accepted: 12/23/2022] [Indexed: 01/28/2023] Open
Abstract
Zika virus (ZIKV) diagnostics are crucial for proper antenatal and postnatal care and also for surveillance and serosurvey studies. Since the viremia during ZIKV infection is fleeting, serological testing is highly valuable to inform diagnosis. However, current serology tests using whole virus antigens frequently suffer from cross reactivity issues, delays, and technical complexity, especially in low and middle income countries (LMICs) and endemic countries. Here, we describe an indirect ELISA to detect specific IgG antibodies using the ZIKV envelope domain III (EDIII) protein expressed in Drosophila S2 cells as an immunogen. Using a total of 367 clinical samples, we showed that the EDIII-ELISA was able to detect IgG antibodies against ZIKV with high sensitivity of 100.0% and specificity of 94.7% when compared to plaque reduction neutralization tests (PRNTs) as the gold standard and using 0.208 as the cut-off OD value. These results show the usefulness of the recombinant envelope domain III as an alternative to standard whole virus proteins for ZIKV diagnostics as it improves the sensitivity and specificity of IgG ELISA assay when used as an immunogen. This method should, therefore, be extended to serological diagnostic techniques for other members of the flavivirus genus and for use in IgM diagnostic testing.
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Khongwichit S, Chuchaona W, Vongpunsawad S, Poovorawan Y. Molecular surveillance of arboviruses circulation and co-infection during a large chikungunya virus outbreak in Thailand, October 2018 to February 2020. Sci Rep 2022; 12:22323. [PMID: 36566236 PMCID: PMC9789961 DOI: 10.1038/s41598-022-27028-7] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2022] [Accepted: 12/23/2022] [Indexed: 12/25/2022] Open
Abstract
A large national outbreak of chikungunya virus (CHIKV) was recently reported in Thailand. While dengue virus (DENV) infection tends to occur year-round with an upsurge in the rainy season, Zika virus (ZIKV) also circulates in the country. The overlap in the distribution of these viruses increased the probability of co-infections during the heightened CHIKV activity. By examining 1806 patient serum samples submitted for CHIKV diagnostics from October 2018-February 2020 (511 CHIKV-negatives and 1295 CHIKV-positives), we used real-time reverse transcription-polymerase chain reaction to identify DENV and ZIKV individually. A total of 29 ZIKV and 36 DENV single-infections were identified. Interestingly, 13 co-infection cases were observed, of which 8 were CHIKV/DENV, 3 were CHIKV/ZIKV, and 2 were DENV/ZIKV. There were six DENV genotypes (13 DENV-1 genotype I, 10 DENV-2 Asian I, 10 DENV-2 Cosmopolitan, 6 DENV-3 genotype I, 2 DENV-3 genotype III, and 5 DENV-4 genotype I). Additionally, ZIKV strains identified in this study either clustered with strains previously circulating in Thailand and Singapore, or with strains previously reported in China, French Polynesia, and the Americas. Our findings reveal the co-infection and genetic diversity patterns of mosquito-borne viruses circulating in Thailand.
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Affiliation(s)
- Sarawut Khongwichit
- Center of Excellence in Clinical Virology, Faculty of Medicine, Chulalongkorn University, 1873 Rama 4 Road, Pathumwan, Bangkok, 10330, Thailand
| | - Watchaporn Chuchaona
- Center of Excellence in Clinical Virology, Faculty of Medicine, Chulalongkorn University, 1873 Rama 4 Road, Pathumwan, Bangkok, 10330, Thailand
| | - Sompong Vongpunsawad
- Center of Excellence in Clinical Virology, Faculty of Medicine, Chulalongkorn University, 1873 Rama 4 Road, Pathumwan, Bangkok, 10330, Thailand
| | - Yong Poovorawan
- Center of Excellence in Clinical Virology, Faculty of Medicine, Chulalongkorn University, 1873 Rama 4 Road, Pathumwan, Bangkok, 10330, Thailand.
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Mao ZQ, Minakawa N, Moi ML. Novel Antiviral Efficacy of Hedyotis diffusa and Artemisia capillaris Extracts against Dengue Virus, Japanese Encephalitis Virus, and Zika Virus Infection and Immunoregulatory Cytokine Signatures. PLANTS (BASEL, SWITZERLAND) 2022; 11:plants11192589. [PMID: 36235456 PMCID: PMC9571899 DOI: 10.3390/plants11192589] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/28/2022] [Revised: 09/20/2022] [Accepted: 09/20/2022] [Indexed: 05/25/2023]
Abstract
Currently, there are no specific therapeutics for flavivirus infections, including dengue virus (DENV) and Zika virus (ZIKV). In this study, we evaluated extracts from the plants Hedyotis diffusa (HD) and Artemisia capillaris (AC) to determine the antiviral activity against DENV, ZIKV, and Japanese encephalitis virus (JEV). HD and AC demonstrated inhibitory activity against JEV, ZIKV, and DENV replication and reduced viral RNA levels in a dose-responsive manner, with non-cytotoxic concentration ranging from 0.1 to 10 mg/mL. HD and AC had low cytotoxicity to Vero cells, with CC50 values of 33.7 ± 1.6 and 30.3 ± 1.7 mg/mL (mean ± SD), respectively. The anti-flavivirus activity of HD and AC was also consistent in human cell lines, including human glioblastoma (T98G), human chronic myeloid leukemia (K562), and human embryonic kidney (HEK-293T) cells. Viral-infected, HD-treated cells demonstrated downregulation of cytokines including CCR1, CCL26, CCL15, CCL5, IL21, and IL17C. In contrast, CCR1, CCL26, and AIMP1 were elevated following AC treatment in viral-infected cells. Overall, HD and AC plant extracts demonstrated flavivirus replication inhibitory activity, and together with immunoregulatory cytokine signatures, these results suggest that HD and AC possess bioactive compounds that may further be refined as promising candidates for clinical applications.
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Affiliation(s)
- Zhan Qiu Mao
- Institute of Tropical Medicine, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki 852-8523, Japan
| | - Noboru Minakawa
- Institute of Tropical Medicine, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki 852-8523, Japan
| | - Meng Ling Moi
- Institute of Tropical Medicine, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki 852-8523, Japan
- School of International Health, Graduate School of Medicine, The University of Tokyo, Tokyo 113-0033, Japan
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Choudhury S, Tellier R, Fonseca K, Berenger BM. Experience with a triplex arbovirus nucleic acid test (NAT) at a Canadian Public Health Laboratory. BMC Infect Dis 2021; 21:1147. [PMID: 34758738 PMCID: PMC8579575 DOI: 10.1186/s12879-021-06842-w] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2020] [Accepted: 11/03/2021] [Indexed: 11/21/2022] Open
Abstract
BACKGROUND Dengue, chikungunya and zika infections occur in tropical and subtropical regions of the world. We describe the utilization of an in-house nucleic acid test (NAT) targeting all three viruses for febrile returning travelers in Alberta, Canada. METHODS NAT was performed until 40 days from symptom onset or exposure due to the prolonged duration of zika virus RNA detection. From Sept 1, 2017 to August 31, 2019, 2552 specimens from 1932 patients were tested. RESULTS Approximately 2% of patients tested were NAT positive for dengue virus (n = 42), chikungunya virus (n = 4), and zika virus (n = 1). The majority presented with fever, myalgia and rash. Regions with the most frequent travel included SouthEast Asia (68.5%), South America (25%) and the Caribbean (6.5%). Ct values were stronger (~ 1.5 logs) for patients within 1-3 days following onset of clinical symptoms than those presenting later. Nineteen patients had urine and plasma submitted; 5 were positive for both specimens and 2 were positive only for dengue virus in the urine. Also, Ct values were lower for plasma when compared to the corresponding urine. RNA was detected until 10 days and 5 days post-exposure in plasma and urine respectively for dengue virus. CONCLUSIONS Owing to dengue viremia detected beyond the conventional 7 days and low levels of circulating zika virus globally, a cutoff of 14 days from symptom onset to NAT is sufficient to diagnose acute cases. Inclusion of a zoonotic history form that collects appropriate clinical history results in improved test utilization.
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Affiliation(s)
- Saugata Choudhury
- Dept of Pathology and Laboratory Medicine, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada.
- Public Health Laboratory, Alberta Precision Laboratories, Calgary, AB, Canada.
- Dorevitch Laboratories, 18 Banksia Street, Heidelberg, Melbourne, Australia.
| | - Raymond Tellier
- Div of Infectious Diseases, Dept of Medicine, McGill University Montreal, Montreal, Canada
| | - Kevin Fonseca
- Public Health Laboratory, Alberta Precision Laboratories, Calgary, AB, Canada
- Dept of Microbiology, Immunology and Infectious Diseases, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada
| | - Byron M Berenger
- Dept of Pathology and Laboratory Medicine, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada
- Public Health Laboratory, Alberta Precision Laboratories, Calgary, AB, Canada
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7
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Christy MP, Uekusa Y, Gerwick L, Gerwick WH. Natural Products with Potential to Treat RNA Virus Pathogens Including SARS-CoV-2. JOURNAL OF NATURAL PRODUCTS 2021; 84:161-182. [PMID: 33352046 PMCID: PMC7771248 DOI: 10.1021/acs.jnatprod.0c00968] [Citation(s) in RCA: 42] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/02/2020] [Indexed: 05/03/2023]
Abstract
Three families of RNA viruses, the Coronaviridae, Flaviviridae, and Filoviridae, collectively have great potential to cause epidemic disease in human populations. The current SARS-CoV-2 (Coronaviridae) responsible for the COVID-19 pandemic underscores the lack of effective medications currently available to treat these classes of viral pathogens. Similarly, the Flaviviridae, which includes such viruses as Dengue, West Nile, and Zika, and the Filoviridae, with the Ebola-type viruses, as examples, all lack effective therapeutics. In this review, we present fundamental information concerning the biology of these three virus families, including their genomic makeup, mode of infection of human cells, and key proteins that may offer targeted therapies. Further, we present the natural products and their derivatives that have documented activities to these viral and host proteins, offering hope for future mechanism-based antiviral therapeutics. By arranging these potential protein targets and their natural product inhibitors by target type across these three families of virus, new insights are developed, and crossover treatment strategies are suggested. Hence, natural products, as is the case for other therapeutic areas, continue to be a promising source of structurally diverse new anti-RNA virus therapeutics.
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Affiliation(s)
- Mitchell P. Christy
- Center for Marine Biotechnology and Biomedicine, Scripps Institution of Oceanography, University of California San Diego, La Jolla, California 92093, United States
| | - Yoshinori Uekusa
- Center for Marine Biotechnology and Biomedicine, Scripps Institution of Oceanography, University of California San Diego, La Jolla, California 92093, United States
- Faculty of Pharmacy, Keio University, 1-5-30 Shibakoen, Minato-ku, Tokyo, 105-8512, Japan
| | - Lena Gerwick
- Center for Marine Biotechnology and Biomedicine, Scripps Institution of Oceanography, University of California San Diego, La Jolla, California 92093, United States
| | - William H. Gerwick
- Center for Marine Biotechnology and Biomedicine, Scripps Institution of Oceanography, University of California San Diego, La Jolla, California 92093, United States
- Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, La Jolla, California 92093, United States
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8
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Ryan SJ. Mapping Thermal Physiology of Vector-Borne Diseases in a Changing Climate: Shifts in Geographic and Demographic Risk of Suitability. Curr Environ Health Rep 2020; 7:415-423. [PMID: 32902817 PMCID: PMC7748992 DOI: 10.1007/s40572-020-00290-5] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Abstract
PURPOSE OF REVIEW To describe a collection of recent work published on thermal suitability for vector-borne diseases, in which mapping approaches illustrated the geographic shifts, and spatial approaches describe the demographic impact anticipated with a changing climate. RECENT FINDINGS While climate change predictions of warming indicate an expansion in VBD suitability risk in some parts of the globe, while in others, optimal temperatures for transmission may be exceeded, as seen for malaria in Western Africa, resulting in declining risk. The thermal suitability of specific vector-pathogen pairs can have large impacts on geographic range of risk, and changes in human demography itself will intersect with this risk to create different vulnerability profiles over the coming century. Using a physiological approach to describe the thermal suitability of transmission for vector-borne diseases allows us to illustrate the future risk as mapped information. This in turn can be coupled with demographic projections to anticipate changing risk, and even changing vulnerability within that population change.
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Affiliation(s)
- Sadie J Ryan
- Quantitative Disease Ecology and Conservation (QDEC) Lab, Department of Geography, University of Florida, Gainesville, FL, 32611, USA.
- Emerging Pathogens Institute, University of Florida, Gainesville, FL, 32611, USA.
- School of Life Sciences, University of KwaZulu Natal, Durban, 4041, South Africa.
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9
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In HJ, Lee YH, Jang S, Lim HJ, Kim MY, Kim JA, Yoo JS, Chung GT, Kim YJ. Enhanced effect of modified Zika virus E antigen on the immunogenicity of DNA vaccine. Virology 2020; 549:25-31. [PMID: 32818729 DOI: 10.1016/j.virol.2020.07.014] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2020] [Revised: 07/10/2020] [Accepted: 07/21/2020] [Indexed: 01/21/2023]
Abstract
It has been reported worldwide that the Zika virus (ZIKV) could be transmitted through placentas and sexual contact. ZIKV can also cause Guillain-Barre syndrome, microcephaly and neurological abnormalities. However, there are no approved vaccines available. We constructed six DNA vaccine candidates and tested the immunogenicity. Tandem repeated envelope domain Ⅲ (ED Ⅲ × 3) induced highly total IgG and neutralization antibody, as well as CD8+ T cell responses. Also, stem region-removed envelope (E ΔSTEM) elicited a robust production of IFN-γ in mice. To examine in vivo protection, we used mice treated with an IFNAR1 blocking antibody before and after the challenge. Vaccination with the two candidates led to a decline in the level of viral RNAs in organs. Moreover, the sera from the vaccinated mice did not enhance the infection of Dengue virus in K562 cells. These findings suggest the potential for the development of a novel ZIKV DNA vaccine.
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Affiliation(s)
- Hyun Ju In
- Division of Vaccine Research, Korea National Institute of Health, Korea Centers for Disease Control and Prevention, CheongJu, Chungbuk, 28160, Republic of Korea
| | - Yun Ha Lee
- Division of Vaccine Research, Korea National Institute of Health, Korea Centers for Disease Control and Prevention, CheongJu, Chungbuk, 28160, Republic of Korea
| | - Sundong Jang
- College of Pharmacy, Chungbuk National University, CheongJu, Chungbuk, 28160, Republic of Korea
| | - Hee Ji Lim
- Division of Vaccine Research, Korea National Institute of Health, Korea Centers for Disease Control and Prevention, CheongJu, Chungbuk, 28160, Republic of Korea
| | - Mi Young Kim
- Division of Vaccine Research, Korea National Institute of Health, Korea Centers for Disease Control and Prevention, CheongJu, Chungbuk, 28160, Republic of Korea
| | - Joo Ae Kim
- Division of Vaccine Research, Korea National Institute of Health, Korea Centers for Disease Control and Prevention, CheongJu, Chungbuk, 28160, Republic of Korea
| | - Jung-Sik Yoo
- Division of Vaccine Research, Korea National Institute of Health, Korea Centers for Disease Control and Prevention, CheongJu, Chungbuk, 28160, Republic of Korea
| | - Gyung Tae Chung
- Division of Vaccine Research, Korea National Institute of Health, Korea Centers for Disease Control and Prevention, CheongJu, Chungbuk, 28160, Republic of Korea
| | - You-Jin Kim
- Division of Vaccine Research, Korea National Institute of Health, Korea Centers for Disease Control and Prevention, CheongJu, Chungbuk, 28160, Republic of Korea.
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10
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Sanchez Clemente N, Brickley EB, Paixão ES, De Almeida MF, Gazeta RE, Vedovello D, Rodrigues LC, Witkin SS, Passos SD. Zika virus infection in pregnancy and adverse fetal outcomes in São Paulo State, Brazil: a prospective cohort study. Sci Rep 2020; 10:12673. [PMID: 32728054 PMCID: PMC7391725 DOI: 10.1038/s41598-020-69235-0] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2019] [Accepted: 07/09/2020] [Indexed: 01/17/2023] Open
Abstract
Robust epidemiological and biological evidence supports a causal link between prenatal Zika Virus (ZIKV) infection and congenital brain abnormalities including microcephaly. However, it remains uncertain if ZIKV infection in pregnancy also increases the risk for other adverse fetal and birth outcomes. In a prospective cohort study we investigated the influence of ZIKV on the prevalence of prematurity, low birth weight, small-for-gestational-age, and fetal death as well as microcephaly (i.e., overall and disproportionate) in the offspring of women attending a high-risk pregnancy clinic during the recent ZIKV outbreak in Brazil. During the recruitment period (01 March 2016-23 August 2017), urine samples were tested for ZIKV by RT-PCR from all women attending the high-risk pregnancy clinic at Jundiaí University Hospital and from the neonates after delivery. Of the 574 women evaluated, 44 (7.7%) were ZIKV RT-PCR positive during pregnancy. Of the 409 neonates tested, 19 (4.6%) were ZIKV RT-PCR positive in the first 10 days of life. In this cohort, maternal ZIKV exposure was not associated with increased risks of prematurity, low birth weight, small-for-gestational-age, or fetal death. However, relative to ZIKV-negative neonates, ZIKV-positive infants had a five-fold increased risk of microcephaly overall (RR 5.1, 95% CI 1.2-22.5) and a ten-fold increased risk of disproportionate microcephaly (RR 10.3, 95% CI 2.0-52.6). Our findings provide new evidence that, in a high-risk pregnancy cohort, ZIKV RT-PCR positivity in the neonate at birth is strongly associated with microcephaly. However, ZIKV infection during pregnancy does not appear to influence the risks of prematurity, low birth weight, small-for-gestational-age or fetal death in women who already have gestational comorbidities. The results suggest disproportion between neonatal head circumference and weight may be a useful screening indicator for the detection of congenital microcephaly associated with ZIKV infection.
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Affiliation(s)
- Nuria Sanchez Clemente
- Department of Epidemiology, University of São Paulo, São Paulo, Brazil.
- Department of Infectious Disease Epidemiology, London School of Hygiene and Tropical Medicine, Keppel Street, London, WC1E 7HT, UK.
| | - Elizabeth B Brickley
- Department of Infectious Disease Epidemiology, London School of Hygiene and Tropical Medicine, Keppel Street, London, WC1E 7HT, UK
| | - Enny S Paixão
- Department of Infectious Disease Epidemiology, London School of Hygiene and Tropical Medicine, Keppel Street, London, WC1E 7HT, UK
| | | | - Rosa E Gazeta
- Jundiaí Medical School, Jundiaí University, São Paulo, Brazil
| | | | - Laura C Rodrigues
- Department of Infectious Disease Epidemiology, London School of Hygiene and Tropical Medicine, Keppel Street, London, WC1E 7HT, UK
| | - Steven S Witkin
- Department of Obstetrics and Gynecology, Weill Cornell Medicine, New York, NY, USA
- Institute of Tropical Medicine, University of Sao Paulo Medical School, São Paulo, Brazil
| | - Saulo D Passos
- Jundiaí Medical School, Jundiaí University, São Paulo, Brazil
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11
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Lemanski NJ, Schwab SR, Fonseca DM, Fefferman NH. Coordination among neighbors improves the efficacy of Zika control despite economic costs. PLoS Negl Trop Dis 2020; 14:e0007870. [PMID: 32569323 PMCID: PMC7332071 DOI: 10.1371/journal.pntd.0007870] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2019] [Revised: 07/02/2020] [Accepted: 03/30/2020] [Indexed: 01/09/2023] Open
Abstract
Emerging mosquito-borne viruses like Zika, dengue, and chikungunya pose a major threat to public health, especially in low-income regions of Central and South America, southeast Asia, and the Caribbean. Outbreaks of these diseases are likely to have long-term social and economic consequences due to Zika-induced congenital microcephaly and other complications. Larval control of the container-inhabiting mosquitoes that transmit these infections is an important tool for mitigating outbreaks. However, metapopulation theory suggests that spatiotemporally uneven larvicide treatment can impede control effectiveness, as recolonization compensates for mortality within patches. Coordinating the timing of treatment among patches could therefore substantially improve epidemic control, but we must also consider economic constraints, since coordination may have costs that divert resources from treatment. To inform practical disease management strategies, we ask how coordination among neighbors in the timing of mosquito control efforts influences the size of a mosquito-borne infectious disease outbreak under the realistic assumption that coordination has costs. Using an SIR (Susceptible-Infectious-Recovered)/metapopulation model of mosquito and disease dynamics, we examine whether sharing surveillance information and coordinating larvicide treatment among neighboring patches reduces human infections when incorporating coordination costs. We examine how different types of coordination costs and different surveillance methods jointly influence the effectiveness of larval control. We find that the effect of coordination depends on both costs and the type of surveillance used to inform treatment. With epidemiological surveillance, coordination improves disease outcomes, even when costly. With demographic surveillance, coordination either improves or hampers disease control, depending on the type of costs and surveillance sensitivity. Our results suggest coordination among neighbors can improve management of mosquito-borne epidemics under many, but not all, assumptions about costs. Therefore, estimating coordination costs is an important step for most effectively applying metapopulation theory to strategies for managing outbreaks of mosquito-borne viral infections.
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Affiliation(s)
- Natalie J. Lemanski
- Department of Ecology and Evolutionary Biology, University of Tennessee, Knoxville, Tennessee, United States of America
- * E-mail:
| | - Samantha R. Schwab
- Department of Ecology, Evolution, and Natural Resources, Rutgers University, New Brunswick, New Jersey, United States of America
| | - Dina M. Fonseca
- Center for Vector Biology, Department of Entomology, Rutgers University, New Brunswick, New Jersey, United States of America
| | - Nina H. Fefferman
- Department of Ecology and Evolutionary Biology, University of Tennessee, Knoxville, Tennessee, United States of America
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12
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Human Type I Interferon Antiviral Effects in Respiratory and Reemerging Viral Infections. J Immunol Res 2020; 2020:1372494. [PMID: 32455136 PMCID: PMC7231083 DOI: 10.1155/2020/1372494] [Citation(s) in RCA: 33] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2019] [Revised: 02/17/2020] [Accepted: 04/02/2020] [Indexed: 12/13/2022] Open
Abstract
Type I interferons (IFN-I) are a group of related proteins that help regulate the activity of the immune system and play a key role in host defense against viral infections. Upon infection, the IFN-I are rapidly secreted and induce a wide range of effects that not only act upon innate immune cells but also modulate the adaptive immune system. While IFN-I and many IFN stimulated genes are well-known for their protective antiviral role, recent studies have associated them with potential pathogenic functions. In this review, we summarize the current knowledge regarding the complex effects of human IFN-I responses in respiratory as well as reemerging flavivirus infections of public health significance and the molecular mechanisms by which viral proteins antagonize the establishment of an antiviral host defense. Antiviral effects and immune modulation of IFN-stimulated genes is discussed in resisting and controlling pathogens. Understanding the mechanisms of these processes will be crucial in determining how viral replication can be effectively controlled and in developing safe and effective vaccines and novel therapeutic strategies.
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13
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Gomez HM, Mejia Arbelaez C, Ocampo Cañas JA. A qualitative study of the experiences of pregnant women in accessing healthcare services during the Zika virus epidemic in Villavicencio, Colombia, 2015-2016. Int J Gynaecol Obstet 2020; 148 Suppl 2:29-35. [PMID: 31975397 PMCID: PMC7065052 DOI: 10.1002/ijgo.13045] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Objective To explore the perceptions and experiences of pregnant women in accessing healthcare services during the epidemic in Colombia during 2015–2016. Methods A qualitative study using semistructured interviews was conducted in Villavicencio. Six women who had been diagnosed with Zika virus infection during their pregnancies and whose fetus had suspected microcephaly participated in the investigation. Grounded theory was used and thematic content analysis was made for each category identified. Results Three main themes affecting access to healthcare services were identified: (1) women knew basic information about the virus, but it was limited; (2) access to services was delayed due to their lack of availability or limited supply in the municipality; and (3) most of the participants made out‐of‐pocket payments to get access to services that were not provided. Conclusions Several gaps were identified in the provision of healthcare services to pregnant women during the Zika epidemic. Policy makers need to utilize the results from affected communities to develop and implement public policies that adapt and respond to their priorities and needs. Policy makers need to consider identified gaps when they adapt and implement new clinical care guidelines for maternal and perinatal health.
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Affiliation(s)
- Hector M Gomez
- Public Health, Medical Education, and Professionalism, School of Medicine, University of los Andes, Bogotá, Colombia
| | - Carlos Mejia Arbelaez
- Public Health, Medical Education, and Professionalism, School of Medicine, University of los Andes, Bogotá, Colombia
| | - Jovana A Ocampo Cañas
- Public Health, Medical Education, and Professionalism, School of Medicine, University of los Andes, Bogotá, Colombia
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14
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Wang L, Wang R, Wang L, Ben H, Yu L, Gao F, Shi X, Yin C, Zhang F, Xiang Y, Zhang L. Structural Basis for Neutralization and Protection by a Zika Virus-Specific Human Antibody. Cell Rep 2020; 26:3360-3368.e5. [PMID: 30893607 DOI: 10.1016/j.celrep.2019.02.062] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2017] [Revised: 11/22/2018] [Accepted: 02/13/2019] [Indexed: 12/26/2022] Open
Abstract
We previously reported a human monoclonal antibody, ZK2B10, capable of protection against Zika virus (ZIKV) infection and microcephaly in developing mouse embryos. Here, we report the structural features and mechanism of action of ZK2B10. The crystal structure at a resolution of 2.32 Å revealed that the epitope is located on the lateral ridge of DIII of the envelope glycoprotein. Cryo-EM structure with mature ZIKV showed that the antibody binds to DIIIs around the icosahedral 2-fold, 3-fold, and 5-fold axes, a distinct feature compared to those reported for DIII-specific antibodies. The binding of ZK2B10 to ZIKV has no detectable effect on viral attachment to target cells or on conformational changes of the E glycoprotein in the acidic environment, suggesting that ZK2B10 functions at steps between the formation of the fusion intermediate and membrane fusion. These results provide structural and mechanistic insights into how ZK2B10 mediates protection against ZIKV infection.
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Affiliation(s)
- Lin Wang
- Beijing Advanced Innovation Center for Structural Biology, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Center for Global Health and Infectious Diseases, Department of Basic Medical Sciences, School of Medicine, Tsinghua University, Beijing 100084, China
| | - Ruoke Wang
- Comprehensive AIDS Research Center, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Beijing Advanced Innovation Center for Structural Biology, Center for Global Health and Infectious Diseases, Department of Basic Medical Sciences, School of Medicine, Tsinghua University, Beijing 100084, China
| | - Lei Wang
- Beijing Advanced Innovation Center for Structural Biology, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Center for Global Health and Infectious Diseases, Department of Basic Medical Sciences, School of Medicine, Tsinghua University, Beijing 100084, China
| | - Haijing Ben
- Comprehensive AIDS Research Center, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Beijing Advanced Innovation Center for Structural Biology, Center for Global Health and Infectious Diseases, Department of Basic Medical Sciences, School of Medicine, Tsinghua University, Beijing 100084, China
| | - Lei Yu
- Guangzhou Eighth People's Hospital, Guangzhou Medical University, Guangzhou 510060, China
| | - Fei Gao
- Comprehensive AIDS Research Center, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Beijing Advanced Innovation Center for Structural Biology, Center for Global Health and Infectious Diseases, Department of Basic Medical Sciences, School of Medicine, Tsinghua University, Beijing 100084, China
| | - Xuanling Shi
- Comprehensive AIDS Research Center, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Beijing Advanced Innovation Center for Structural Biology, Center for Global Health and Infectious Diseases, Department of Basic Medical Sciences, School of Medicine, Tsinghua University, Beijing 100084, China
| | - Chibiao Yin
- Guangzhou Eighth People's Hospital, Guangzhou Medical University, Guangzhou 510060, China
| | - Fuchun Zhang
- Guangzhou Eighth People's Hospital, Guangzhou Medical University, Guangzhou 510060, China
| | - Ye Xiang
- Beijing Advanced Innovation Center for Structural Biology, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Center for Global Health and Infectious Diseases, Department of Basic Medical Sciences, School of Medicine, Tsinghua University, Beijing 100084, China.
| | - Linqi Zhang
- Comprehensive AIDS Research Center, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Beijing Advanced Innovation Center for Structural Biology, Center for Global Health and Infectious Diseases, Department of Basic Medical Sciences, School of Medicine, Tsinghua University, Beijing 100084, China.
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15
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Broeders S, Garlant L, Fraiture MA, Vandermassen E, Suin V, Vanhomwegen J, Dupont-Rouzeyrol M, Rousset D, Van Gucht S, Roosens N. A new multiplex RT-qPCR method for the simultaneous detection and discrimination of Zika and chikungunya viruses. Int J Infect Dis 2020; 92:160-170. [PMID: 31884173 PMCID: PMC7129992 DOI: 10.1016/j.ijid.2019.12.028] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2019] [Revised: 12/11/2019] [Accepted: 12/20/2019] [Indexed: 12/19/2022] Open
Abstract
OBJECTIVE The re-emergence and spread of tropical viruses to new areas has raised a wave of concern worldwide. In order to treat patients at an early stage and prevent the diffusion of an outbreak, early diagnosis, and therefore fast and adequate detection, is needed. To this end, a multiplex reverse transcription real-time polymerase chain reaction TaqMan method was designed to detect Zika (ZIKV) and chikungunya (CHIKV) viruses simultaneously. METHODS Two methods targeting different genome segments were selected from the literature for each virus. These were adapted for high genome coverage and combined in a four-plex assay that was thoroughly validated in-house. The SCREENED tool was used to evaluate the sequence coverage of the method. RESULTS The full validation approach showed that the new four-plex method allows the specific and sensitive identification and discrimination of ZIKV and CHIKV in routine samples. The combination of two targets per virus allowing almost 100% coverage of about 500 genomes is shown for the first time. CONCLUSIONS PCR is a reliable user-friendly technique that can be applied in remote areas. Such multiplex methods enable early and efficient diagnosis, leading to rapid treatment and effective confinement in outbreak cases. They may also serve as an aid for surveillance, and the full validation permits easy method-transfer allowing worldwide harmonization.
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Affiliation(s)
- Sylvia Broeders
- Sciensano, Transversal Activities in Applied Genomics, J. Wytsmanstraat 14, 1050 Brussels, Belgium.
| | - Linda Garlant
- Sciensano, Transversal Activities in Applied Genomics, J. Wytsmanstraat 14, 1050 Brussels, Belgium.
| | - Marie-Alice Fraiture
- Sciensano, Transversal Activities in Applied Genomics, J. Wytsmanstraat 14, 1050 Brussels, Belgium.
| | - Els Vandermassen
- Sciensano, Transversal Activities in Applied Genomics, J. Wytsmanstraat 14, 1050 Brussels, Belgium.
| | - Vanessa Suin
- Sciensano, Viral Diseases, J. Wytsmanstraat 14, 1050 Brussels, Belgium.
| | - Jessica Vanhomwegen
- Institut Pasteur France, Cellule d'Intervention Biologique d'Urgence (CIBU), 25-28 rue du docteur Roux, 75724 Paris Cedex 15, France.
| | - Myrielle Dupont-Rouzeyrol
- Institut Pasteur de Nouvelle-Calédonie, URE Dengue et Arboviroses, 11 ave P. Doumer, BP 61, 98845 Nouméa Cedex, New Caledonia.
| | - Dominique Rousset
- Institut Pasteur de la Guyane, Laboratoire de Virologie, 23 avenue Pasteur - BP 6010, 97306 Cayenne Cedex, Guyana.
| | - Steven Van Gucht
- Sciensano, Viral Diseases, J. Wytsmanstraat 14, 1050 Brussels, Belgium.
| | - Nancy Roosens
- Sciensano, Transversal Activities in Applied Genomics, J. Wytsmanstraat 14, 1050 Brussels, Belgium.
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16
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Association of past dengue fever epidemics with the risk of Zika microcephaly at the population level in Brazil. Sci Rep 2020; 10:1752. [PMID: 32019953 PMCID: PMC7000767 DOI: 10.1038/s41598-020-58407-7] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2019] [Accepted: 12/17/2019] [Indexed: 11/08/2022] Open
Abstract
Despite all the research done on the first Zika virus (ZIKV) epidemics, it was only after the Brazilian epidemic that the Congenital Zika Syndrome was described. This was made possible due to the large number of babies born with microcephaly in the Northeast region (NE) in a narrow time. We hypothesize that the fivefold difference in the rate of microcephalic neonates between the NE and other regions is partially an effect of the population prior immunity against Dengue viruses (DENV), that cross-react with ZIKV. In this ecological study, we analysed the interaction between dengue fever epidemics from 2001 to 2014 and the 2015/2016 microcephaly epidemic in 400 microregions in Brazil using random-effects models under a Bayesian approach. The estimated effect of the time lag between the most recent large dengue epidemic (>400/100,000 inhabitants) and the microcephaly epidemic ranged from protection (up to 6 years prior) to an increased risk (from 7 to 12 years). This sustained window of protection, larger than described in previous longitudinal studies, is possibly an effect of herd immunity and of multiple exposures to DENV that could boost immunity.
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17
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Laviada-Molina H, Huchim-Lara O, Méndez-Domínguez N. Health and Well-being in the Yucatan Peninsula Revisited with a Human Ecology Perspective. CULTURE, ENVIRONMENT AND HEALTH IN THE YUCATAN PENINSULA 2020:259-276. [DOI: 10.1007/978-3-030-27001-8_14] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/02/2024]
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18
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Vouga M, Chiu YC, Pomar L, de Meyer SV, Masmejan S, Genton B, Musso D, Baud D, Stojanov M. Dengue, Zika and chikungunya during pregnancy: pre- and post-travel advice and clinical management. J Travel Med 2019; 26:taz077. [PMID: 31616923 PMCID: PMC6927317 DOI: 10.1093/jtm/taz077] [Citation(s) in RCA: 48] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/05/2019] [Revised: 09/30/2019] [Accepted: 10/09/2019] [Indexed: 02/06/2023]
Abstract
RATIONALE FOR REVIEW Young adults of childbearing age and pregnant women are travelling more frequently to tropical areas, exposing them to specific arboviral infections such as dengue, zika and chikungunya viruses, which may impact ongoing and future pregnancies. In this narrative review, we analyse their potential consequences on pregnancy outcomes and discuss current travel recommendations. MAIN FINDINGS Dengue virus may be associated with severe maternal complications, particularly post-partum haemorrhage. Its association with adverse fetal outcomes remains unclear, but prematurity, growth retardation and stillbirths may occur, particularly in cases of severe maternal infection. Zika virus is a teratogenic infectious agent associated with severe brain lesions, with similar risks to other well-known TORCH pathogens. Implications of chikungunya virus in pregnancy are mostly related to intrapartum transmission that may be associated with severe neonatal infections and long-term morbidity. TRAVEL RECOMMENDATIONS Few agencies provide specific travel recommendations for travelling pregnant patients or couples trying to conceive and discrepancies exist, particularly regarding Zika virus prevention. The risks significantly depend on epidemiological factors that may be difficult to predict. Prevention relies principally on mosquito control measures. Couples trying to conceive and pregnant women should receive adequate information about the potential risks. It seems reasonable to advise pregnant women to avoid unnecessary travel to Aedes spp. endemic regions. The current rationale to avoid travel and delay conception is debatable in the absence of any epidemic. Post-travel laboratory testing should be reserved for symptomatic patients.
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Affiliation(s)
- Manon Vouga
- Materno-fetal and Obstetrics Research Unit, Department Woman-Mother-Child, Lausanne University Hospital (CHUV), Lausanne, Switzerland
| | - Yen-Chi Chiu
- Materno-fetal and Obstetrics Research Unit, Department Woman-Mother-Child, Lausanne University Hospital (CHUV), Lausanne, Switzerland
| | - Léo Pomar
- Materno-fetal and Obstetrics Research Unit, Department Woman-Mother-Child, Lausanne University Hospital (CHUV), Lausanne, Switzerland
| | - Sara V de Meyer
- Materno-fetal and Obstetrics Research Unit, Department Woman-Mother-Child, Lausanne University Hospital (CHUV), Lausanne, Switzerland
| | - Sophie Masmejan
- Materno-fetal and Obstetrics Research Unit, Department Woman-Mother-Child, Lausanne University Hospital (CHUV), Lausanne, Switzerland
| | - Blaise Genton
- Travel Medicine, Lausanne University Hospital (CHUV), Lausanne, Switzerland
| | - Didier Musso
- Aix Marseille University, IRD, AP-HM, SSA, VITROME, IHU-Méditerranée Infection, Marseille, France
| | - David Baud
- Materno-fetal and Obstetrics Research Unit, Department Woman-Mother-Child, Lausanne University Hospital (CHUV), Lausanne, Switzerland
| | - Milos Stojanov
- Materno-fetal and Obstetrics Research Unit, Department Woman-Mother-Child, Lausanne University Hospital (CHUV), Lausanne, Switzerland
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19
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Lineage-dependent differences of Zika virus infection in a susceptible mouse model are associated with different profiles of cytokines, chemokines, growth factors and acute phase proteins. Cytokine 2019; 125:154864. [PMID: 31577989 DOI: 10.1016/j.cyto.2019.154864] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2019] [Revised: 09/23/2019] [Accepted: 09/25/2019] [Indexed: 12/28/2022]
Abstract
Zika virus (ZIKV) is phylogenetically divided into two lineages comprising African (ZIKVAF) and Asian (ZIKVAS) genotypes. In the type-I interferon receptor deficient mouse model, ZIKVAF causes severe disease with all mice meeting humane endpoints with doses as low as 10 plaque-forming units (pfu) whereas a much milder infection is seen after challenge with ZIKVAS, including with doses as high as 106 pfu. Using this mouse model, the elucidation of cytokine, chemokine, growth factor and acute phase protein responses over the course of infection were studied to determine whether these analytes contributed to the stark difference in clinical outcome. Results demonstrated some significant differences, with the ZIKVAF infection being associated with increases in a higher number of biomarkers than ZIKVAS. When low (10 pfu) and high (106 pfu) challenge doses were compared, animals given the lower virus inoculum showed a wider range of responses, indicating a different disease progression compared to those challenged with high doses. These results aid with elucidating the different outcomes with the two lineages of ZIKV and with future work to assess pathogenicity of virus infection.
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20
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Wong CP, Xu Z, Hou S, Limonta D, Kumar A, Power C, Hobman TC. Interplay between Zika Virus and Peroxisomes during Infection. Cells 2019; 8:cells8070725. [PMID: 31311201 PMCID: PMC6678468 DOI: 10.3390/cells8070725] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2019] [Revised: 07/10/2019] [Accepted: 07/12/2019] [Indexed: 12/23/2022] Open
Abstract
Zika virus (ZIKV) has emerged as an important human pathogen that can cause congenital defects in the fetus and neurological conditions in adults. The interferon (IFN) system has proven crucial in restricting ZIKV replication and pathogenesis. The canonical IFN response is triggered by the detection of viral RNA through RIG-I like receptors followed by activation of the adaptor protein MAVS on mitochondrial membranes. Recent studies have shown that a second organelle, peroxisomes, also function as a signaling platforms for the IFN response. Here, we investigated how ZIKV infection affects peroxisome biogenesis and antiviral signaling. We show that ZIKV infection depletes peroxisomes in human fetal astrocytes, a brain cell type that can support persistent infection. The peroxisome biogenesis factor PEX11B was shown to inhibit ZIKV replication, likely by increasing peroxisome numbers and enhancing downstream IFN-dependent antiviral signaling. Given that peroxisomes play critical roles in brain development and nerve function, our studies provide important insights into the roles of peroxisomes in regulating ZIKV infection and potentially neuropathogenesis.
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Affiliation(s)
- Cheung Pang Wong
- Department of Medical Microbiology & Immunology, University of Alberta, Edmonton, AB T6G 2E1, Canada
| | - Zaikun Xu
- Department of Cell Biology, University of Alberta, Edmonton, AB T6G 2H7, Canada
| | - Shangmei Hou
- Department of Cell Biology, University of Alberta, Edmonton, AB T6G 2H7, Canada
| | - Daniel Limonta
- Department of Cell Biology, University of Alberta, Edmonton, AB T6G 2H7, Canada
| | - Anil Kumar
- Department of Cell Biology, University of Alberta, Edmonton, AB T6G 2H7, Canada
| | - Christopher Power
- Department of Medical Microbiology & Immunology, University of Alberta, Edmonton, AB T6G 2E1, Canada
- Department of Medicine, University of Alberta, Edmonton, AB T6G 2E1, Canada
- Women & Children's Health Research Institute, University of Alberta, Edmonton, AB T6G 1C9, Canada
- Li Ka Shing Institute of Virology, University of Alberta, Edmonton, AB T6G 2E1, Canada
| | - Tom C Hobman
- Department of Medical Microbiology & Immunology, University of Alberta, Edmonton, AB T6G 2E1, Canada.
- Department of Cell Biology, University of Alberta, Edmonton, AB T6G 2H7, Canada.
- Women & Children's Health Research Institute, University of Alberta, Edmonton, AB T6G 1C9, Canada.
- Li Ka Shing Institute of Virology, University of Alberta, Edmonton, AB T6G 2E1, Canada.
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21
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Siddique R, Liu Y, Nabi G, Sajjad W, Xue M, Khan S. Zika Virus Potentiates the Development of Neurological Defects and Microcephaly: Challenges and Control Strategies. Front Neurol 2019; 10:319. [PMID: 31024421 PMCID: PMC6465516 DOI: 10.3389/fneur.2019.00319] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2019] [Accepted: 03/14/2019] [Indexed: 12/15/2022] Open
Abstract
Since the beginning of the Zika Virus (ZIKV) epidemic, thousands of cases presenting ZIKV symptoms were recorded in Brazil, Colombia (South America), French Polynesia and other countries of Central and North America. In Brazil, during ZIKV outbreak thousands of microcephaly cases occurred that caused a state of urgency among scientists and researchers to confirm the suspected association between ZIKV infection and microcephaly. In this review article we comprehensively studied scientific literature to analyze ZIKV relationship with microcephaly, recent experimental studies, challenge and shortcomings in previously published reports to know about the current status of this association. The evidences supporting the association of ZIKV infection with congenital microcephaly and fetal brain tissue damage is rapidly increasing, and supplying recent information about pathology, clinical medicine, epidemiology, mechanism and experimental studies. However, serious attention is required toward ZIKV vaccine development, standardization of anthropometric techniques, centralization of data, and advance research to clearly understand the mechanism of ZIKV infection causing microcephaly.
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Affiliation(s)
- Rabeea Siddique
- Henan Medical Key Laboratory of Translational Cerebrovascular Diseases, Zhengzhou University, Zhengzhou, China.,The Department of Cerebrovascular Diseases, The Second Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Yang Liu
- Henan Medical Key Laboratory of Translational Cerebrovascular Diseases, Zhengzhou University, Zhengzhou, China.,The Department of Cerebrovascular Diseases, The Second Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Ghulam Nabi
- The Key Laboratory of Aquatic Biodiversity and Conservation of Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan, China.,University of Chinese Academy of Sciences, Beijing, China
| | - Wasim Sajjad
- University of Chinese Academy of Sciences, Beijing, China.,Key Laboratory of Petroleum Resources, Gansu Province/Key Laboratory of Petroleum Resources Research, Institute of Geology and Geophysics, Chinese Academy of Sciences, Lanzhou, China
| | - Mengzhou Xue
- Henan Medical Key Laboratory of Translational Cerebrovascular Diseases, Zhengzhou University, Zhengzhou, China.,The Department of Cerebrovascular Diseases, The Second Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Suliman Khan
- Henan Medical Key Laboratory of Translational Cerebrovascular Diseases, Zhengzhou University, Zhengzhou, China.,The Department of Cerebrovascular Diseases, The Second Affiliated Hospital of Zhengzhou University, Zhengzhou, China.,The Key Laboratory of Aquatic Biodiversity and Conservation of Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan, China
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22
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Negligible contribution of M2634V substitution to ZIKV pathogenesis in AG6 mice revealed by a bacterial promoter activity reduced infectious clone. Sci Rep 2018; 8:10491. [PMID: 30002446 PMCID: PMC6043478 DOI: 10.1038/s41598-018-28890-0] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2018] [Accepted: 06/19/2018] [Indexed: 01/10/2023] Open
Abstract
ZIKV has emerged as a significant human pathogene for the severe neurological complications, including Guillain-Barré(GBS) syndrome in adults and a variety of fetal abnormalities such as microcephaly. A stable and efficient infectious clone of Brazilian ZIKV isolate is required to study pathogenesis of epidemic ZIKV and virus evolution impact on it. Here we successfully constructed infectious cDNA clone on an early Brazilian isolate by eliminating the activity of predicted bacterial promoter in 1–3000 nt of ZIKV genome, leading to a stable infectious cDNA clone (pZL1). pZL1 derived virus could infect different cell lines and cause lethal effect to AG6 mice. We further investigated the role of a recent emerged substitution in NS5 (M2634V). We found that a reverse mutation (V2634M) caused negligible effect on the ZIKV viral genome replication and infectious progeny production in multiple cell culture systems. Additionally, this mutation did not alter the pathogenesis feature and virulence of ZIKV in AG6 mice. In summary, our results present another robust infectious ZIKV clone from Brazilian isolate and provide evidences to support that M2634V single mutation did not alter virus life cycle in cell culture and pathogenesis in AG6 mouse model.
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23
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Liu Y, Gordesky-Gold B, Leney-Greene M, Weinbren NL, Tudor M, Cherry S. Inflammation-Induced, STING-Dependent Autophagy Restricts Zika Virus Infection in the Drosophila Brain. Cell Host Microbe 2018; 24:57-68.e3. [PMID: 29934091 DOI: 10.1016/j.chom.2018.05.022] [Citation(s) in RCA: 191] [Impact Index Per Article: 27.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2018] [Revised: 04/16/2018] [Accepted: 05/11/2018] [Indexed: 12/19/2022]
Abstract
The emerging arthropod-borne flavivirus Zika virus (ZIKV) is associated with neurological complications. Innate immunity is essential for the control of virus infection, but the innate immune mechanisms that impact viral infection of neurons remain poorly defined. Using the genetically tractable Drosophila system, we show that ZIKV infection of the adult fly brain leads to NF-kB-dependent inflammatory signaling, which serves to limit infection. ZIKV-dependent NF-kB activation induces the expression of Drosophila stimulator of interferon genes (dSTING) in the brain. dSTING protects against ZIKV by inducing autophagy in the brain. Loss of autophagy leads to increased ZIKV infection of the brain and death of the infected fly, while pharmacological activation of autophagy is protective. These data suggest an essential role for an inflammation-dependent STING pathway in the control of neuronal infection and a conserved role for STING in antimicrobial autophagy, which may represent an ancestral function for this essential innate immune sensor.
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Affiliation(s)
- Yuan Liu
- Department of Microbiology, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Beth Gordesky-Gold
- Department of Microbiology, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Michael Leney-Greene
- Department of Microbiology, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Nathan L Weinbren
- Department of Microbiology, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Matthew Tudor
- Department of Cell and Developmental Biology, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Sara Cherry
- Department of Microbiology, University of Pennsylvania, Philadelphia, PA 19104, USA.
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24
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Ryan SJ, Carlson CJ, Stewart-Ibarra AM, Borbor-Cordova MJ, Romero MM, Cox SA, Mahon R, Trotman A, St. Ville S, Ahmed S. Outbreak of Zika Virus Infections, Dominica, 2016. Emerg Infect Dis 2018; 23:1926-1927. [PMID: 29048289 PMCID: PMC5652428 DOI: 10.3201/eid2311.171140] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Abstract
In February 2016, the World Health Organization declared the pandemic of Zika virus a public health emergency. On March 4, 2016, Dominica reported its first autochthonous Zika virus disease case; subsequently, 1,263 cases were reported. We describe the outbreak through November 2016, when the last known case was reported.
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25
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ZIKV Infection Induces an Inflammatory Response but Fails to Activate Types I, II, and III IFN Response in Human PBMC. Mediators Inflamm 2018; 2018:2450540. [PMID: 29967565 PMCID: PMC6008743 DOI: 10.1155/2018/2450540] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2017] [Revised: 03/28/2018] [Accepted: 04/30/2018] [Indexed: 12/27/2022] Open
Abstract
The recent epidemic in the Americas caused by Zika virus (ZIKV), Asian lineage, spurred the research towards a better understanding of how ZIKV infection affects the host immune response. The aim of this study was to evaluate the effects of Asian and East African ZIKV strain infection on the induction of IFN and proinflammatory and Th2 cytokines in human PBMC. We reported a slight modulation of type II IFN in PBMC exposed to Asian strain, but not to African strain, and a complete lack of type I and III IFN induction by both strains, suggesting the ability of ZIKV to evade the IFN system not only inhibiting the antiviral IFN response but also IFN production. Moreover, we highlighted a polyfunctional immune activation only in PBMC exposed to Asian strain, due to the induction of an inflammatory profile (IL-6, IL-8) and of a Th9 (IL-9) response. Overall, our data show a different ability of the ZIKV Asian strain, with respect to the African strain, to activate host immune response that may have pathogenetic implications for virus spread in vivo, including mother-to-child transmission and induction of severe fetal complications, as birth defects and neurological disorders.
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Ryan SJ, Lippi CA, Carlson CJ, Stewart-Ibarra AM, Borbor-Cordova MJ, Romero M, Cox SA, Mahon R, Trotman A, Rollock L, Gittens-St Hilaire M, King D, Daniel S. Zika Virus Outbreak, Barbados, 2015-2016. Am J Trop Med Hyg 2018; 98:1857-1859. [PMID: 29637883 PMCID: PMC6086174 DOI: 10.4269/ajtmh.17-0978] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
Barbados is a Caribbean island country of approximately 285,000 people, with a thriving tourism industry. In 2015, Zika spread rapidly throughout the Americas, and its proliferation through the Caribbean islands followed suit. Barbados reported its first confirmed autochthonous Zika transmission to the Pan American Health Organization in January 2016, a month before the global public health emergency was declared. After detection of suspected Zika cases on Barbados in 2015, 926 individuals were described as suspected cases, and 147 laboratory-confirmed cases were reported through December 2016, the end of the most recent epidemiological year. In this short report, we describe the epidemiological characteristics of 926 clinical case records that were originally suspected as cases of Zika, and which were subsequently sent for testing and confirmation; 147 were found positive for Zika, using reverse transcription-polymerase chain reaction methods, another 276 tested negative, and the remaining 503 were either pending results or still in the suspected category. Women were represented at about twice the rate of men in case records where gender was reported (71.9%), and confirmed cases (78.2%), and 19 of the confirmed positive cases were children under the age of 10.
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Affiliation(s)
- Sadie J Ryan
- Emerging Pathogens Institute, University of Florida, Gainesville, Florida.,School of Life Sciences, University of KwaZulu-Natal, Durban, South Africa.,Quantitative Disease Ecology and Conservation Lab, Department of Geography, University of Florida, Gainesville, Florida
| | - Catherine A Lippi
- Emerging Pathogens Institute, University of Florida, Gainesville, Florida.,Quantitative Disease Ecology and Conservation Lab, Department of Geography, University of Florida, Gainesville, Florida
| | - Colin J Carlson
- National Socio-Environmental Synthesis Center, University of Maryland, Annapolis, Maryland.,Department of Biology, Georgetown University, Washington, DC
| | - Anna M Stewart-Ibarra
- Center for Global Health and Translational Science, State University of New York (SUNY) Upstate Medical University, Syracuse, New York
| | - Mercy J Borbor-Cordova
- Facultad de Ingeniería Marítima, Ciencias Oceánicas y Recursos Naturales (FIMCBOR), Escuela Superior Politécnica del Litoral (ESPOL), Guayaquil, Ecuador
| | - Moory Romero
- Center for Global Health and Translational Science, State University of New York (SUNY) Upstate Medical University, Syracuse, New York
| | - Shelly-Ann Cox
- Caribbean Institute for Meteorology and Hydrology (CIMH), Bridgetown, Barbados
| | - Roché Mahon
- Caribbean Institute for Meteorology and Hydrology (CIMH), Bridgetown, Barbados
| | - Adrian Trotman
- Caribbean Institute for Meteorology and Hydrology (CIMH), Bridgetown, Barbados
| | | | - Marquita Gittens-St Hilaire
- Faculty of Medical Sciences, University of the West Indies at Cave Hill, Bridgetown, St. Michael, Barbados.,Barbados Leptospira Laboratory, Ministry of Health, St. Michael, Barbados
| | - Desmond King
- Caribbean Institute for Meteorology and Hydrology (CIMH), Bridgetown, Barbados
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Panchaud A, Vouga M, Musso D, Baud D. An international registry for women exposed to Zika virus during pregnancy: time for answers. THE LANCET. INFECTIOUS DISEASES 2018; 16:995-996. [PMID: 27684333 DOI: 10.1016/s1473-3099(16)30255-9] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/25/2016] [Accepted: 07/12/2016] [Indexed: 10/21/2022]
Affiliation(s)
- Alice Panchaud
- School of Pharmaceutical Sciences, University of Geneva, Geneva, Switzerland; School of Pharmaceutical Sciences, University of Lausanne, Lausanne, Switzerland; Swiss Teratogen Information Service and Division of Clinical Pharmacology, University Hospital of Lausanne, Lausanne, Switzerland; Department of Epidemiology, Harvard T H Chan School of Public Health, Boston, MA, USA
| | - Manon Vouga
- Materno-fetal and Obstetrics Research Unit, Department "Femme-Mère-Enfant", University Hospital, Lausanne, Switzerland; Institute of Microbiology, Faculty of Biology and Medicine, University of Lausanne and University Hospital, Lausanne, Switzerland
| | - Didier Musso
- Unit of Emerging Infectious Diseases, Institut Louis Malardé, Tahiti, French Polynesia
| | - David Baud
- Materno-fetal and Obstetrics Research Unit, Department "Femme-Mère-Enfant", University Hospital, Lausanne, Switzerland; Institute of Microbiology, Faculty of Biology and Medicine, University of Lausanne and University Hospital, Lausanne, Switzerland; Materno-fetal & Obstetrics Research Unit, Department of Obstetrics and Gynecology, Centre Hospitalier Universitaire Vaudois, 1011 Lausanne, Switzerland.
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28
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Shi Y, Li S, Wu Q, Sun L, Zhang J, Pan N, Wang Q, Bi Y, An J, Lu X, Gao GF, Wang X. Vertical Transmission of the Zika Virus Causes Neurological Disorders in Mouse Offspring. Sci Rep 2018; 8:3541. [PMID: 29476066 PMCID: PMC5824946 DOI: 10.1038/s41598-018-21894-w] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2017] [Accepted: 02/13/2018] [Indexed: 01/16/2023] Open
Abstract
The association between Zika virus (ZIKV) infection and congenital malformations such as microcephaly in infants is a public health emergency. Although various in vivo and in vitro models are used for ZIKV research, few animal models are available for resolving the effects of maternal ZIKV infection on neonatal development. Here, we established an immunocompetent mouse model via intrauterine inoculation. Our results confirmed that ZIKV, but not dengue virus, infection caused spontaneous abortions, brain malformations, ocular abnormalities, spinal cord defects and paralysis in mouse offspring. Aside from microcephaly and hippocampal dysplasia, eye abnormalities, including microphthalmia, thinner optic nerves, damaged retinae, and deficient visual projection, were also observed following ZIKV infection. Moreover, ZIKV-infected offspring showed a loss of alpha motor neurons in the spinal cord and cerebellar malformation, which may cause paralysis. ZIKV also impaired adult neurogenesis in neonatal mice. Due to its intact immunity, our rodent model can be used to systematically evaluate the impact of ZIKV on embryonic and neonatal development and to explore potential therapies.
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Affiliation(s)
- Yingchao Shi
- State Key Laboratory of Brain and Cognitive Science, CAS Center for Excellence in Brain Science and Intelligence Technology (Shanghai), Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, China.,University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Shihua Li
- CAS Key Laboratory of Pathogenic Microbiology & Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, 100101, China
| | - Qian Wu
- State Key Laboratory of Brain and Cognitive Science, CAS Center for Excellence in Brain Science and Intelligence Technology (Shanghai), Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, China.,University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Le Sun
- State Key Laboratory of Brain and Cognitive Science, CAS Center for Excellence in Brain Science and Intelligence Technology (Shanghai), Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, China.,University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Junjing Zhang
- State Key Laboratory of Brain and Cognitive Science, CAS Center for Excellence in Brain Science and Intelligence Technology (Shanghai), Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, China
| | - Na Pan
- State Key Laboratory of Brain and Cognitive Science, CAS Center for Excellence in Brain Science and Intelligence Technology (Shanghai), Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, China.,University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Qihui Wang
- CAS Key Laboratory of Pathogenic Microbiology & Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, 100101, China
| | - Yuhai Bi
- CAS Key Laboratory of Pathogenic Microbiology & Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, 100101, China
| | - Jing An
- Beijing Institute for Brain Disorders, Beijing, 100069, China.,Department of Microbiology, School of Basic Medical Sciences, Capital Medical University, Beijing, 100069, China
| | - Xuancheng Lu
- Laboratory Animal Center, Chinese Center for Disease Control and Prevention, Beijing, 102206, China
| | - George Fu Gao
- CAS Key Laboratory of Pathogenic Microbiology & Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, 100101, China. .,Savaid Medical School, University of Chinese Academy of Sciences, Beijing, 100049, China. .,National Institute for Viral Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing, 102206, China. .,Research Network of Immunity and Health, Beijing Institutes of Life Science, Chinese Academy of Sciences, Beijing, 100101, China.
| | - Xiaoqun Wang
- State Key Laboratory of Brain and Cognitive Science, CAS Center for Excellence in Brain Science and Intelligence Technology (Shanghai), Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, China. .,University of Chinese Academy of Sciences, Beijing, 100049, China. .,Beijing Institute for Brain Disorders, Beijing, 100069, China.
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29
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Fuller TL, Calvet G, Genaro Estevam C, Rafael Angelo J, Abiodun GJ, Halai UA, De Santis B, Carvalho Sequeira P, Machado Araujo E, Alves Sampaio S, Lima de Mendonça MC, Fabri A, Ribeiro RM, Harrigan R, Smith TB, Raja Gabaglia C, Brasil P, Bispo de Filippis AM, Nielsen-Saines K. Behavioral, climatic, and environmental risk factors for Zika and Chikungunya virus infections in Rio de Janeiro, Brazil, 2015-16. PLoS One 2017; 12:e0188002. [PMID: 29145452 PMCID: PMC5690671 DOI: 10.1371/journal.pone.0188002] [Citation(s) in RCA: 41] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2017] [Accepted: 10/30/2017] [Indexed: 12/20/2022] Open
Abstract
The burden of arboviruses in the Americas is high and may result in long-term sequelae with infants disabled by Zika virus infection (ZIKV) and arthritis caused by infection with Chikungunya virus (CHIKV). We aimed to identify environmental drivers of arbovirus epidemics to predict where the next epidemics will occur and prioritize municipalities for vector control and eventual vaccination. We screened sera and urine samples (n = 10,459) from residents of 48 municipalities in the state of Rio de Janeiro for CHIKV, dengue virus (DENV), and ZIKV by molecular PCR diagnostics. Further, we assessed the spatial pattern of arbovirus incidence at the municipal and neighborhood scales and the timing of epidemics and major rainfall events. Lab-confirmed cases included 1,717 infections with ZIKV (43.8%) and 2,170 with CHIKV (55.4%) and only 29 (<1%) with DENV. ZIKV incidence was greater in neighborhoods with little access to municipal water infrastructure (r = -0.47, p = 1.2x10-8). CHIKV incidence was weakly correlated with urbanization (r = 0.2, p = 0.02). Rains began in October 2015 and were followed one month later by the largest wave of ZIKV epidemic. ZIKV cases markedly declined in February 2016, which coincided with the start of a CHIKV outbreak. Rainfall predicted ZIKV and CHIKV with a lead time of 3 weeks each time. The association between rainfall and epidemics reflects vector ecology as the larval stages of Aedes aegypti require pools of water to develop. The temporal dynamics of ZIKV and CHIKV may be explained by the shorter incubation period of the viruses in the mosquito vector; 2 days for CHIKV versus 10 days for ZIKV.
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Affiliation(s)
- Trevon L. Fuller
- Institute of the Environment and Sustainability, University of California Los Angeles, Los Angeles, California, United States of America
- * E-mail:
| | - Guilherme Calvet
- Instituto Nacional de Infectologia Evandro Chagas, Fundação Oswaldo Cruz, Rio de Janeiro, Brazil
| | | | | | - Gbenga J. Abiodun
- Foundation for Professional Development, Pretoria, Gauteng, South Africa
| | - Umme-Aiman Halai
- David Geffen UCLA School of Medicine, Los Angeles, California, United States of America
| | - Bianca De Santis
- Laboratorio de Referência de Flavivirus, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Rio de Janeiro, Brazil
| | - Patricia Carvalho Sequeira
- Laboratorio de Referência de Flavivirus, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Rio de Janeiro, Brazil
| | - Eliane Machado Araujo
- Laboratorio de Referência de Flavivirus, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Rio de Janeiro, Brazil
| | - Simone Alves Sampaio
- Laboratorio de Referência de Flavivirus, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Rio de Janeiro, Brazil
| | | | - Allison Fabri
- Laboratorio de Referência de Flavivirus, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Rio de Janeiro, Brazil
| | - Rita Maria Ribeiro
- Laboratorio de Referência de Flavivirus, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Rio de Janeiro, Brazil
| | - Ryan Harrigan
- Institute of the Environment and Sustainability, University of California Los Angeles, Los Angeles, California, United States of America
| | - Thomas B. Smith
- Institute of the Environment and Sustainability, University of California Los Angeles, Los Angeles, California, United States of America
- Department of Ecology and Evolutionary Biology, University of California Los Angeles, Los Angeles, California, United States of America
| | - Claudia Raja Gabaglia
- Biomedical Research Institute of Southern California, Oceanside, California, United States of America
| | - Patrícia Brasil
- Instituto Nacional de Infectologia Evandro Chagas, Fundação Oswaldo Cruz, Rio de Janeiro, Brazil
| | - Ana Maria Bispo de Filippis
- Laboratorio de Referência de Flavivirus, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Rio de Janeiro, Brazil
| | - Karin Nielsen-Saines
- David Geffen UCLA School of Medicine, Los Angeles, California, United States of America
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30
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Musso D, Bossin H, Mallet HP, Besnard M, Broult J, Baudouin L, Levi JE, Sabino EC, Ghawche F, Lanteri MC, Baud D. Zika virus in French Polynesia 2013-14: anatomy of a completed outbreak. THE LANCET. INFECTIOUS DISEASES 2017; 18:e172-e182. [PMID: 29150310 DOI: 10.1016/s1473-3099(17)30446-2] [Citation(s) in RCA: 91] [Impact Index Per Article: 11.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/22/2016] [Revised: 06/15/2017] [Accepted: 06/30/2017] [Indexed: 10/18/2022]
Abstract
The Zika virus crisis exemplified the risk associated with emerging pathogens and was a reminder that preparedness for the worst-case scenario, although challenging, is needed. Herein, we review all data reported during the unexpected emergence of Zika virus in French Polynesia in late 2013. We focus on the new findings reported during this outbreak, especially the first description of severe neurological complications in adults and the retrospective description of CNS malformations in neonates, the isolation of Zika virus in semen, the potential for blood-transfusion transmission, mother-to-child transmission, and the development of new diagnostic assays. We describe the effect of this outbreak on health systems, the implementation of vector-borne control strategies, and the line of communication used to alert the international community of the new risk associated with Zika virus. This outbreak highlighted the need for careful monitoring of all unexpected events that occur during an emergence, to implement surveillance and research programmes in parallel to management of cases, and to be prepared to the worst-case scenario.
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Affiliation(s)
- Didier Musso
- Pôle de Recherche et de Veille sur les Maladies Infectieuses Émergentes, Institut Louis Malardé, Paea, Tahiti, French Polynesia.
| | - Hervé Bossin
- Unité d'Entomologie Médicale, Institut Louis Malardé, Paea, Tahiti, French Polynesia
| | - Henri Pierre Mallet
- Bureau de Veille Sanitaire, Direction de la Santé, Papeete, Tahiti, French Polynesia
| | - Marianne Besnard
- Service de Réanimation néonatale, Centre Hospitalier du Taaone, Pirae, Tahiti, French Polynesia
| | - Julien Broult
- Centre de Transfusion Sanguine, Centre Hospitalier du Taaone, Pirae, Tahiti, French Polynesia
| | - Laure Baudouin
- Réanimation, Centre Hospitalier du Taaone, Pirae, Tahiti, French Polynesia
| | - José Eduardo Levi
- Tropical Medicine Institute, University of São Paulo, São Paulo, Brazil; Hospital Israelita Albert Einstein, São Paulo, Brazil
| | - Ester C Sabino
- Tropical Medicine Institute, University of São Paulo, São Paulo, Brazil; Department of Infectious Diseases, Medical School, University of São Paulo, São Paulo, Brazil
| | - Frederic Ghawche
- Service de Neurologie, Centre Hospitalier du Taaone, Pirae, Tahiti, French Polynesia
| | - Marion C Lanteri
- Blood Systems Research Institute, San Francisco, CA, USA; Department of Laboratory Medicine, University of California San Francisco, San Francisco, CA, USA; Cerus Corporation, Concord, CA, USA
| | - David Baud
- Materno-Fetal and Obstetrics Research Unit, Department Femme-Mère-Enfant, University Hospital, Lausanne, Switzerland
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31
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Abrams RPM, Solis J, Nath A. Therapeutic Approaches for Zika Virus Infection of the Nervous System. Neurotherapeutics 2017; 14:1027-1048. [PMID: 28952036 PMCID: PMC5722777 DOI: 10.1007/s13311-017-0575-2] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
Zika virus has spread rapidly in the Americas and has caused devastation of human populations affected in these regions. The virus causes teratogenic effects involving the nervous system, and in adults and children can cause a neuropathy similar to Guillain-Barré syndrome, an anterior myelitis, or, rarely, an encephalitis. While major efforts have been undertaken to control mosquito populations that spread the virus and to develop a vaccine, drug development that directly targets the virus in an infected individual to prevent or treat the neurological manifestations is necessary. Rational and targeted drug development is possible since the viral life cycle and the structure of the key viral proteins are now well understood. While several groups have identified therapeutic candidates, their approaches differ in the types of screening processes and viral assays used. Animal studies are available for only a few compounds. Here we provide an exhaustive review and compare each of the classes of drugs discovered, the methods used for drug discovery, and their potential use in humans for the prevention or treatment of neurological complications of Zika virus infection.
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Affiliation(s)
- Rachel P M Abrams
- Section of Infections of the Nervous System, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA
| | - Jamie Solis
- Section of Infections of the Nervous System, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA
| | - Avindra Nath
- Section of Infections of the Nervous System, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA.
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32
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Zhang Q, Sun K, Chinazzi M, Pastore Y Piontti A, Dean NE, Rojas DP, Merler S, Mistry D, Poletti P, Rossi L, Bray M, Halloran ME, Longini IM, Vespignani A. Spread of Zika virus in the Americas. Proc Natl Acad Sci U S A 2017; 114:E4334-E4343. [PMID: 28442561 PMCID: PMC5465916 DOI: 10.1073/pnas.1620161114] [Citation(s) in RCA: 185] [Impact Index Per Article: 23.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Abstract
We use a data-driven global stochastic epidemic model to analyze the spread of the Zika virus (ZIKV) in the Americas. The model has high spatial and temporal resolution and integrates real-world demographic, human mobility, socioeconomic, temperature, and vector density data. We estimate that the first introduction of ZIKV to Brazil likely occurred between August 2013 and April 2014 (90% credible interval). We provide simulated epidemic profiles of incident ZIKV infections for several countries in the Americas through February 2017. The ZIKV epidemic is characterized by slow growth and high spatial and seasonal heterogeneity, attributable to the dynamics of the mosquito vector and to the characteristics and mobility of the human populations. We project the expected timing and number of pregnancies infected with ZIKV during the first trimester and provide estimates of microcephaly cases assuming different levels of risk as reported in empirical retrospective studies. Our approach represents a modeling effort aimed at understanding the potential magnitude and timing of the ZIKV epidemic and it can be potentially used as a template for the analysis of future mosquito-borne epidemics.
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Affiliation(s)
- Qian Zhang
- Laboratory for the Modeling of Biological and Socio-technical Systems, Northeastern University, Boston, MA 02115
| | - Kaiyuan Sun
- Laboratory for the Modeling of Biological and Socio-technical Systems, Northeastern University, Boston, MA 02115
| | - Matteo Chinazzi
- Laboratory for the Modeling of Biological and Socio-technical Systems, Northeastern University, Boston, MA 02115
| | - Ana Pastore Y Piontti
- Laboratory for the Modeling of Biological and Socio-technical Systems, Northeastern University, Boston, MA 02115
| | - Natalie E Dean
- Department of Biostatistics, College of Public Health and Health Professions, University of Florida, Gainesville, FL 32611
| | - Diana Patricia Rojas
- Department of Epidemiology, College of Public Health and Health Professions, University of Florida, Gainesville, FL 32611
| | | | - Dina Mistry
- Laboratory for the Modeling of Biological and Socio-technical Systems, Northeastern University, Boston, MA 02115
| | - Piero Poletti
- Dondena Centre for Research on Social Dynamics and Public Policy, Universitá Commerciale L. Bocconi, 20136 Milan, Italy
| | - Luca Rossi
- Institute for Scientific Interchange Foundation, 10126 Turin, Italy
| | - Margaret Bray
- Laboratory for the Modeling of Biological and Socio-technical Systems, Northeastern University, Boston, MA 02115
| | - M Elizabeth Halloran
- Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109
- Department of Biostatistics, University of Washington, Seattle, WA 98195
| | - Ira M Longini
- Department of Biostatistics, College of Public Health and Health Professions, University of Florida, Gainesville, FL 32611
| | - Alessandro Vespignani
- Laboratory for the Modeling of Biological and Socio-technical Systems, Northeastern University, Boston, MA 02115;
- Institute for Scientific Interchange Foundation, 10126 Turin, Italy
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34
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Study of the mechanism of protonated histidine-induced conformational changes in the Zika virus dimeric envelope protein using accelerated molecular dynamic simulations. J Mol Graph Model 2017; 74:203-214. [PMID: 28445832 DOI: 10.1016/j.jmgm.2017.04.009] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2017] [Revised: 04/09/2017] [Accepted: 04/10/2017] [Indexed: 11/23/2022]
Abstract
The Zika virus has drawn worldwide attention because of the epidemic diseases it causes. It is a flavivirus that has an icosahedral protein shell constituted by an envelope glycoprotein (E-protein) and membrane protein (M-protein) in the mature virion. The multistep process of membrane fusion to infect the host cell is pH-induced. To understand the mechanism of the conformational changes in the (E-M)2 protein homodimer embedded in the membrane, two 200-ns accelerated dynamic simulations were performed under different pH conditions. The low pH condition weakens the interactions and correlations in both E-protein monomers and in the E-M heterodimer. The highly conserved residues, His249, His288, His323 and His446, are protonated under low pH conditions and play key roles in driving the fusion process. The analysis and discussion in this study may provide some insight into the molecular mechanism of Zika virus infection.
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35
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Intrauterine Zika virus infection of pregnant immunocompetent mice models transplacental transmission and adverse perinatal outcomes. Nat Commun 2017; 8:14575. [PMID: 28220786 PMCID: PMC5321801 DOI: 10.1038/ncomms14575] [Citation(s) in RCA: 128] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2016] [Accepted: 01/12/2017] [Indexed: 12/30/2022] Open
Abstract
Zika virus (ZIKV) crosses the placenta and causes congenital disease. Here we develop an animal model utilizing direct ZIKV inoculation into the uterine wall of pregnant, immunocompetent mice to evaluate transplacental transmission. Intrauterine inoculation at embryonic day (E) 10, but not E14, with African, Asian or American strains of ZIKV reduces fetal viability and increases infection of placental and fetal tissues. ZIKV inoculation at E10 causes placental inflammation, placental dysfunction and reduces neonatal brain cortical thickness, which is associated with increased activation of microglia. Viral antigen localizes in trophoblast and endothelial cells in the placenta, and endothelial, microglial and neural progenitor cells in the fetal brain. ZIKV infection of the placenta increases production of IFNβ and expression of IFN-stimulated genes 48 h after infection. This mouse model provides a platform for identifying factors at the maternal-fetal interface that contribute to adverse perinatal outcomes in a host with an intact immune system.
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A Mutation Identified in Neonatal Microcephaly Destabilizes Zika Virus NS1 Assembly in Vitro. Sci Rep 2017; 7:42580. [PMID: 28198446 PMCID: PMC5309781 DOI: 10.1038/srep42580] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2016] [Accepted: 01/12/2017] [Indexed: 12/11/2022] Open
Abstract
An unprecedented epidemic of Zika virus (ZIKV) infection had spread to South and Central America. ZIKV infection was recently confirmed by CDC (the Centers for Disease Control and Prevention) to cause neonatal microcephaly, which posed a significant public health emergency of international concern. No specific vaccines or drugs are currently available to fight ZIKV infection. ZIKV nonstructural protein 1 (NS1) plays an essential role in viral replication and immune evasion. We determined the crystal structure of ZIKV NS1172–352, which forms a head-to-head, symmetric dimer with a unique 14-stranded β-ladder conserved among flaviviruses. The assembly of the β-ladder dimer is concentration dependent. Strikingly, one pathogenic mutation T233A (NCBI accession no. KU527068), found in the brain tissue of infected fetus with neonatal microcephaly, is located at the dimer interface. Thr233, a unique residue found in ZIKV but not in other flaviviruses, organizes a central hydrogen bonding network at NS1 dimer interface. Mutation of Thr233 to Ala disrupts this elaborated interaction network, and destabilizes the NS1 dimeric assembly in vitro. In addition, our structural comparison of epitopes for protective antibody 22NS1, targeting West Nile Virus NS1, could potentially be valuable in understanding its anti-virus specificities and in the development of antibodies against ZIKV.
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Cao RY, Xu YF, Zhang TH, Yang JJ, Yuan Y, Hao P, Shi Y, Zhong J, Zhong W. Pediatric Drug Nitazoxanide: A Potential Choice for Control of Zika. Open Forum Infect Dis 2017; 4:ofx009. [PMID: 28480282 PMCID: PMC5414027 DOI: 10.1093/ofid/ofx009] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2016] [Accepted: 01/19/2017] [Indexed: 12/04/2022] Open
Abstract
Zika virus (ZIKV) infection can be the cause of congenital malformations, including microcephaly in infants and can cause other disorders such as Guillain-Barré syndrome, meningoencephalitis, and myelitis, which can also occur in some infected adults. However, at this time, there is no drug approved to treat ZIKV infection. Drug repurposing is the promptest way to obtain an effective drug during a global public health emergency such as the spread of Zika virus. In this study, we report a US Food and Drug Admistration-approved drug that is safe for pediatric use. Nitazoxanide and its bioactive metabolite, tizoxanide, have anti-ZIKV potential in vitro, and we identified that they exerts antiviral effect possibly by targeting the viral postattachment step.
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Affiliation(s)
- Rui-Yuan Cao
- Beijing Institute of Pharmacology and Toxicology, China
| | - Yong-Fen Xu
- Beijing Institute of Pharmacology and Toxicology, China
| | | | | | - Ye Yuan
- Beijing Institute of Pharmacology and Toxicology, China
| | - Pei Hao
- Institut Pasteur of Shanghai, Chinese Academy of Sciences, Shanghai, China
| | - Yi Shi
- Institute of Microbiology, Chinese Academy of Sciences, Beijing, China
| | - Jin Zhong
- Institut Pasteur of Shanghai, Chinese Academy of Sciences, Shanghai, China
| | - Wu Zhong
- Beijing Institute of Pharmacology and Toxicology, China
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38
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Teng Y, Bi D, Xie G, Jin Y, Huang Y, Lin B, An X, Feng D, Tong Y. Dynamic Forecasting of Zika Epidemics Using Google Trends. PLoS One 2017; 12:e0165085. [PMID: 28060809 PMCID: PMC5217860 DOI: 10.1371/journal.pone.0165085] [Citation(s) in RCA: 83] [Impact Index Per Article: 10.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2016] [Accepted: 12/18/2016] [Indexed: 02/06/2023] Open
Abstract
We developed a dynamic forecasting model for Zika virus (ZIKV), based on real-time online search data from Google Trends (GTs). It was designed to provide Zika virus disease (ZVD) surveillance and detection for Health Departments, and predictive numbers of infection cases, which would allow them sufficient time to implement interventions. In this study, we found a strong correlation between Zika-related GTs and the cumulative numbers of reported cases (confirmed, suspected and total cases; p<0.001). Then, we used the correlation data from Zika-related online search in GTs and ZIKV epidemics between 12 February and 20 October 2016 to construct an autoregressive integrated moving average (ARIMA) model (0, 1, 3) for the dynamic estimation of ZIKV outbreaks. The forecasting results indicated that the predicted data by ARIMA model, which used the online search data as the external regressor to enhance the forecasting model and assist the historical epidemic data in improving the quality of the predictions, are quite similar to the actual data during ZIKV epidemic early November 2016. Integer-valued autoregression provides a useful base predictive model for ZVD cases. This is enhanced by the incorporation of GTs data, confirming the prognostic utility of search query based surveillance. This accessible and flexible dynamic forecast model could be used in the monitoring of ZVD to provide advanced warning of future ZIKV outbreaks.
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Affiliation(s)
- Yue Teng
- Beijing Institute of Microbiology and Epidemiology, Beijing, China
- State Key Laboratory of Pathogen and Biosecurity, Beijing, China
- * E-mail: (YT); (DF); (YT)
| | - Dehua Bi
- State Key Laboratory of Pathogen and Biosecurity, Beijing, China
- Department of Mechanical and Mechatronics Engineering, University of Waterloo, Waterloo, Ontario, Canada
| | - Guigang Xie
- State Key Laboratory of Pathogen and Biosecurity, Beijing, China
| | - Yuan Jin
- State Key Laboratory of Pathogen and Biosecurity, Beijing, China
- Beijing Institute of Biotechnology, Beijing, China
| | - Yong Huang
- Beijing Institute of Microbiology and Epidemiology, Beijing, China
- State Key Laboratory of Pathogen and Biosecurity, Beijing, China
| | - Baihan Lin
- Computational Neuroscience Program, Department of Psychology, Physics, and Computer Science and Engineering; Institute for Protein Design, University of Washington, Seattle, United States of America
| | - Xiaoping An
- Beijing Institute of Microbiology and Epidemiology, Beijing, China
- State Key Laboratory of Pathogen and Biosecurity, Beijing, China
| | - Dan Feng
- Division of Standard Operational Management, Institute of Hospital Management, Chinese PLA General Hospital, Beijing, China
- * E-mail: (YT); (DF); (YT)
| | - Yigang Tong
- Beijing Institute of Microbiology and Epidemiology, Beijing, China
- State Key Laboratory of Pathogen and Biosecurity, Beijing, China
- * E-mail: (YT); (DF); (YT)
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39
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Green RJ. Emerging Zoonotic and Vector-Borne Viral Diseases. VIRAL INFECTIONS IN CHILDREN, VOLUME I 2017. [PMCID: PMC7114986 DOI: 10.1007/978-3-319-54033-7_5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 12/01/2022]
Abstract
Many vector-borne and zoonotic diseases are considered to be emerging; since they are either newly reported to cause human disease, or are causing disease in geographical locations or species not previously documented. In the past 15 years, significant outbreaks of Severe Acute Respiratory Syndrome (or SARS) and Middle Eastern Respiratory Syndrome (or MERS), Nipah and Hendra, Ebola virus disease and Zika fever and others have been reported. In this chapter the clinical characteristics, epidemiological aspects, treatment and prevention and information related to the laboratory investigation of important zoonotic and vector-borne diseases that have emerged in the past 10 years, and how this affects children, will be discussed. Furthermore rabies, considered a neglected viral disease with the majority of victims in Africa being children, will also be addressed.
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Affiliation(s)
- Robin J. Green
- Department of Paediatrics and Child Health, University of Pretoria, School of Medicine, Pretoria, ZA, South Africa
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40
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Blázquez AB, Saiz JC. Neurological manifestations of Zika virus infection. World J Virol 2016; 5:135-143. [PMID: 27878100 PMCID: PMC5105046 DOI: 10.5501/wjv.v5.i4.135] [Citation(s) in RCA: 42] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/08/2016] [Revised: 06/29/2016] [Accepted: 08/11/2016] [Indexed: 02/05/2023] Open
Abstract
Zika virus (ZIKV) is a flavivirus (Flaviviridae family) transmitted mainly by Aedes mosquitoes. The virus was restricted to the African continent until its spread to south-east Asia in the 1980's, the Micronesia in 2007, the French Polynesia in 2013 and, more recently in the Americas in 2015, where, up to date, the World Health Organization (WHO) has estimated about 3-4 million total cases of ZIKV infection. During outbreaks in the French Polynesia and Brazil in 2013 and 2015, respectively, national health authorities reported potential neurological complications of ZIKV disease, chiefly an upsurge in Guillain-Barré syndrome, which coincided with ZIKV outbreaks. On the other hand, the emergence of ZIKV in Brazil has been associated with a striking increase in the number of reported cases of microcephaly in fetus and newborns, twenty times higher than in that reported in previous years. While investigations are currently assessing whether there is an actual association between neurological complications and ZIKV infections, the evidence was enough worrisome for WHO to declare a public health emergency of international concern. Here we present an updated review addressing what is currently known about the possible association between ZIKV infection and the development of severe neurological disorders.
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41
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ZIKA virus elicits P53 activation and genotoxic stress in human neural progenitors similar to mutations involved in severe forms of genetic microcephaly. Cell Death Dis 2016; 7:e2440. [PMID: 27787521 PMCID: PMC5133962 DOI: 10.1038/cddis.2016.266] [Citation(s) in RCA: 65] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2016] [Revised: 07/20/2016] [Accepted: 07/26/2016] [Indexed: 12/30/2022]
Abstract
Epidemiological evidence from the current outbreak of Zika virus (ZIKV) and recent studies in animal models indicate a strong causal link between ZIKV and microcephaly. ZIKV infection induces cell-cycle arrest and apoptosis in proliferating neural progenitors. However, the mechanisms leading to these phenotypes are still largely obscure. In this report, we explored the possible similarities between transcriptional responses induced by ZIKV in human neural progenitors and those elicited by three different genetic mutations leading to severe forms of microcephaly in mice. We found that the strongest similarity between all these conditions is the activation of common P53 downstream genes. In agreement with these observations, we report that ZIKV infection increases total P53 levels and nuclear accumulation, as well as P53 Ser15 phosphorylation, correlated with genotoxic stress and apoptosis induction. Interestingly, increased P53 activation and apoptosis are induced not only in cells expressing high levels of viral antigens but also in cells showing low or undetectable levels of the same proteins. These results indicate that P53 activation is an early and specific event in ZIKV-infected cells, which could result from cell-autonomous and/or non-cell-autonomous mechanisms. Moreover, we highlight a small group of P53 effector proteins that could act as critical mediators, not only in ZIKV-induced microcephaly but also in many genetic microcephaly syndromes.
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Kumar A, Hou S, Airo AM, Limonta D, Mancinelli V, Branton W, Power C, Hobman TC. Zika virus inhibits type-I interferon production and downstream signaling. EMBO Rep 2016; 17:1766-1775. [PMID: 27797853 DOI: 10.15252/embr.201642627] [Citation(s) in RCA: 247] [Impact Index Per Article: 27.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2016] [Revised: 09/13/2016] [Accepted: 09/22/2016] [Indexed: 12/22/2022] Open
Abstract
Zika virus is an emerging mosquito-borne pathogen that is associated with Guillain-Barré syndrome in adults and microcephaly and other neurological defects in newborns. Despite being declared an international emergency by the World Health Organization, comparatively little is known about its biology. Here, we investigate the strategies employed by the virus to suppress the host antiviral response. We observe that once established, Zika virus infection is impervious to interferon treatment suggesting that the virus deploys effective countermeasures to host cell defences. This is confirmed by experiments showing that Zika virus infection impairs the induction of type-I interferon as well as downstream interferon-stimulated genes. Multiple viral proteins affect these processes. Virus-mediated degradation of STAT2 acts to reduce type-I and type-III interferon-mediated signaling. Further, the NS5 of Zika virus binds to STAT2, and its expression is correlated with STAT2 degradation by the proteasome. Together, our findings provide key insights into how Zika virus blocks cellular defense systems. This in turn is important for understanding pathogenesis and may aid in designing antiviral therapies.
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Affiliation(s)
- Anil Kumar
- Department of Cell Biology, University of Alberta, Edmonton, Canada
| | - Shangmei Hou
- Department of Cell Biology, University of Alberta, Edmonton, Canada
| | - Adriana M Airo
- Department of Medical Microbiology & Immunology, University of Alberta, Edmonton, Canada
| | - Daniel Limonta
- Department of Cell Biology, University of Alberta, Edmonton, Canada
| | | | - William Branton
- Department of Medicine, University of Alberta, Edmonton, Canada
| | | | - Tom C Hobman
- Department of Cell Biology, University of Alberta, Edmonton, Canada .,Department of Medical Microbiology & Immunology, University of Alberta, Edmonton, Canada.,Li Ka Shing Institute of Virology, University of Alberta, Edmonton, Canada.,Women & Childrens Health Research Institute, University of Alberta, Edmonton, Canada
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43
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Affiliation(s)
- Susan B. Moskosky
- US Department of Health and Human Services, Office of Population Affairs, Washington, D.C., USA
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44
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Boëte C. Yellow Fever Outbreak: O Vector Control, Where Art Thou? JOURNAL OF MEDICAL ENTOMOLOGY 2016; 53:1048-1049. [PMID: 27330101 DOI: 10.1093/jme/tjw087] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/04/2016] [Accepted: 05/10/2016] [Indexed: 06/06/2023]
Affiliation(s)
- Christophe Boëte
- UMR "Emergence des Pathologies Virales", Aix-Marseille Université" - IRD 190 - Inserm 1207 - EHESP, 27, Bd Jean Moulin 13385 Marseille Cedex 5 France
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45
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46
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Structural basis of Zika virus helicase in recognizing its substrates. Protein Cell 2016; 7:562-70. [PMID: 27430951 PMCID: PMC4980333 DOI: 10.1007/s13238-016-0293-2] [Citation(s) in RCA: 58] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2016] [Accepted: 06/29/2016] [Indexed: 01/07/2023] Open
Abstract
The recent explosive outbreak of Zika virus (ZIKV) infection has been reported in South and Central America and the Caribbean. Neonatal microcephaly associated with ZIKV infection has already caused a public health emergency of international concern. No specific vaccines or drugs are currently available to treat ZIKV infection. The ZIKV helicase, which plays a pivotal role in viral RNA replication, is an attractive target for therapy. We determined the crystal structures of ZIKV helicase-ATP-Mn(2+) and ZIKV helicase-RNA. This is the first structure of any flavivirus helicase bound to ATP. Comparisons with related flavivirus helicases have shown that although the critical P-loop in the active site has variable conformations among different species, it adopts an identical mode to recognize ATP/Mn(2+). The structure of ZIKV helicase-RNA has revealed that upon RNA binding, rotations of the motor domains can cause significant conformational changes. Strikingly, although ZIKV and dengue virus (DENV) apo-helicases share conserved residues for RNA binding, their different manners of motor domain rotations result in distinct individual modes for RNA recognition. It suggests that flavivirus helicases could have evolved a conserved engine to convert chemical energy from nucleoside triphosphate to mechanical energy for RNA unwinding, but different motor domain rotations result in variable RNA recognition modes to adapt to individual viral replication.
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47
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Panchaud A, Stojanov M, Ammerdorffer A, Vouga M, Baud D. Emerging Role of Zika Virus in Adverse Fetal and Neonatal Outcomes. Clin Microbiol Rev 2016; 29:659-94. [PMID: 27281741 PMCID: PMC4978612 DOI: 10.1128/cmr.00014-16] [Citation(s) in RCA: 116] [Impact Index Per Article: 12.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
The rapid spread of the Zika virus (ZIKV) in the Americas and its potential association with thousands of suspected cases of microcephaly in Brazil and higher rates of Guillain-Barré syndrome meet the conditions for a Public Health Emergency of International Concern, as stated by the World Health Organization in February 2016. Two months later, the Centers for Disease Control and Prevention (CDC) announced that the current available evidence supports the existence of a causal relationship between prenatal Zika virus infection and microcephaly and other serious brain anomalies. Microcephaly can be caused by several factors, and its clinical course and prognosis are difficult to predict. Other pathogens with proven teratogenicity have been identified long before the current ZIKV epidemic. Despite the growing number of cases with maternal signs of infection and/or presence of ZIKV in tissues of affected newborns or fetuses, it is currently difficult to assess the magnitude of increase of microcephaly prevalence in Brazil, as well as the role of other factors in the development of congenital neurological conditions. Meanwhile, health agencies and medical organizations have issued cautious guidelines advising health care practitioners and expectant couples traveling to, returning from, or living in affected areas. Analogous to dengue virus (DENV) epidemics, ZIKV has the potential to become endemic in all countries infested by Aedes mosquitoes, while new mutations could impact viral replication in humans, leading to increased virulence and consequently heightened chances of viral transmission to additional naive mosquito vectors. Studies are urgently needed to answer the questions surrounding ZIKV and its role in congenital neurological conditions.
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Affiliation(s)
- Alice Panchaud
- School of Pharmaceutical Sciences, University of Geneva and University of Lausanne, Geneva, Switzerland Department of Epidemiology, Harvard T. H. Chan School of Public Health, Boston, Massachusetts, USA Swiss Teratogen Information Service and Division of Clinical Pharmacology, University of Lausanne and University Hospital, Lausanne, Switzerland
| | - Miloš Stojanov
- Institute of Microbiology, Faculty of Biology and Medicine, University of Lausanne and University Hospital, Lausanne, Switzerland Materno-fetal and Obstetrics Research Unit, Department Femme-Mère-Enfant, University of Lausanne and University Hospital, Lausanne, Switzerland
| | - Anne Ammerdorffer
- Institute of Microbiology, Faculty of Biology and Medicine, University of Lausanne and University Hospital, Lausanne, Switzerland Materno-fetal and Obstetrics Research Unit, Department Femme-Mère-Enfant, University of Lausanne and University Hospital, Lausanne, Switzerland
| | - Manon Vouga
- Institute of Microbiology, Faculty of Biology and Medicine, University of Lausanne and University Hospital, Lausanne, Switzerland Materno-fetal and Obstetrics Research Unit, Department Femme-Mère-Enfant, University of Lausanne and University Hospital, Lausanne, Switzerland
| | - David Baud
- Institute of Microbiology, Faculty of Biology and Medicine, University of Lausanne and University Hospital, Lausanne, Switzerland Materno-fetal and Obstetrics Research Unit, Department Femme-Mère-Enfant, University of Lausanne and University Hospital, Lausanne, Switzerland
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48
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Rocklöv J, Quam MB, Sudre B, German M, Kraemer MUG, Brady O, Bogoch II, Liu-Helmersson J, Wilder-Smith A, Semenza JC, Ong M, Aaslav KK, Khan K. Assessing Seasonal Risks for the Introduction and Mosquito-borne Spread of Zika Virus in Europe. EBioMedicine 2016; 9:250-256. [PMID: 27344225 PMCID: PMC4972550 DOI: 10.1016/j.ebiom.2016.06.009] [Citation(s) in RCA: 73] [Impact Index Per Article: 8.1] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2016] [Revised: 05/26/2016] [Accepted: 06/06/2016] [Indexed: 11/21/2022] Open
Abstract
The explosive Zika virus epidemic in the Americas is amplifying spread of this emerging pathogen into previously unaffected regions of the world, including Europe (Gulland, 2016), where local populations are immunologically naïve. As summertime approaches in the northern hemisphere, Aedes mosquitoes in Europe may find suitable climatic conditions to acquire and subsequently transmit Zika virus from viremic travellers to local populations. While Aedes albopictus has proven to be a vector for the transmission of dengue and chikungunya viruses in Europe (Delisle, E., et al., 2015, ECDC,, n.d) there is growing experimental and ecological evidence to suggest that it may also be competent for Zika virus(Chouin-Carneiro et al., 2016; Grard et al., 2014; Li et al., 2012; Wong et al., 2013). Here we analyze and overlay the monthly flows of airline travellers arriving into European cities from Zika affected areas across the Americas, the predicted monthly estimates of the basic reproduction number of Zika virus in areas where Aedes mosquito populations reside in Europe (Aedes aegypti in Madeira, Portugal and Ae. albopictus in continental Europe), and human populations living within areas where mosquito-borne transmission of Zika virus may be possible. We highlight specific geographic areas and timing of risk for Zika virus introduction and possible spread within Europe to inform the efficient use of human disease surveillance, vector surveillance and control, and public education resources.
A validated climate model suggests mosquito-borne Zika transmission risk peaks in July and August in parts of Southern Europe This analysis assumes European and Latin American Aedes vectors have similar competence to transmit Zika virus Air travel peak from regions of the Americas aligns with peak predicted capacity of European Aedes vectors to transmit Zika Findings could help health officials identify where and when risk for Zika importation and local transmission is heightened The imminent arrival of summer in the northern hemisphere brings an elevated risk of Zika virus epidemics outside of the Americas. In Europe, established populations of Aedes aegypti and Aedes albopictus mosquitoes might be capable of transmitting Zika virus locally, if travellers introduce the virus from other areas of the world. Here we calibrate a model of vectorial capacity for Zika virus transmission in Europe, which we overlay with arriving air travellers into Europe from Zika affected areas in the Americas. We highlight specific geographic areas and timing of risk for Zika virus introduction and potential autochthonous transmission to inform European disease surveillance and control activities.
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Affiliation(s)
- Joacim Rocklöv
- Department of Public Health and Clinical Medicine, Epidemiology and Global Health, Umeå University, Sweden.
| | - Mikkel Brandon Quam
- Department of Public Health and Clinical Medicine, Epidemiology and Global Health, Umeå University, Sweden
| | - Bertrand Sudre
- European Centre for Disease Prevention and Control (ECDC), Stockholm, Sweden
| | - Matthew German
- Li Ka Shing Knowledge Institute, St Michael's Hospital, Toronto, ON, Canada
| | - Moritz U G Kraemer
- Spatial Ecology and Epidemiology Group, Department of Zoology, University of Oxford; Oxford, UK
| | - Oliver Brady
- Wellcome Trust Centre for Human Genetics, University of Oxford; Oxford, UK
| | - Isaac I Bogoch
- Department of Medicine, Division of Infectious Diseases, University of Toronto, Toronto, ON, Canada; Divisions of Internal Medicine and Infectious Diseases, University Health Network, Toronto, Canada
| | - Jing Liu-Helmersson
- Department of Public Health and Clinical Medicine, Epidemiology and Global Health, Umeå University, Sweden
| | - Annelies Wilder-Smith
- Department of Public Health and Clinical Medicine, Epidemiology and Global Health, Umeå University, Sweden; Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore
| | - Jan C Semenza
- European Centre for Disease Prevention and Control (ECDC), Stockholm, Sweden
| | - Mark Ong
- Geomatics Program, University of Waterloo, Waterloo, ON, Canada
| | - Kaja Kaasik Aaslav
- European Centre for Disease Prevention and Control (ECDC), Stockholm, Sweden
| | - Kamran Khan
- Li Ka Shing Knowledge Institute, St Michael's Hospital, Toronto, ON, Canada; Department of Medicine, Division of Infectious Diseases, University of Toronto, Toronto, ON, Canada
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