|
1
|
Connors J, Cusimano G, Mege N, Woloszczuk K, Konopka E, Bell M, Joyner D, Marcy J, Tardif V, Kutzler MA, Muir R, Haddad EK. Using the power of innate immunoprofiling to understand vaccine design, infection, and immunity. Hum Vaccin Immunother 2023; 19:2267295. [PMID: 37885158 PMCID: PMC10760375 DOI: 10.1080/21645515.2023.2267295] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2023] [Accepted: 10/03/2023] [Indexed: 10/28/2023] Open
Abstract
In the field of immunology, a systems biology approach is crucial to understanding the immune response to infection and vaccination considering the complex interplay between genetic, epigenetic, and environmental factors. Significant progress has been made in understanding the innate immune response, including cell players and critical signaling pathways, but many questions remain unanswered, including how the innate immune response dictates host/pathogen responses and responses to vaccines. To complicate things further, it is becoming increasingly clear that the innate immune response is not a linear pathway but is formed from complex networks and interactions. To further our understanding of the crosstalk and complexities, systems-level analyses and expanded experimental technologies are now needed. In this review, we discuss the most recent immunoprofiling techniques and discuss systems approaches to studying the global innate immune landscape which will inform on the development of personalized medicine and innovative vaccine strategies.
Collapse
Affiliation(s)
- Jennifer Connors
- Department of Microbiology and Immunology, Drexel University College of Medicine, Philadelphia, PA, USA
- Department of Medicine, Division of Infectious Diseases and HIV Medicine, Drexel University College of Medicine, Philadelphia, PA, USA
| | - Gina Cusimano
- Department of Microbiology and Immunology, Drexel University College of Medicine, Philadelphia, PA, USA
- Department of Medicine, Division of Infectious Diseases and HIV Medicine, Drexel University College of Medicine, Philadelphia, PA, USA
| | - Nathan Mege
- Tower Health, Reading Hospital, West Reading, PA, USA
| | - Kyra Woloszczuk
- Department of Microbiology and Immunology, Drexel University College of Medicine, Philadelphia, PA, USA
- Department of Medicine, Division of Infectious Diseases and HIV Medicine, Drexel University College of Medicine, Philadelphia, PA, USA
| | - Emily Konopka
- Department of Microbiology and Immunology, Drexel University College of Medicine, Philadelphia, PA, USA
- Department of Medicine, Division of Infectious Diseases and HIV Medicine, Drexel University College of Medicine, Philadelphia, PA, USA
| | - Matthew Bell
- Department of Microbiology and Immunology, Drexel University College of Medicine, Philadelphia, PA, USA
- Department of Medicine, Division of Infectious Diseases and HIV Medicine, Drexel University College of Medicine, Philadelphia, PA, USA
| | - David Joyner
- Department of Medicine, Division of Infectious Diseases and HIV Medicine, Drexel University College of Medicine, Philadelphia, PA, USA
- Department of Molecular and Cellular Biology, Drexel University College of Medicine, Philadelphia, PA, USA
| | - Jennifer Marcy
- Department of Molecular and Cellular Biology, Drexel University College of Medicine, Philadelphia, PA, USA
| | - Virginie Tardif
- Department of Medicine, Division of Infectious Diseases and HIV Medicine, Drexel University College of Medicine, Philadelphia, PA, USA
| | - Michele A. Kutzler
- Department of Microbiology and Immunology, Drexel University College of Medicine, Philadelphia, PA, USA
- Department of Medicine, Division of Infectious Diseases and HIV Medicine, Drexel University College of Medicine, Philadelphia, PA, USA
| | - Roshell Muir
- Department of Medicine, Division of Infectious Diseases and HIV Medicine, Drexel University College of Medicine, Philadelphia, PA, USA
- Department of Family, Community, and Preventative Medicine, Drexel University College of Medicine, Philadelphia, PA, USA
| | - Elias K. Haddad
- Department of Microbiology and Immunology, Drexel University College of Medicine, Philadelphia, PA, USA
- Department of Medicine, Division of Infectious Diseases and HIV Medicine, Drexel University College of Medicine, Philadelphia, PA, USA
| |
Collapse
|
|
2
|
Coombs KM, Simon PF, McLeish NJ, Zahedi-Amiri A, Kobasa D. Aptamer Profiling of A549 Cells Infected with Low-Pathogenicity and High-Pathogenicity Influenza Viruses. Viruses 2019; 11:v11111028. [PMID: 31694171 PMCID: PMC6893437 DOI: 10.3390/v11111028] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2019] [Revised: 10/30/2019] [Accepted: 11/04/2019] [Indexed: 12/17/2022] Open
Abstract
Influenza A viruses (IAVs) are important animal and human emerging and re-emerging pathogens that are responsible for yearly seasonal epidemics and sporadic pandemics. IAVs cause a wide range of clinical illnesses, from relatively mild infections by seasonal strains, to acute respiratory distress during infections with highly pathogenic avian IAVs (HPAI). For this study, we infected A549 human lung cells with lab prototype A/PR/8/34 (H1N1) (PR8), a seasonal H1N1 (RV733), the 2009 pandemic H1N1 (pdm09), or with two avian strains, an H5N1 HPAI strain or an H7N9 strain that has low pathogenicity in birds but high pathogenicity in humans. We used a newly-developed aptamer-based multiplexed technique (SOMAscan®) to examine >1300 human lung cell proteins affected by the different IAV strains, and identified more than 500 significantly dysregulated cellular proteins. Our analyses indicated that the avian strains induced more profound changes in the A549 global proteome compared to all tested low-pathogenicity H1N1 strains. The PR8 strain induced a general activation, primarily by upregulating many immune molecules, the seasonal RV733 and pdm09 strains had minimal effect upon assayed molecules, and the avian strains induced significant downregulation, primarily in antimicrobial response, cardiovascular and post-translational modification systems.
Collapse
Affiliation(s)
- Kevin M. Coombs
- Department of Medical Microbiology & Infectious Diseases, University of Manitoba, Winnipeg, MB R3E 0J9, Canada (A.Z.-A.); (D.K.)
- Manitoba Centre for Proteomics & Systems Biology, University of Manitoba, Winnipeg, MB R3E 3P4, Canada
- Children’s Hospital Research Institute of Manitoba, University of Manitoba, Winnipeg, MB R3E 3P4, Canada
- Correspondence: ; Tel.: +1-204-7893-976
| | - Philippe F. Simon
- Department of Medical Microbiology & Infectious Diseases, University of Manitoba, Winnipeg, MB R3E 0J9, Canada (A.Z.-A.); (D.K.)
- Special Pathogen Program, National Microbiology Laboratory, Public Health Agency of Canada, Winnipeg, MB R3E 3R2, Canada
| | - Nigel J. McLeish
- Department of Medical Microbiology & Infectious Diseases, University of Manitoba, Winnipeg, MB R3E 0J9, Canada (A.Z.-A.); (D.K.)
| | - Ali Zahedi-Amiri
- Department of Medical Microbiology & Infectious Diseases, University of Manitoba, Winnipeg, MB R3E 0J9, Canada (A.Z.-A.); (D.K.)
- Manitoba Centre for Proteomics & Systems Biology, University of Manitoba, Winnipeg, MB R3E 3P4, Canada
| | - Darwyn Kobasa
- Department of Medical Microbiology & Infectious Diseases, University of Manitoba, Winnipeg, MB R3E 0J9, Canada (A.Z.-A.); (D.K.)
- Special Pathogen Program, National Microbiology Laboratory, Public Health Agency of Canada, Winnipeg, MB R3E 3R2, Canada
| |
Collapse
|
|
3
|
Bao S, Jia L, Zhou X, Zhang ZG, Wu HWL, Yu Z, Ng G, Fan Y, Wong DSM, Huang S, Wang To KK, Yuen KY, Yeung ML, Song YQ. Integrated analysis of mRNA-seq and miRNA-seq for host susceptibilities to influenza A (H7N9) infection in inbred mouse lines. Funct Integr Genomics 2018; 18:411-424. [PMID: 29564647 DOI: 10.1007/s10142-018-0602-3] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2018] [Accepted: 03/12/2018] [Indexed: 02/05/2023]
Abstract
Host genetic factors play an important role in diverse host outcomes after influenza A (H7N9) infection. Studying differential responses of inbred mouse lines with distinct genetic backgrounds to influenza virus infection could substantially increase our understanding of the contributory roles of host genetic factors to disease severity. Here, we utilized an integrated approach of mRNA-seq and miRNA-seq to investigate the transcriptome expression and regulation of host genes in C57BL/6J and DBA/2J mouse strains during influenza virus infection. The differential pathogenicity of influenza virus in C57BL/6J and DBA/2J has been fully demonstrated through immunohistochemical staining, histopathological analyses, and viral replication assessment. A transcriptional molecular signature correlates to differential host response to infection has been uncovered. With the introduction of temporal expression pattern analysis, we demonstrated that host factors responsible for influenza virus replication and host-virus interaction were significantly enriched in genes exhibiting distinct temporal dynamics between different inbred mouse lines. A combination of time-series expression analysis and temporal expression pattern analysis has provided a list of promising candidate genes for future studies. An integrated miRNA regulatory network from both mRNA-seq and miRNA-seq revealed several regulatory modules responsible for regulating host susceptibilities and disease severity. Overall, a comprehensive framework for analyzing host susceptibilities to influenza infection was established by integrating mRNA-seq and miRNA-seq data of inbred mouse lines. This work suggests novel putative molecular targets for therapeutic interventions in seasonal and pandemic influenza.
Collapse
Affiliation(s)
- Suying Bao
- Schoolof Biomedical Sciences, The University of Hong Kong, Hong Kong, China
| | - Lilong Jia
- Department of Microbiology, The University of Hong Kong, Hong Kong, China
| | - Xueya Zhou
- Department of Psychiatry, The University of Hong Kong, Hong Kong, China
| | - Zhi-Gang Zhang
- Schoolof Biomedical Sciences, The University of Hong Kong, Hong Kong, China
| | - Hazel Wai Lan Wu
- Department of Microbiology, The University of Hong Kong, Hong Kong, China
| | - Zhe Yu
- Schoolof Biomedical Sciences, The University of Hong Kong, Hong Kong, China
| | - Gordon Ng
- Schoolof Biomedical Sciences, The University of Hong Kong, Hong Kong, China
| | - Yanhui Fan
- Schoolof Biomedical Sciences, The University of Hong Kong, Hong Kong, China
| | - Dana S M Wong
- Schoolof Biomedical Sciences, The University of Hong Kong, Hong Kong, China
| | - Shishu Huang
- Department of Orthopedic Surgery, West China Hospital, Sichuan University, Chengdu, China
| | - Kelvin Kai Wang To
- Department of Microbiology, The University of Hong Kong, Hong Kong, China
| | - Kwok-Yung Yuen
- Department of Microbiology, The University of Hong Kong, Hong Kong, China
| | - Man Lung Yeung
- Department of Microbiology, The University of Hong Kong, Hong Kong, China.
| | - You-Qiang Song
- Schoolof Biomedical Sciences, The University of Hong Kong, Hong Kong, China.
- Department of Psychiatry, The University of Hong Kong, Hong Kong, China.
- HKU-SIRI/ZIRI, The University of Hong Kong, Hong Kong, China.
- HKU-SUSTech Joint Laboratories of Matrix Biology and Diseases, The University of Hong Kong, Hong Kong, China.
| |
Collapse
|
|
4
|
Zheng Y, Lou X, Yang P, Shi W, Chu Y, Yan M, Jiang C, Wu D, Pan Y, Zhao J, Li Y, Dong Y, Chen L, Liu S, Wang Q. Proteomic Analysis of Avian Influenza A (H7N9) Patients within a Family Cluster. J Glob Infect Dis 2018; 10:58-66. [PMID: 29910565 PMCID: PMC5987373 DOI: 10.4103/jgid.jgid_159_16] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/02/2022] Open
Abstract
Background: To date, there is limited information on the progression of human infections of avian influenza virus A (H7N9). This study investigated differential blood protein profiling of a H7N9-infected family cluster to find a slice of crucial proteins concerning disease attack and virus clearance. Materials and Methods: Plasma samples from one family cluster (including one index case and one asymptomatic case) were collected at four time points. The protein profiles were identified by isobaric tagging for relative and absolute quantification-based quantitative differential LC/MS/MS, and their functional annotations were analyzed by PANTHER and STRING tools. Results: A total of 1257 nonredundant proteins were identified from 3027 unique peptides. Three differential protein profiles for each subject were generated by comparing relative protein abundance between samples of each of the first three time points and the last time point. Gene ontology analysis indicated that differential protein profiles for the two cases were mainly enriched in the biological processes of response to stimulus, immunity, blood coagulation, lipid transport, and cell adhesion. Two groups of proteins with an upward or downward expression change according to the postinfection time points were detected for each case. STRING analysis further indicated that the hubs in the network of these time-dependent proteins were mostly apolipoproteins. Conclusions: Significant perturbation of the response upon viral infection occurred immediately after confirmation of H7N9 virus infection. The differential protein profiles shed further light on distinguishing the index case from the asymptomatic one. Furthermore, apolipoproteins may play an important role in the progression of the disease.
Collapse
Affiliation(s)
- Yang Zheng
- Institute for Infectious Disease and Endemic Disease Control, Beijing Center for Disease Prevention and Control, Beijing, China.,Research Center for Preventive Medicine of Beijing, Beijing, China
| | - Xiaomin Lou
- Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing, China
| | - Peng Yang
- Institute for Infectious Disease and Endemic Disease Control, Beijing Center for Disease Prevention and Control, Beijing, China.,Research Center for Preventive Medicine of Beijing, Beijing, China
| | - Weixian Shi
- Institute for Infectious Disease and Endemic Disease Control, Beijing Center for Disease Prevention and Control, Beijing, China.,Research Center for Preventive Medicine of Beijing, Beijing, China
| | - Yanda Chu
- Beijing Protein Innovation, Beijing, China
| | | | | | - Di Wu
- Beijing Protein Innovation, Beijing, China
| | - Yang Pan
- Institute for Infectious Disease and Endemic Disease Control, Beijing Center for Disease Prevention and Control, Beijing, China.,Research Center for Preventive Medicine of Beijing, Beijing, China
| | - Jiachen Zhao
- Institute for Infectious Disease and Endemic Disease Control, Beijing Center for Disease Prevention and Control, Beijing, China.,Research Center for Preventive Medicine of Beijing, Beijing, China
| | - Yang Li
- Beijing Protein Innovation, Beijing, China
| | | | - Lijuan Chen
- Institute for Infectious Disease and Endemic Disease Control, Beijing Center for Disease Prevention and Control, Beijing, China.,Research Center for Preventive Medicine of Beijing, Beijing, China
| | - Siqi Liu
- Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing, China.,Beijing Protein Innovation, Beijing, China
| | - Quanyi Wang
- Institute for Infectious Disease and Endemic Disease Control, Beijing Center for Disease Prevention and Control, Beijing, China.,Research Center for Preventive Medicine of Beijing, Beijing, China
| |
Collapse
|
|
5
|
Na-Ek P, Thewsoongnoen J, Thanunchai M, Wiboon-Ut S, Sa-Ard-Iam N, Mahanonda R, Thitithanyanont A. The activation of B cells enhances DC-SIGN expression and promotes susceptibility of B cells to HPAI H5N1 infection. Biochem Biophys Res Commun 2017; 490:1301-1306. [PMID: 28688767 DOI: 10.1016/j.bbrc.2017.07.017] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2017] [Accepted: 07/04/2017] [Indexed: 11/30/2022]
Abstract
The interplay between highly pathogenic avian influenza (HPAI) H5N1 virus and immune cells has been extensively studied for years, as host immune components are thought to play significant roles in promoting the systemic spread of the virus and responsible for cytokine storm. Previous studies suggested that the interaction of B cells and monocytes could promote HPAI H5N1 infection by enhancing avian influenza virus receptor expression. In this study, we further investigate the relationship between the HPAI H5N1 virus, activated B cells, and DC-SIGN expression. DC-SIGN has been described as an important factor for mediating various types of viral infection. Here, we first demonstrate that HPAI H5N1 infection could induce an activation of B cells, which was associated with DC-SIGN expression. Using CD40L and recombinant IL-4 for B cell stimulation, we determined that DC-SIGN expressed on activated B cells was able to enhance its susceptibility to HPAI H5N1 infection. Our findings uncover the interplay between this H5N1 virus and B cells and provide important information in understanding how the virus overcomes our immune system, contributing to its unusual immunopathogenesis.
Collapse
Affiliation(s)
- Prasit Na-Ek
- Department of Microbiology, Faculty of Science, Mahidol University, Bangkok, Thailand
| | - Jutarat Thewsoongnoen
- Department of Microbiology, Faculty of Science, Mahidol University, Bangkok, Thailand
| | - Maytawan Thanunchai
- Department of Clinical Pathology, Faculty of Medicine Vajira Hospital, Navamindradhiraj University, Bangkok, Thailand
| | - Suwimon Wiboon-Ut
- Department of Microbiology, Faculty of Science, Mahidol University, Bangkok, Thailand
| | - Noppadol Sa-Ard-Iam
- Department of Periodontology, Faculty of Dentistry, Chulalongkorn University, Bangkok, Thailand
| | - Rangsini Mahanonda
- Department of Periodontology, Faculty of Dentistry, Chulalongkorn University, Bangkok, Thailand
| | | |
Collapse
|
|
6
|
Abstract
Viral infections are a major burden to human and animal health. Immune response against viruses consists of innate and adaptive immunity which are both critical for the eradication of the viral infection. The innate immune system is the first line of defense against viral infections. Proper innate immune response is required for the activation of adaptive, humoral and cell-mediated immunity. Macrophages are innate immune cells which have a central role in detecting viral infections including influenza A and human immunodeficiency viruses. Macrophages and other host cells respond to viral infection by modulating their protein expression levels, proteins' posttranslational modifications, as well as proteins' intracellular localization and secretion. Therefore the detailed characterization how viruses dynamically manipulate host proteome is needed for understanding the molecular mechanisms of viral infection. It is critical to identify cellular host factors which are exploited by different viruses, and which are less prone for mutations and could serve as potential targets for novel antiviral compounds. Here, we review how proteomics studies have enhanced our understanding of macrophage response to viral infection with special focus on Influenza A and Human immunodeficiency viruses, and virus infections of swine. SIGNIFICANCE Influenza A viruses (IAVs) and human immunodeficiency viruses (HIV) infect annually millions of people worldwide and they form a severe threat to human health. Both IAVs and HIV-1 can efficiently antagonize host response and develop drug-resistant variants. Most current antiviral drugs are directed against viral proteins, and there is a constant need to develop new next-generation drugs targeting host proteins that are essential for viral replication. Porcine reproductive and respiratory syndrome virus (PRRSV) and porcine circovirus type 2 (PCV2) are economically important swine pathogens. Both PRRSV and PCV2 cause severe respiratory tract illnesses in swine. IAVs, HIV-1, and swine viruses infect macrophages activating antiviral response against these viruses. Macrophages also have a central role in the replication and spread of these viruses. However, macrophage response to these viruses is incompletely understood. Current proteomics methods can provide a global view of host-response to viral infection which is needed for in-depth understanding the molecular mechanisms of viral infection. Here we review the current proteomics studies on macrophage response to viral infection and provide insight into the global host proteome changes upon viral infection.
Collapse
Affiliation(s)
- Tuula A Nyman
- Department of Immunology, Institute of Clinical Medicine, University of Oslo and Rikshospitalet Oslo, Oslo, Norway.
| | - Sampsa Matikainen
- University of Helsinki and Helsinki University Hospital, Rheumatology, Helsinki, Finland
| |
Collapse
|
|
7
|
Wani SA, Sahu AR, Saxena S, Hussain S, Pandey A, Kanchan S, Sahoo AP, Mishra B, Tiwari AK, Mishra BP, Gandham RK, Singh RK. Systems biology approach: Panacea for unravelling host-virus interactions and dynamics of vaccine induced immune response. GENE REPORTS 2016; 5:23-29. [PMID: 32289096 PMCID: PMC7104209 DOI: 10.1016/j.genrep.2016.08.002] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2016] [Revised: 06/24/2016] [Accepted: 08/01/2016] [Indexed: 12/18/2022]
Abstract
Systems biology is an interdisciplinary research field in life sciences, which involves a comprehensive and quantitative analysis of the interactions between all of the components of biological systems over time. For the past 50 years the discipline of virology has overly focused on the pathogen itself. However, we now know that the host response is equally or more important in defining the eventual pathological outcome of infection. Systems biology has in recent years been increasingly recognised for its importance to infectious disease research. Host-virus interactions can be better understood by taking into account the dynamical molecular networks that constitute a biological system. To decipher the pathobiological mechanisms of any disease requires a deep knowledge of how multiple and concurrent signal-transduction pathways operate and are deregulated. Hence the intricacies of signalling pathways can be dissected only by system level approaches.
Deciphering the host virus interactions through system biology approach reviewed High throughput techniques to understand the host pathogen interactions examined Shift from virus-centric perspective to spectrum of virus-host interactions Modeling of host-virus cross talk
Collapse
Affiliation(s)
- Sajad Ahmad Wani
- Division of Veterinary Biotechnology, ICAR-Indian Veterinary Research Institute, Izatnagar 243122, India
| | - Amit Ranjan Sahu
- Division of Veterinary Biotechnology, ICAR-Indian Veterinary Research Institute, Izatnagar 243122, India
| | - Shikha Saxena
- Division of Veterinary Biotechnology, ICAR-Indian Veterinary Research Institute, Izatnagar 243122, India
| | - Shahid Hussain
- Division of Veterinary Biotechnology, ICAR-Indian Veterinary Research Institute, Izatnagar 243122, India
| | - Aruna Pandey
- Division of Veterinary Biotechnology, ICAR-Indian Veterinary Research Institute, Izatnagar 243122, India
| | - Sonam Kanchan
- Division of Veterinary Biotechnology, ICAR-Indian Veterinary Research Institute, Izatnagar 243122, India
| | - Aditya Prasad Sahoo
- Division of Veterinary Biotechnology, ICAR-Indian Veterinary Research Institute, Izatnagar 243122, India
| | - Bina Mishra
- Division of Biological Products, ICAR-Indian Veterinary Research Institute, Izatnagar 243122, India
| | - Ashok Kumar Tiwari
- Division of Biological Standardization, ICAR-Indian Veterinary Research Institute, Izatnagar 243122, India
| | - Bishnu Prasad Mishra
- Division of Veterinary Biotechnology, ICAR-Indian Veterinary Research Institute, Izatnagar 243122, India
| | - Ravi Kumar Gandham
- Division of Veterinary Biotechnology, ICAR-Indian Veterinary Research Institute, Izatnagar 243122, India
| | - Raj Kumar Singh
- Division of Veterinary Biotechnology, ICAR-Indian Veterinary Research Institute, Izatnagar 243122, India
| |
Collapse
|
|
8
|
Ding X, Lu J, Yu R, Wang X, Wang T, Dong F, Peng B, Wu W, Liu H, Geng Y, Zhang R, Ma H, Cheng J, Yu M, Fang S. Preliminary Proteomic Analysis of A549 Cells Infected with Avian Influenza Virus H7N9 and Influenza A Virus H1N1. PLoS One 2016; 11:e0156017. [PMID: 27223893 PMCID: PMC4880285 DOI: 10.1371/journal.pone.0156017] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/01/2016] [Accepted: 05/09/2016] [Indexed: 11/18/2022] Open
Abstract
A newly emerged H7N9 influenza virus poses high risk to human beings. However, the pathogenic mechanism of the virus remains unclear. The temporal response of primary human alveolar adenocarcinoma epithelial cells (A549) infected with H7N9 influenza virus and H1N1 influenza A virus (H1N1, pdm09) were evaluated using the proteomics approaches (2D-DIGE combined with MALDI-TOF-MS/MS) at 24, 48 and 72 hours post of the infection (hpi). There were 11, 12 and 33 proteins with significant different expressions (P<0.05) at 24, 48 and 72hpi, especially F-actin-capping protein subunit alpha-1 (CAPZA1), Ornithine aminotransferase (OAT), Poly(rC)-binding protein 1 (PCBP1), Eukaryotic translation initiation factor 5A-1 (EIF5A) and Platelet-activating factor acetylhydrolaseⅠb subunit beta (PAFAH1B2) were validated by western-blot analysis. The functional analysis revealed that the differential proteins in A549 cells involved in regulating cytopathic effect. Among them, the down-regulation of CAPZA1, OAT, PCBP1, EIF5A are related to the death of cells infected by H7N9 influenza virus. This is the first time show that the down-regulation of PAFAH1B2 is related to the later clinical symptoms of patients infected by H7N9 influenza virus. These findings may improve our understanding of pathogenic mechanism of H7N9 influenza virus in proteomics.
Collapse
Affiliation(s)
- Xiaoman Ding
- School of Public Health, Sun Yat-sen University, Guangzhou, China
| | - Jiahai Lu
- School of Public Health, Sun Yat-sen University, Guangzhou, China
| | - Ruoxi Yu
- Southern Medical University, Guangzhou, China
| | - Xin Wang
- Major Infectious Disease Control Key Laboratory, Key Reference Laboratory of Pathogen and Biosafety, Shenzhen Center for Disease Control and Prevention, Shenzhen, China
| | - Ting Wang
- Nanshan Center for Disease Control and Prevention, Shenzhen, China
| | - Fangyuan Dong
- Major Infectious Disease Control Key Laboratory, Key Reference Laboratory of Pathogen and Biosafety, Shenzhen Center for Disease Control and Prevention, Shenzhen, China
| | - Bo Peng
- Major Infectious Disease Control Key Laboratory, Key Reference Laboratory of Pathogen and Biosafety, Shenzhen Center for Disease Control and Prevention, Shenzhen, China
| | - Weihua Wu
- Major Infectious Disease Control Key Laboratory, Key Reference Laboratory of Pathogen and Biosafety, Shenzhen Center for Disease Control and Prevention, Shenzhen, China
| | - Hui Liu
- Major Infectious Disease Control Key Laboratory, Key Reference Laboratory of Pathogen and Biosafety, Shenzhen Center for Disease Control and Prevention, Shenzhen, China
| | - Yijie Geng
- Major Infectious Disease Control Key Laboratory, Key Reference Laboratory of Pathogen and Biosafety, Shenzhen Center for Disease Control and Prevention, Shenzhen, China
| | - Renli Zhang
- Major Infectious Disease Control Key Laboratory, Key Reference Laboratory of Pathogen and Biosafety, Shenzhen Center for Disease Control and Prevention, Shenzhen, China
| | - Hanwu Ma
- Major Infectious Disease Control Key Laboratory, Key Reference Laboratory of Pathogen and Biosafety, Shenzhen Center for Disease Control and Prevention, Shenzhen, China
| | - Jinquan Cheng
- Major Infectious Disease Control Key Laboratory, Key Reference Laboratory of Pathogen and Biosafety, Shenzhen Center for Disease Control and Prevention, Shenzhen, China
| | - Muhua Yu
- Nanshan Center for Disease Control and Prevention, Shenzhen, China
- * E-mail: (MHY); (SSF)
| | - Shisong Fang
- Major Infectious Disease Control Key Laboratory, Key Reference Laboratory of Pathogen and Biosafety, Shenzhen Center for Disease Control and Prevention, Shenzhen, China
- * E-mail: (MHY); (SSF)
| |
Collapse
|
|
9
|
Marion T, Elbahesh H, Thomas PG, DeVincenzo JP, Webby R, Schughart K. Respiratory Mucosal Proteome Quantification in Human Influenza Infections. PLoS One 2016; 11:e0153674. [PMID: 27088501 PMCID: PMC4835085 DOI: 10.1371/journal.pone.0153674] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2015] [Accepted: 04/01/2016] [Indexed: 01/08/2023] Open
Abstract
Respiratory influenza virus infections represent a serious threat to human health. Underlying medical conditions and genetic make-up predispose some influenza patients to more severe forms of disease. To date, only a few studies have been performed in patients to correlate a selected group of cytokines and chemokines with influenza infection. Therefore, we evaluated the potential of a novel multiplex micro-proteomics technology, SOMAscan, to quantify proteins in the respiratory mucosa of influenza A and B infected individuals. The analysis included but was not limited to quantification of cytokines and chemokines detected in previous studies. SOMAscan quantified more than 1,000 secreted proteins in small nasal wash volumes from infected and healthy individuals. Our results illustrate the utility of micro-proteomic technology for analysis of proteins in small volumes of respiratory mucosal samples. Furthermore, when we compared nasal wash samples from influenza-infected patients with viral load ≥ 28 and increased IL-6 and CXCL10 to healthy controls, we identified 162 differentially-expressed proteins between the two groups. This number greatly exceeds the number of DEPs identified in previous studies in human influenza patients. Most of the identified proteins were associated with the host immune response to infection, and changes in protein levels of 151 of the DEPs were significantly correlated with viral load. Most important, SOMAscan identified differentially expressed proteins heretofore not associated with respiratory influenza infection in humans. Our study is the first report for the use of SOMAscan to screen nasal secretions. It establishes a precedent for micro-proteomic quantification of proteins that reflect ongoing response to respiratory infection.
Collapse
Affiliation(s)
- Tony Marion
- University of Tennessee Health Science Center, Department of Microbiology, Immunology and Biochemistry, Memphis, United States of America
| | - Husni Elbahesh
- University of Tennessee Health Science Center, Department of Microbiology, Immunology and Biochemistry, Memphis, United States of America
| | - Paul G. Thomas
- Department of Immunology, St. Jude Children’s Research Hospital, Memphis, United States of America
| | - John P. DeVincenzo
- University of Tennessee Health Science Center, Department of Microbiology, Immunology and Biochemistry, Memphis, United States of America
- University of Tennessee Health Science Center, Department of Pediatrics, Memphis, United States of America
- Children’s Foundation Research Center at Le Bonheur Children’s Hospital, Memphis, United States of America
| | - Richard Webby
- Department of Infectious Diseases, St Jude Children’s Research Hospital, Memphis, United States of America
| | - Klaus Schughart
- University of Tennessee Health Science Center, Department of Microbiology, Immunology and Biochemistry, Memphis, United States of America
- Department of Infection Genetics, Helmholtz Centre for Infection Research, Braunschweig, Germany
- University of Veterinary Medicine Hannover, Hannover, Germany
- * E-mail:
| |
Collapse
|
|
10
|
Tripathi S, Garcia-Sastre A. Antiviral innate immunity through the lens of systems biology. Virus Res 2015; 218:10-7. [PMID: 26657882 DOI: 10.1016/j.virusres.2015.11.024] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2015] [Accepted: 11/30/2015] [Indexed: 12/25/2022]
Abstract
Cellular innate immunity poses the first hurdle against invading viruses in their attempt to establish infection. This antiviral response is manifested with the detection of viral components by the host cell, followed by transduction of antiviral signals, transcription and translation of antiviral effectors and leads to the establishment of an antiviral state. These events occur in a rather branched and interconnected sequence than a linear path. Traditionally, these processes were studied in the context of a single virus and a host component. However, with the advent of rapid and affordable OMICS technologies it has become feasible to address such questions on a global scale. In the discipline of Systems Biology', extensive omics datasets are assimilated using computational tools and mathematical models to acquire deeper understanding of complex biological processes. In this review we have catalogued and discussed the application of Systems Biology approaches in dissecting the antiviral innate immune responses.
Collapse
Affiliation(s)
- Shashank Tripathi
- Department of Microbiology, Icahn School of Medicine at Mount Sinai, NY, USA; Global Health and Emerging Pathogens Institute, Icahn School of Medicine at Mount Sinai, NY, USA
| | - Adolfo Garcia-Sastre
- Department of Microbiology, Icahn School of Medicine at Mount Sinai, NY, USA; Global Health and Emerging Pathogens Institute, Icahn School of Medicine at Mount Sinai, NY, USA; Department of Medicine, Division of Infectious Diseases, Icahn School of Medicine at Mount Sinai, NY, USA.
| |
Collapse
|
|
11
|
Simon PF, McCorrister S, Hu P, Chong P, Silaghi A, Westmacott G, Coombs KM, Kobasa D. Highly Pathogenic H5N1 and Novel H7N9 Influenza A Viruses Induce More Profound Proteomic Host Responses than Seasonal and Pandemic H1N1 Strains. J Proteome Res 2015; 14:4511-23. [PMID: 26381135 DOI: 10.1021/acs.jproteome.5b00196] [Citation(s) in RCA: 46] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Influenza A viruses (IAV) are important human and animal pathogens with potential for causing pandemics. IAVs exhibit a wide spectrum of clinical illness in humans, from relatively mild infections by seasonal strains to acute respiratory distress syndrome during infections with some highly pathogenic avian influenza (HPAI) viruses. In the present study, we infected A549 human cells with seasonal H1N1 (sH1N1), 2009 pandemic H1N1 (pdmH1N1), or novel H7N9 and HPAI H5N1 strains. We used multiplexed isobaric tags for relative and absolute quantification to measure proteomic host responses to these different strains at 1, 3, and 6 h post-infection. Our analyses revealed that both H7N9 and H5N1 strains induced more profound changes to the A549 global proteome compared to those with low-pathogenicity H1N1 virus infection, which correlates with the higher pathogenicity these strains exhibit at the organismal level. Bioinformatics analysis revealed important modulation of the nuclear factor erythroid 2-related factor 2 (NRF2) oxidative stress response in infection. Cellular fractionation and Western blotting suggested that the phosphorylated form of NRF2 is not imported to the nucleus in H5N1 and H7N9 virus infections. Fibronectin was also strongly inhibited in infection with H5N1 and H7N9 strains. This is the first known comparative proteomic study of the host response to H7N9, H5N1, and H1N1 viruses and the first time NRF2 is shown to be implicated in infection with highly pathogenic strains of influenza.
Collapse
Affiliation(s)
- Philippe François Simon
- Department of Medical Microbiology and Infectious Diseases, University of Manitoba , Winnipeg, Manitoba, R3E 0J9 Canada
| | | | - Pingzhao Hu
- Department of Biochemistry and Medical Genetics, University of Manitoba , Winnipeg, Manitoba, R3T 2N2 Canada
| | | | - Alex Silaghi
- Department of Medical Microbiology and Infectious Diseases, University of Manitoba , Winnipeg, Manitoba, R3E 0J9 Canada
| | | | - Kevin M Coombs
- Department of Medical Microbiology and Infectious Diseases, University of Manitoba , Winnipeg, Manitoba, R3E 0J9 Canada.,Manitoba Center for Proteomics and Systems Biology, University of Manitoba , Winnipeg, Manitoba, R3E 3P4 Canada
| | - Darwyn Kobasa
- Department of Medical Microbiology and Infectious Diseases, University of Manitoba , Winnipeg, Manitoba, R3E 0J9 Canada
| |
Collapse
|
|
12
|
Abstract
Systems-level analysis of biological processes strives to comprehensively and quantitatively evaluate the interactions between the relevant molecular components over time, thereby enabling development of models that can be employed to ultimately predict behavior. Rapid development in measurement technologies (omics), when combined with the accessible nature of the cellular constituents themselves, is allowing the field of innate immunity to take significant strides toward this lofty goal. In this review, we survey exciting results derived from systems biology analyses of the immune system, ranging from gene regulatory networks to influenza pathogenesis and systems vaccinology.
Collapse
|
|
13
|
Arilahti V, Mäkelä SM, Tynell J, Julkunen I, Österlund P. Novel avian influenza A (H7N9) virus induces impaired interferon responses in human dendritic cells. PLoS One 2014; 9:e96350. [PMID: 24804732 PMCID: PMC4012951 DOI: 10.1371/journal.pone.0096350] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2014] [Accepted: 04/07/2014] [Indexed: 01/01/2023] Open
Abstract
In March 2013 a new avian influenza A(H7N9) virus emerged in China and infected humans with a case fatality rate of over 30%. Like the highly pathogenic H5N1 virus, H7N9 virus is causing severe respiratory distress syndrome in most patients. Based on genetic analysis this avian influenza A virus shows to some extent adaptation to mammalian host. In the present study, we analyzed the activation of innate immune responses by this novel H7N9 influenza A virus and compared these responses to those induced by the avian H5N1 and seasonal H3N2 viruses in human monocyte-derived dendritic cells (moDCs). We observed that in H7N9 virus-infected cells, interferon (IFN) responses were weak although the virus replicated as well as the H5N1 and H3N2 viruses in moDCs. H7N9 virus-induced expression of pro-inflammatory cytokines remained at a significantly lower level as compared to H5N1 virus-induced “cytokine storm” seen in human moDCs. However, the H7N9 virus was extremely sensitive to the antiviral effects of IFN-α and IFN-β in pretreated cells. Our data indicates that different highly pathogenic avian viruses may show considerable differences in their ability to induce host antiviral responses in human primary cell models such as moDCs. The unexpected appearance of the novel H7N9 virus clearly emphasizes the importance of the global influenza surveillance system. It is, however, equally important to systematically characterize in normal human cells the replication capacity of the new viruses and their ability to induce and respond to natural antiviral substances such as IFNs.
Collapse
Affiliation(s)
- Veera Arilahti
- Virology Unit, National Institute for Health and Welfare, Helsinki, Finland
| | - Sanna M. Mäkelä
- Virology Unit, National Institute for Health and Welfare, Helsinki, Finland
| | - Janne Tynell
- Virology Unit, National Institute for Health and Welfare, Helsinki, Finland
| | - Ilkka Julkunen
- Virology Unit, National Institute for Health and Welfare, Helsinki, Finland
- Department of Virology, University of Turku, Turku, Finland
| | - Pamela Österlund
- Virology Unit, National Institute for Health and Welfare, Helsinki, Finland
- * E-mail:
| |
Collapse
|
|
14
|
Bos LDJ, de Jong MD, Sterk PJ, Schultz MJ. How integration of global omics-data could help preparing for pandemics - a scent of influenza. Front Genet 2014; 5:80. [PMID: 24795745 PMCID: PMC4000993 DOI: 10.3389/fgene.2014.00080] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2013] [Accepted: 03/25/2014] [Indexed: 01/14/2023] Open
Abstract
Pandemics caused by novel emerging or re-emerging infectious diseases could lead to high mortality and morbidity world-wide when left uncontrolled. In this perspective, we evaluate the possibility of integration of global omics-data in order to timely prepare for pandemics. Such an approach requires two major innovations. First, data that is obtained should be shared with the global community instantly. The strength of rapid integration of simple signals is exemplified by Google's(TM) Flu Trend, which could predict the incidence of influenza-like illness based on online search engine queries. Second, omics technologies need to be fast and high-throughput. We postulate that analysis of the exhaled breath would be a simple, rapid and non-invasive alternative. Breath contains hundreds of volatile organic compounds that are altered by infection and inflammation. The molecular fingerprint of breath (breathprint) can be obtained using an electronic nose, which relies on sensor technology. These breathprints can be stored in an online database (a "breathcloud") and coupled to clinical data. Comparison of the breathprint of a suspected subject to the breathcloud allows for a rapid decision on the presence or absence of a pathogen.
Collapse
Affiliation(s)
- Lieuwe D J Bos
- Department of Intensive Care Medicine, Academic Medical Center, University of Amsterdam Amsterdam, Netherlands ; Department of Respiratory Medicine, Academic Medical Center, University of Amsterdam Amsterdam, Netherlands ; Laboratory of Experimental Intensive Care and Anesthesiology, Academic Medical Center, University of Amsterdam Amsterdam, Netherlands
| | - Menno D de Jong
- Department of Medical Microbiology, Academic Medical Center, University of Amsterdam Amsterdam, Netherlands
| | - Peter J Sterk
- Department of Respiratory Medicine, Academic Medical Center, University of Amsterdam Amsterdam, Netherlands
| | - Marcus J Schultz
- Department of Intensive Care Medicine, Academic Medical Center, University of Amsterdam Amsterdam, Netherlands ; Laboratory of Experimental Intensive Care and Anesthesiology, Academic Medical Center, University of Amsterdam Amsterdam, Netherlands
| |
Collapse
|
|
15
|
Kroeker AL, Coombs KM. Systems biology unravels interferon responses to respiratory virus infections. World J Biol Chem 2014; 5:12-25. [PMID: 24600511 PMCID: PMC3942539 DOI: 10.4331/wjbc.v5.i1.12] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/10/2013] [Revised: 12/11/2013] [Accepted: 01/06/2014] [Indexed: 02/05/2023] Open
Abstract
Interferon production is an important defence against viral replication and its activation is an attractive therapeutic target. However, it has long been known that viruses perpetually evolve a multitude of strategies to evade these host immune responses. In recent years there has been an explosion of information on virus-induced alterations of the host immune response that have resulted from data-rich omics technologies. Unravelling how these systems interact and determining the overall outcome of the host response to viral infection will play an important role in future treatment and vaccine development. In this review we focus primarily on the interferon pathway and its regulation as well as mechanisms by which respiratory RNA viruses interfere with its signalling capacity.
Collapse
|
|
16
|
Josset L, Tisoncik-Go J, Katze MG. Moving H5N1 studies into the era of systems biology. Virus Res 2013; 178:151-67. [PMID: 23499671 PMCID: PMC3834220 DOI: 10.1016/j.virusres.2013.02.011] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2012] [Accepted: 02/24/2013] [Indexed: 12/20/2022]
Abstract
The dynamics of H5N1 influenza virus pathogenesis are multifaceted and can be seen as an emergent property that cannot be comprehended without looking at the system as a whole. In past years, most of the high-throughput studies on H5N1-host interactions have focused on the host transcriptomic response, at the cellular or the lung tissue level. These studies pointed out that the dynamics and magnitude of the innate immune response and immune cell infiltration is critical to H5N1 pathogenesis. However, viral-host interactions are multidimensional and advances in technologies are creating new possibilities to systematically measure additional levels of 'omic data (e.g. proteomic, metabolomic, and RNA profiling) at each temporal and spatial scale (from the single cell to the organism) of the host response. Natural host genetic variation represents another dimension of the host response that determines pathogenesis. Systems biology models of H5N1 disease aim at understanding and predicting pathogenesis through integration of these different dimensions by using intensive computational modeling. In this review, we describe the importance of 'omic studies for providing a more comprehensive view of infection and mathematical models that are being developed to integrate these data. This review provides a roadmap for what needs to be done in the future and what computational strategies should be used to build a global model of H5N1 pathogenesis. It is time for systems biology of H5N1 pathogenesis to take center stage as the field moves toward a more comprehensive view of virus-host interactions.
Collapse
Affiliation(s)
- Laurence Josset
- Department of Microbiology, School of Medicine, University of Washington, Seattle, WA 98195, United States
| | | | | |
Collapse
|
|
17
|
Tchitchek N, Eisfeld AJ, Tisoncik-Go J, Josset L, Gralinski LE, Bécavin C, Tilton SC, Webb-Robertson BJ, Ferris MT, Totura AL, Li C, Neumann G, Metz TO, Smith RD, Waters KM, Baric R, Kawaoka Y, Katze MG. Specific mutations in H5N1 mainly impact the magnitude and velocity of the host response in mice. BMC SYSTEMS BIOLOGY 2013; 7:69. [PMID: 23895213 PMCID: PMC3750405 DOI: 10.1186/1752-0509-7-69] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/14/2013] [Accepted: 06/27/2013] [Indexed: 11/10/2022]
Abstract
BACKGROUND Influenza infection causes respiratory disease that can lead to death. The complex interplay between virus-encoded and host-specific pathogenicity regulators - and the relative contributions of each toward viral pathogenicity - is not well-understood. RESULTS By analyzing a collection of lung samples from mice infected by A/Vietnam/1203/2004 (H5N1; VN1203), we characterized a signature of transcripts and proteins associated with the kinetics of the host response. Using a new geometrical representation method and two criteria, we show that inoculation concentrations and four specific mutations in VN1203 mainly impact the magnitude and velocity of the host response kinetics, rather than specific sets of up- and down- regulated genes. We observed analogous kinetic effects using lung samples from mice infected with A/California/04/2009 (H1N1), and we show that these effects correlate with morbidity and viral titer. CONCLUSIONS We have demonstrated the importance of the kinetics of the host response to H5N1 pathogenesis and its relationship with clinical disease severity and virus replication. These kinetic properties imply that time-matched comparisons of 'omics profiles to viral infections give limited views to differentiate host-responses. Moreover, these results demonstrate that a fast activation of the host-response at the earliest time points post-infection is critical for protective mechanisms against fast replicating viruses.
Collapse
Affiliation(s)
- Nicolas Tchitchek
- Department of Microbiology, University of Washington, Seattle, WA 98195 USA
| | - Amie J Eisfeld
- School of Veterinary Medicine, Department of Pathobiological Sciences, Influenza Research Institute, University of Wisconsin-Madison, Madison, WI, USA
| | | | - Laurence Josset
- Department of Microbiology, University of Washington, Seattle, WA 98195 USA
| | - Lisa E Gralinski
- Department of Microbiology and Immunology, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Christophe Bécavin
- Unité des Interactions Bactéries-Cellules, Institut Pasteur, 75015 Paris, France
| | - Susan C Tilton
- Biological Sciences Division, Pacific Northwest National Laboratory, Richland, WA, USA
| | | | - Martin T Ferris
- Department of Microbiology and Immunology, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Allison L Totura
- Department of Microbiology and Immunology, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Chengjun Li
- School of Veterinary Medicine, Department of Pathobiological Sciences, Influenza Research Institute, University of Wisconsin-Madison, Madison, WI, USA
| | - Gabriele Neumann
- School of Veterinary Medicine, Department of Pathobiological Sciences, Influenza Research Institute, University of Wisconsin-Madison, Madison, WI, USA
| | - Thomas O Metz
- Biological Sciences Division, Pacific Northwest National Laboratory, Richland, WA, USA
| | - Richard D Smith
- Biological Sciences Division, Pacific Northwest National Laboratory, Richland, WA, USA
| | - Katrina M Waters
- Biological Sciences Division, Pacific Northwest National Laboratory, Richland, WA, USA
| | - Ralph Baric
- Department of Microbiology and Immunology, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Yoshihiro Kawaoka
- School of Veterinary Medicine, Department of Pathobiological Sciences, Influenza Research Institute, University of Wisconsin-Madison, Madison, WI, USA
| | - Michael G Katze
- Department of Microbiology, University of Washington, Seattle, WA 98195 USA
- Washington National Primate Research Center, University of Washington, Seattle, WA, USA
| |
Collapse
|
|
18
|
Chan RWY, Chan MCW, Nicholls JM, Malik Peiris JS. Use of ex vivo and in vitro cultures of the human respiratory tract to study the tropism and host responses of highly pathogenic avian influenza A (H5N1) and other influenza viruses. Virus Res 2013; 178:133-45. [PMID: 23684848 DOI: 10.1016/j.virusres.2013.03.003] [Citation(s) in RCA: 38] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2012] [Revised: 02/24/2013] [Accepted: 03/05/2013] [Indexed: 12/27/2022]
Abstract
The tropism of influenza viruses for the human respiratory tract is a key determinant of host-range, and consequently, of pathogenesis and transmission. Insights can be obtained from clinical and autopsy studies of human disease and relevant animal models. Ex vivo cultures of the human respiratory tract and in vitro cultures of primary human cells can provide complementary information provided they are physiologically comparable in relevant characteristics to human tissues in vivo, e.g. virus receptor distribution, state of differentiation. We review different experimental models for their physiological relevance and summarize available data using these cultures in relation to highly pathogenic avian influenza H5N1, in comparison where relevant, with other influenza viruses. Transformed continuous cell-lines often differ in important ways to the corresponding tissues in vivo. The state of differentiation of primary human cells (respiratory epithelium, macrophages) can markedly affect virus tropism and host responses. Ex vivo cultures of human respiratory tissues provide a close resemblance to tissues in vivo and may be used to risk assess animal viruses for pandemic threat. Physiological factors (age, inflammation) can markedly affect virus receptor expression and virus tropism. Taken together with data from clinical studies on infected humans and relevant animal models, data from ex vivo and in vitro cultures of human tissues and cells can provide insights into virus transmission and pathogenesis and may provide understanding that leads to novel therapeutic interventions.
Collapse
Affiliation(s)
- Renee W Y Chan
- Department of Pathology, The University of Hong Kong, Hong Kong Special Administrative Region; Centre of Influenza Research, The University of Hong Kong, Hong Kong Special Administrative Region.
| | | | | | | |
Collapse
|
|
19
|
Abstract
Avian influenza virus infections in the human population are rare due to their inefficient direct human-to-human transmission. However, when humans are infected, a strong inflammatory response is usually induced, characterized by elevated levels of cytokines and chemokines in serum, believed to be important in the severe pathogenesis that develops in a high proportion of these patients. Extensive research has been performed to understand the molecular viral mechanisms involved in the H5N1 pathogenesis in humans, providing interesting insights about the virus-host interaction and the regulation of the innate immune response by these highly pathogenic viruses. In this review we summarize and discuss the most important findings in this field, focusing mainly on H5N1 virulence factors and their impact on the modulation of the innate immunity in humans.
Collapse
Affiliation(s)
- Irene Ramos
- Authors to whom correspondence should be addressed; (A.F.S.); (I.R.); Tel. +1-212-241-5182 (A.F.S.); +1-212 241-0994 (I.R.); Fax: +1-212-534-1684 (A.F.S.); +1-212-534-1684 (I.R.)
| | - Ana Fernandez-Sesma
- Authors to whom correspondence should be addressed; (A.F.S.); (I.R.); Tel. +1-212-241-5182 (A.F.S.); +1-212 241-0994 (I.R.); Fax: +1-212-534-1684 (A.F.S.); +1-212-534-1684 (I.R.)
| |
Collapse
|