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1
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Cherrak Y, Younes AA, Perez-Molphe-Montoya E, Maurer L, Yilmaz K, Enz U, Zeder C, Kiefer P, Christen P, Gül E, Vorholt JA, von Mering C, Hardt WD. Neutrophil recruitment during intestinal inflammation primes Salmonella elimination by commensal E. coli in a context-dependent manner. Cell Host Microbe 2025; 33:358-372.e4. [PMID: 40023150 DOI: 10.1016/j.chom.2025.02.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2024] [Revised: 12/19/2024] [Accepted: 02/05/2025] [Indexed: 03/04/2025]
Abstract
Foodborne bacterial diarrhea involves complex pathogen-microbiota-host interactions. Pathogen-displacing probiotics are increasingly popular, but heterogeneous patient outcomes highlighted the need to understand individualized host-probiotic activity. Using the mouse gut commensal Escherichia coli 8178 and the human probiotic E. coli Nissle 1917, we found that the degree of protection against the enteric pathogen Salmonella enterica serovar Typhimurium (S. Tm) varies across mice with distinct gut microbiotas. Pathogen clearance is linked to enteropathy severity and subsequent recruitment of intraluminal neutrophils, which differs in a microbiota-dependent manner. By combining mouse knockout and antibody-mediated depletion models with bacterial genetics, we show that neutrophils and host-derived reactive oxygen species directly influence E. coli-mediated S. Tm displacement by potentiating siderophore-bound toxin killing. Our work demonstrates how host immune factors shape pathogen-displacing probiotic efficiency while also revealing an unconventional antagonistic interaction where a gut commensal and the host synergize to displace an enteric pathogen.
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Affiliation(s)
- Yassine Cherrak
- Institute of Microbiology, Department of Biology, ETH Zurich, 8093 Zurich, Switzerland.
| | - Andrew Abi Younes
- Institute of Microbiology, Department of Biology, ETH Zurich, 8093 Zurich, Switzerland
| | - Eugenio Perez-Molphe-Montoya
- Department of Molecular Life Sciences and Swiss Institute of Bioinformatics, University of Zurich, 8057 Zurich, Switzerland
| | - Luca Maurer
- Institute of Microbiology, Department of Biology, ETH Zurich, 8093 Zurich, Switzerland
| | - Koray Yilmaz
- Institute of Microbiology, Department of Biology, ETH Zurich, 8093 Zurich, Switzerland
| | - Ursina Enz
- Institute of Microbiology, Department of Biology, ETH Zurich, 8093 Zurich, Switzerland
| | - Christophe Zeder
- Laboratory of Nutrition and Metabolic Epigenetics, Department of Health Science and Technology, 8092 Zurich, Switzerland
| | - Patrick Kiefer
- Institute of Microbiology, Department of Biology, ETH Zurich, 8093 Zurich, Switzerland
| | - Philipp Christen
- Institute of Microbiology, Department of Biology, ETH Zurich, 8093 Zurich, Switzerland
| | - Ersin Gül
- Institute of Microbiology, Department of Biology, ETH Zurich, 8093 Zurich, Switzerland
| | - Julia A Vorholt
- Institute of Microbiology, Department of Biology, ETH Zurich, 8093 Zurich, Switzerland
| | - Christian von Mering
- Department of Molecular Life Sciences and Swiss Institute of Bioinformatics, University of Zurich, 8057 Zurich, Switzerland
| | - Wolf-Dietrich Hardt
- Institute of Microbiology, Department of Biology, ETH Zurich, 8093 Zurich, Switzerland.
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2
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Feakins RM. Inflammatory disorders of the large intestine. MORSON AND DAWSON'S GASTROINTESTINAL PATHOLOGY 2024:709-857. [DOI: 10.1002/9781119423195.ch35] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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3
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Beutler M, Eberl C, Garzetti D, Herp S, Münch P, Ring D, Dolowschiak T, Brugiroux S, Schiller P, Hussain S, Basic M, Bleich A, Stecher B. Contribution of bacterial and host factors to pathogen "blooming" in a gnotobiotic mouse model for Salmonella enterica serovar Typhimurium-induced enterocolitis. Infect Immun 2024; 92:e0031823. [PMID: 38189339 PMCID: PMC10863408 DOI: 10.1128/iai.00318-23] [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: 08/17/2023] [Accepted: 12/05/2023] [Indexed: 01/09/2024] Open
Abstract
Inflammation has a pronounced impact on the intestinal ecosystem by driving an expansion of facultative anaerobic bacteria at the cost of obligate anaerobic microbiota. This pathogen "blooming" is also a hallmark of enteric Salmonella enterica serovar Typhimurium (S. Tm) infection. Here, we analyzed the contribution of bacterial and host factors to S. Tm "blooming" in a gnotobiotic mouse model for S. Tm-induced enterocolitis. Mice colonized with the Oligo-Mouse-Microbiota (OMM12), a minimal bacterial community, develop fulminant colitis by day 4 after oral infection with wild-type S. Tm but not with an avirulent mutant. Inflammation leads to a pronounced reduction in overall intestinal bacterial loads, distinct microbial community shifts, and pathogen blooming (relative abundance >50%). S. Tm mutants attenuated in inducing gut inflammation generally elicit less pronounced microbiota shifts and reduction in total bacterial loads. In contrast, S. Tm mutants in nitrate respiration, salmochelin production, and ethanolamine utilization induced strong inflammation and S. Tm "blooming." Therefore, individual Salmonella-specific inflammation-fitness factors seem to be of minor importance for competition against this minimal microbiota in the inflamed gut. Finally, we show that antibody-mediated neutrophil depletion normalized gut microbiota loads but not intestinal inflammation or microbiota shifts. This suggests that neutrophils equally reduce pathogen and commensal bacterial loads in the inflamed gut.
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Affiliation(s)
- Markus Beutler
- Max von Pettenkofer Institute of Hygiene and Medical Microbiology, Faculty of Medicine, LMU Munich, Munich, Germany
| | - Claudia Eberl
- Max von Pettenkofer Institute of Hygiene and Medical Microbiology, Faculty of Medicine, LMU Munich, Munich, Germany
| | - Debora Garzetti
- Max von Pettenkofer Institute of Hygiene and Medical Microbiology, Faculty of Medicine, LMU Munich, Munich, Germany
| | - Simone Herp
- Max von Pettenkofer Institute of Hygiene and Medical Microbiology, Faculty of Medicine, LMU Munich, Munich, Germany
| | - Philipp Münch
- Max von Pettenkofer Institute of Hygiene and Medical Microbiology, Faculty of Medicine, LMU Munich, Munich, Germany
- Computational Biology of Infection Research, Helmholtz Center for Infection Research, Braunschweig, Germany
- Braunschweig Integrated Center of Systems Biology (BRICS), Technische Universität Braunschweig, Braunschweig, Germany
| | - Diana Ring
- Max von Pettenkofer Institute of Hygiene and Medical Microbiology, Faculty of Medicine, LMU Munich, Munich, Germany
| | - Tamas Dolowschiak
- Institute of Microbiology, D-BIOL, ETH Zürich, Zürich, Switzerland
- Institute of Experimental Immunology, University of Zurich, Zürich, Switzerland
| | - Sandrine Brugiroux
- Max von Pettenkofer Institute of Hygiene and Medical Microbiology, Faculty of Medicine, LMU Munich, Munich, Germany
| | - Patrick Schiller
- Max von Pettenkofer Institute of Hygiene and Medical Microbiology, Faculty of Medicine, LMU Munich, Munich, Germany
| | - Saib Hussain
- Max von Pettenkofer Institute of Hygiene and Medical Microbiology, Faculty of Medicine, LMU Munich, Munich, Germany
| | - Marijana Basic
- Institute for Laboratory Animal Science and Central Animal Facility, Hannover Medical School, Hannover, Germany
| | - André Bleich
- Institute for Laboratory Animal Science and Central Animal Facility, Hannover Medical School, Hannover, Germany
| | - Bärbel Stecher
- Max von Pettenkofer Institute of Hygiene and Medical Microbiology, Faculty of Medicine, LMU Munich, Munich, Germany
- German Center for Infection Research (DZIF), partner site LMU Munich, Munich, Germany
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4
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Lamps LW. Infectious Disease Pathology of the Gastrointestinal Tract: Diagnosing the Challenging Cases. Surg Pathol Clin 2023; 16:779-804. [PMID: 37863566 DOI: 10.1016/j.path.2023.05.011] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/22/2023]
Abstract
Infectious diseases of the GI tract mimic a variety of other GI diseases, including chronic idiopathic inflammatory bowel disease and ischemia. It can be challenging to identify pathogens in tissue sections as well, as many trainees are not exposed to infectious disease pathology other than in the context of microbiology. Our ability to diagnose infections in formalin fixed, paraffin embedded material has grown exponentially with the advent of new histochemical and immunohistochemical stains, as well as more options for molecular testing. Correlating these diagnostic techniques with morphology has led to increasing understanding of the histologic patterns that are associated with specific pathogens.
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Affiliation(s)
- Laura W Lamps
- Department of Pathology, University of Michigan, NCRC Building 35, 2800 Plymouth Road, Ann Arbor, MI 48109, USA.
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5
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Gül E, Enz U, Maurer L, Abi Younes A, Fattinger SA, Nguyen BD, Hausmann A, Furter M, Barthel M, Sellin ME, Hardt WD. Intraluminal neutrophils limit epithelium damage by reducing pathogen assault on intestinal epithelial cells during Salmonella gut infection. PLoS Pathog 2023; 19:e1011235. [PMID: 37384776 PMCID: PMC10337893 DOI: 10.1371/journal.ppat.1011235] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2023] [Revised: 07/12/2023] [Accepted: 06/14/2023] [Indexed: 07/01/2023] Open
Abstract
Recruitment of neutrophils into and across the gut mucosa is a cardinal feature of intestinal inflammation in response to enteric infections. Previous work using the model pathogen Salmonella enterica serovar Typhimurium (S.Tm) established that invasion of intestinal epithelial cells by S.Tm leads to recruitment of neutrophils into the gut lumen, where they can reduce pathogen loads transiently. Notably, a fraction of the pathogen population can survive this defense, re-grow to high density, and continue triggering enteropathy. However, the functions of intraluminal neutrophils in the defense against enteric pathogens and their effects on preventing or aggravating epithelial damage are still not fully understood. Here, we address this question via neutrophil depletion in different mouse models of Salmonella colitis, which differ in their degree of enteropathy. In an antibiotic pretreated mouse model, neutrophil depletion by an anti-Ly6G antibody exacerbated epithelial damage. This could be linked to compromised neutrophil-mediated elimination and reduced physical blocking of the gut-luminal S.Tm population, such that the pathogen density remained high near the epithelial surface throughout the infection. Control infections with a ssaV mutant and gentamicin-mediated elimination of gut-luminal pathogens further supported that neutrophils are protecting the luminal surface of the gut epithelium. Neutrophil depletion in germ-free and gnotobiotic mice hinted that the microbiota can modulate the infection kinetics and ameliorate epithelium-disruptive enteropathy even in the absence of neutrophil-protection. Together, our data indicate that the well-known protective effect of the microbiota is augmented by intraluminal neutrophils. After antibiotic-mediated microbiota disruption, neutrophils are central for maintaining epithelial barrier integrity during acute Salmonella-induced gut inflammation, by limiting the sustained pathogen assault on the epithelium in a critical window of the infection.
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Affiliation(s)
- Ersin Gül
- Institute of Microbiology, Department of Biology, ETH Zurich, Zurich, Switzerland
| | - Ursina Enz
- Institute of Microbiology, Department of Biology, ETH Zurich, Zurich, Switzerland
| | - Luca Maurer
- Institute of Microbiology, Department of Biology, ETH Zurich, Zurich, Switzerland
| | - Andrew Abi Younes
- Institute of Microbiology, Department of Biology, ETH Zurich, Zurich, Switzerland
| | - Stefan A. Fattinger
- Institute of Microbiology, Department of Biology, ETH Zurich, Zurich, Switzerland
- Science for Life Laboratory, Department of Medical Biochemistry and Microbiology, Uppsala University, Uppsala, Sweden
| | - Bidong D. Nguyen
- Institute of Microbiology, Department of Biology, ETH Zurich, Zurich, Switzerland
| | - Annika Hausmann
- Institute of Microbiology, Department of Biology, ETH Zurich, Zurich, Switzerland
- reNEW – NNF Center for Stem Cell Medicine, University of Copenhagen, Denmark
| | - Markus Furter
- Institute of Microbiology, Department of Biology, ETH Zurich, Zurich, Switzerland
| | - Manja Barthel
- Institute of Microbiology, Department of Biology, ETH Zurich, Zurich, Switzerland
| | - Mikael E. Sellin
- Science for Life Laboratory, Department of Medical Biochemistry and Microbiology, Uppsala University, Uppsala, Sweden
| | - Wolf-Dietrich Hardt
- Institute of Microbiology, Department of Biology, ETH Zurich, Zurich, Switzerland
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6
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Zheng BH, Hao WM, Lin HC, Shang GG, Liu H, Ni XJ. Samonella typhi infection-related appendicitis: A case report. World J Clin Cases 2021; 9:8782-8788. [PMID: 34734056 PMCID: PMC8546835 DOI: 10.12998/wjcc.v9.i29.8782] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/07/2021] [Revised: 07/05/2021] [Accepted: 08/02/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Acute appendicitis is one of the most common acute abdominal emergencies around the world, which is always associated with infection. Infection with Salmonella typhi, an enteric pathogen, is a rare cause of acute appendicitis. We here report a patient with acute appendicitis associated with Samonella typhi infection, accompanied with spleen and kidney infarction, providing a rare example for a common surgical emergency. CASE SUMMARY A 25-year-old Pakistani man presented to the hospital with a 3-d history of fevers, vomiting, and abdominal pain. Computed tomography (CT) revealed a thickened intestinal wall of the ileocecal junction with multiple enlarged lymph nodes nearby. He was diagnosed with acute appendicitis and received laparoscopic appendectomy, which showed mild inflammation of the appendix. After the surgery, the patient presented again with a high fever (> 39 °C) and diarrhea. A CT angiography scan indicated spleen and kidney infarction. According to the blood culture, the diagnosis was finally clear to be Samonella typhi infection. The pyrexia and enteric symptoms were relieved after the application of intravenous levofloxacin. CONCLUSION This case, characterized by the combination of Salmonella typhi infection, acute appendicitis, and renal and splenic infraction, serves as a rare example for a common surgical emergency.
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Affiliation(s)
- Bo-Hao Zheng
- Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai 200032, China
| | - Wei-Ming Hao
- Shanghai Medical College, Fudan University, Shanghai 200032, China
| | - Hung-Chen Lin
- Shanghai Medical College, Fudan University, Shanghai 200032, China
| | - Guo-Guo Shang
- Department of Pathology, Zhongshan Hospital, Shanghai 200032, China
| | - Han Liu
- Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai 200032, China
| | - Xiao-Jian Ni
- Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai 200032, China
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7
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Fujimori S. Asymptomatic small intestinal ulcerative lesions: Obesity and Helicobacter pylori are likely to be risk factors. World J Gastroenterol 2021; 27:4484-4492. [PMID: 34366619 PMCID: PMC8326254 DOI: 10.3748/wjg.v27.i28.4484] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/31/2021] [Revised: 04/09/2021] [Accepted: 07/12/2021] [Indexed: 02/06/2023] Open
Abstract
It is often difficult to explain why ulcerative lesions are found in the small intestine because there are no obvious aggressors such as gastric acid. In particular, the treatment of small intestinal ulcerative lesions in asymptomatic patients with no symptoms, normal physical examinations, and normal blood test findings is not well documented. According to a summary of capsule endoscopy studies in healthy subjects, approximately 10% of subjects have small intestinal mucosal breaks. The number of mucosal breaks in these instances is approximately 1-3. We examined small intestinal mucosal breaks in healthy subjects recruited from our past two studies. Mucosal breaks were observed in approximately 10% of subjects, and the average number was 0.24 ± 1.21. The number of mucosal breaks in the small intestine was correlated with body mass index and was significantly higher in Helicobacter pylori-infected subjects and higher in males. These results indicate that 1-2 small ulcerative lesions, such as erosions in the small intestine, can be considered to be in the normal range, and close examination is not required. It is assumed that a follow-up medical examination is required for such asymptomatic persons. The presence of many small ulcerative lesions or an unequivocal ulcer indicates an abnormality for which close examination is desired. However, in many cases, it is sufficient to scrutinize after detecting anemia, but it is difficult to make a judgment due to insufficient reports, and future studies are required.
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Affiliation(s)
- Shunji Fujimori
- Department of Gastroenterology, Chiba Hokusoh Hospital, Nippon Medical School, Chiba 270-1694, Japan
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8
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Maiti S, Howlader DR, Halder P, Bhaumik U, Dutta M, Dutta S, Koley H. Bivalent non-typhoidal Salmonella outer membrane vesicles immunized mice sera confer passive protection against gastroenteritis in a suckling mice model. Vaccine 2020; 39:380-393. [PMID: 33303233 DOI: 10.1016/j.vaccine.2020.11.040] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2020] [Revised: 11/06/2020] [Accepted: 11/15/2020] [Indexed: 11/28/2022]
Abstract
Invasive non-typhoidal Salmonella (iNTS) serovars, especially Salmonella Typhimurium (ST) and Salmonella Enteritidis (SE), cause gastroenteritis worldwide. Due to the emergence of multi-drug resistance in iNTS, a broad-spectrum vaccine is urgently needed for the prevention of iNTS infection. Currently, there is no effective licensed vaccine against iNTS available in the market. We have formulated an outer membrane vesicles (OMVs) based bivalent immunogen as a vaccine candidate to generate broad-spectrum protective immunity against both recently circulating prevalent ST and SE. We have isolated OMVs from ST and SE and formulated the immunogen by mixing both OMVs (1:1 ratio). Three doses of bivalent immunogen significantly induced humoral immune responses against lipopolysaccharides (LPSs) and outer membrane proteins (OMPs) as well as a cell-mediated immune response in adult mice. We also observed that proteins of OMVs act as an adjuvant for generation of high levels of anti-LPS antibodies through T cell activation. We then characterized the one-day old suckling mice model for both ST and SE mediated gastroenteritis and used the model for a passive protection study. In the passive protection study, we found the passive transfer of bivalent OMVs immunized sera significantly reduced ST and SE mediated colonization and gastroenteritis symptoms in the colon of suckling mice compared to non-immunized sera recipients. The overall study demonstrated that OMVs based bivalent vaccine could generate broad-spectrum immunity against prevalent iNTS mediated gastroenteritis. This study also established the suckling mice model as a suitable animal model for vaccine study against iNTS mediated gastroenteritis.
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Affiliation(s)
- Suhrid Maiti
- Division of Bacteriology, ICMR-National Institute of Cholera and Enteric Diseases, P-33 CIT Road, Scheme-XM, Beliaghata, Kolkata 700010, India
| | - Debaki Ranjan Howlader
- Division of Bacteriology, ICMR-National Institute of Cholera and Enteric Diseases, P-33 CIT Road, Scheme-XM, Beliaghata, Kolkata 700010, India
| | - Prolay Halder
- Division of Bacteriology, ICMR-National Institute of Cholera and Enteric Diseases, P-33 CIT Road, Scheme-XM, Beliaghata, Kolkata 700010, India
| | - Ushasi Bhaumik
- Division of Bacteriology, ICMR-National Institute of Cholera and Enteric Diseases, P-33 CIT Road, Scheme-XM, Beliaghata, Kolkata 700010, India
| | - Moumita Dutta
- Division of Electron Microscopy, ICMR-National Institute of Cholera and Enteric Diseases, P-33 CIT Road, Scheme-XM, Beliaghata, Kolkata 700010, India
| | - Shanta Dutta
- Division of Bacteriology, ICMR-National Institute of Cholera and Enteric Diseases, P-33 CIT Road, Scheme-XM, Beliaghata, Kolkata 700010, India
| | - Hemanta Koley
- Division of Bacteriology, ICMR-National Institute of Cholera and Enteric Diseases, P-33 CIT Road, Scheme-XM, Beliaghata, Kolkata 700010, India.
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9
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Hew N, Ng ZQ, Kumarasinghe MP, Agrawal N. Salmonella colitis with perforation in the absence of toxic megacolon. ANZ J Surg 2020; 91:E40-E42. [PMID: 32526078 DOI: 10.1111/ans.16071] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2020] [Accepted: 05/28/2020] [Indexed: 11/26/2022]
Affiliation(s)
- Nicole Hew
- Department of General Surgery, Bunbury Regional Hospital, Bunbury, Western Australia, Australia
| | - Zi Qin Ng
- Department of General Surgery, Bunbury Regional Hospital, Bunbury, Western Australia, Australia
| | - M Priyanthi Kumarasinghe
- PathWest Laboratories, Perth, Western Australia, Australia.,University of Western, Nedlands, Western Australia, Australia
| | - Nikhil Agrawal
- Department of General Surgery, Bunbury Regional Hospital, Bunbury, Western Australia, Australia
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10
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Westerman TL, Bogomolnaya L, Andrews-Polymenis HL, Sheats MK, Elfenbein JR. The Salmonella type-3 secretion system-1 and flagellar motility influence the neutrophil respiratory burst. PLoS One 2018; 13:e0203698. [PMID: 30204776 PMCID: PMC6133356 DOI: 10.1371/journal.pone.0203698] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2018] [Accepted: 08/24/2018] [Indexed: 11/28/2022] Open
Abstract
Neutrophils are innate immune response cells designed to kill invading microorganisms. One of the mechanisms neutrophils use to kill bacteria is generation of damaging reactive oxygen species (ROS) via the respiratory burst. However, during enteric salmonellosis, neutrophil-derived ROS actually facilitates Salmonella expansion and survival in the gut. This seeming paradox led us to hypothesize that Salmonella may possess mechanisms to influence the neutrophil respiratory burst. In this work, we used an in vitro Salmonella-neutrophil co-culture model to examine the impact of enteric infection relevant virulence factors on the respiratory burst of human neutrophils. We report that neutrophils primed with granulocyte-macrophage colony stimulating factor and suspended in serum containing complement produce a robust respiratory burst when stimulated with viable STm. The magnitude of the respiratory burst increases when STm are grown under conditions to induce the expression of the type-3 secretion system-1. STm mutants lacking the type-3 secretion system-1 induce less neutrophil ROS than the virulent WT. In addition, we demonstrate that flagellar motility is a significant agonist of the neutrophil respiratory burst. Together our data demonstrate that both the type-3 secretion system-1 and flagellar motility, which are established virulence factors in enteric salmonellosis, also appear to directly influence the magnitude of the neutrophil respiratory burst in response to STm in vitro.
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Affiliation(s)
- Trina L. Westerman
- Department of Clinical Sciences, College of Veterinary Medicine, North Carolina State University, Raleigh, NC, United States of America
| | - Lydia Bogomolnaya
- Department of Microbial Pathogenesis and Immunology, College of Medicine, Texas A&M University, Bryan, TX, United States of America
- Institute of Fundamental Medicine and Biology, Kazan Federal University, Kazan, Russia
| | - Helene L. Andrews-Polymenis
- Department of Microbial Pathogenesis and Immunology, College of Medicine, Texas A&M University, Bryan, TX, United States of America
| | - M. Katherine Sheats
- Department of Clinical Sciences, College of Veterinary Medicine, North Carolina State University, Raleigh, NC, United States of America
| | - Johanna R. Elfenbein
- Department of Clinical Sciences, College of Veterinary Medicine, North Carolina State University, Raleigh, NC, United States of America
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11
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Palmer AD, Slauch JM. Mechanisms of Salmonella pathogenesis in animal models. HUMAN AND ECOLOGICAL RISK ASSESSMENT : HERA 2017; 23:1877-1892. [PMID: 31031557 PMCID: PMC6484827 DOI: 10.1080/10807039.2017.1353903] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/09/2023]
Abstract
Animal models play an important role in understanding the mechanisms of bacterial pathogenesis. Here we review recent studies of Salmonella infection in various animal models. Although mice are a classic animal model for Salmonella, mice do not normally get diarrhea, raising the question of how well the model represents normal human infection. However, pretreatment of mice with oral streptomycin, which apparently reduces the normal microbiota, leads to an inflammatory diarrheal response upon oral infection with Salmonella. This has led to a re-evaluation of the role of various Salmonella virulence factors in colonization of the intestine and induction of diarrhea. Indeed, it is now clear that Salmonella purposefully induces inflammation, which leads to the production of both carbon sources and terminal electron acceptors by the host that allow Salmonella to outgrow the normal intestinal microbiota. Overall use of this modified mouse model provides a more nuanced understanding of Salmonella intestinal infection in the context of the microbiota with implications for the ability to predict human risk.
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Affiliation(s)
- Alexander D Palmer
- Department of Microbiology, University of Illinois at Urbana-Champaign, Urbana, IL 61801
| | - James M Slauch
- Department of Microbiology, University of Illinois at Urbana-Champaign, Urbana, IL 61801
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12
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Kurtz JR, Goggins JA, McLachlan JB. Salmonella infection: Interplay between the bacteria and host immune system. Immunol Lett 2017; 190:42-50. [PMID: 28720334 DOI: 10.1016/j.imlet.2017.07.006] [Citation(s) in RCA: 169] [Impact Index Per Article: 21.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2017] [Revised: 07/07/2017] [Accepted: 07/10/2017] [Indexed: 12/14/2022]
Abstract
Salmonella infection causes morbidity and mortality throughout the world with the host immune response varying depending on whether the infection is acute and limited, or systemic and chronic. Additionally, Salmonella bacteria have evolved multiple mechanisms to avoid or subvert immunity to its own benefit and often the anatomical location of infection plays a role in both the immune response and bacterial fate. Here, we provide an overview of the interplay between the immune system and Salmonella, while discussing how different host and bacterial factors influence the outcome of infection.
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Affiliation(s)
- Jonathan R Kurtz
- Department of Microbiology and Immunology, Tulane University School of Medicine, New Orleans, LA, United States
| | - J Alan Goggins
- Department of Microbiology and Immunology, Tulane University School of Medicine, New Orleans, LA, United States
| | - James B McLachlan
- Department of Microbiology and Immunology, Tulane University School of Medicine, New Orleans, LA, United States.
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13
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Pathogenic traits of Salmonella Montevideo in experimental infections in vivo and in vitro. Sci Rep 2017; 7:46232. [PMID: 28387311 PMCID: PMC5384224 DOI: 10.1038/srep46232] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2016] [Accepted: 03/14/2017] [Indexed: 12/26/2022] Open
Abstract
Salmonella serovar Montevideo (SM) is frequently associated with human Salmonella infections and causes gastrointestinal disease, cases are common particularly among individuals who come in close contact with live poultry or poultry meat products. To characterize SM disease in chickens, the pathogenic traits and tissue predilections of the disease were investigated. Dissemination of fluorescent-tagged SM (JOL1575GFP) was monitored after oral and intramuscular mock infections of specific-pathogen-free chickens. The spleen was predominantly affected by intramuscular infection while the cecum, spleen, and minimally liver were affected by oral infection. No conspicuous illness was observed in infected birds, and histopathological examination showed minimal damage of the intestinal epithelium and splenic parenchyma though SM was readily isolated from these tissues. Levels of SM internalization by primary chicken peritoneal macrophages were similar to that of Salmonella Typhimurium. SM was more sensitive to chicken than rabbit serum complement killing. Internal egg contamination of SM mock infected layers also occurred at trace levels and lasted for a week after inoculation. This study also confirmed that SM infection in chickens is sub-clinical and asymptomatic, which suggests that latent asymptomatic carriers may excrete a large number of bacteria and transmit the pathogen by contaminating water or food sources.
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14
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Abstract
The anatomic pathologist's ability to diagnose infections, including gastrointestinal infections, in tissue sections has improved greatly in recent years. With the increasing number and availability of new molecular assays and immunostains, pathologists' understanding of the correlation between histologic patterns of inflammation and specific organisms or groups of organisms has expanded, as well as our understanding of how closely infections can mimic other frequently encountered diseases in gastrointestinal pathology (such as chronic idiopathic inflammatory bowel disease and ischemia). Anatomic pathologists continue to play a critical role in the diagnosis of gastrointestinal infections, as the examination of slides may provide a much more rapid result than microbiological cultures or other laboratory assays, and often cultures are not obtained before the patient is treated with antibiotics. Because many gastrointestinal infections are acquired through contaminated water and food, this review will focus primarily on food and water-borne infectious enterocolitides.
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Affiliation(s)
- Laura W Lamps
- Department of Pathology, University of Arkansas for Medical Sciences, Little Rock, AR, USA
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15
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Verma S, Srikanth CV. Understanding the complexities of Salmonella-host crosstalk as revealed by in vivo model organisms. IUBMB Life 2015; 67:482-97. [PMID: 26179888 DOI: 10.1002/iub.1393] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2015] [Accepted: 06/15/2015] [Indexed: 01/03/2023]
Abstract
Foodborne infections caused by non-typhoidal Salmonellae, such as Salmonella enterica serovar Typhimurium (ST), pose a major challenge in the developed and developing world. With constant rise of drug-resistant strains, understanding the epidemiology, microbiology, pathogenesis and host-pathogen interactions biology is a mandatory requirement to enable health systems to be ready to combat these illnesses. Patient data from hospitals, at least from some parts of the world, have aided in epidemiological understanding of ST-mediated disease. Most of the other aspects connected to Salmonella-host crosstalk have come from model systems that offer convenience, genetic tractability and low maintenance costs that make them extremely valuable tools. Complex model systems such as the bovine model have helped in understanding key virulence factors needed for infection. Simple systems such as fruit flies and Caenorhabditis elegans have aided in identification of novel virulence factors, host pathways and mechanistic details of interactions. Some of the path-breaking concepts of the field have come from mice model of ST colitis, which allows genetic manipulations as well as high degree of similarity to human counterpart. Together, they are invaluable for correlating in vitro findings of ST-induced disease progression in vivo. The current review is a compilation of various advances of ST-host interactions at cellular and molecular levels that has come from investigations involving model organisms.
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Affiliation(s)
- Smriti Verma
- Regional Centre for Biotechnology, NCR Biotech Cluster 3rd Milestone, Gurgaon-Faridabad Highway, Village Bhankari, Faridabad, Haryana, India
| | - Chittur V Srikanth
- Regional Centre for Biotechnology, NCR Biotech Cluster 3rd Milestone, Gurgaon-Faridabad Highway, Village Bhankari, Faridabad, Haryana, India
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16
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Sellin ME, Müller AA, Felmy B, Dolowschiak T, Diard M, Tardivel A, Maslowski KM, Hardt WD. Epithelium-intrinsic NAIP/NLRC4 inflammasome drives infected enterocyte expulsion to restrict Salmonella replication in the intestinal mucosa. Cell Host Microbe 2015; 16:237-248. [PMID: 25121751 DOI: 10.1016/j.chom.2014.07.001] [Citation(s) in RCA: 312] [Impact Index Per Article: 31.2] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2014] [Revised: 05/20/2014] [Accepted: 06/30/2014] [Indexed: 01/08/2023]
Abstract
The gut mucosal epithelium separates the host from the microbiota, but enteropathogens such as Salmonella Typhimurium (S.Tm) can invade and breach this barrier. Defenses against such acute insults remain incompletely understood. Using a murine model of Salmonella enterocolitis, we analyzed mechanisms limiting pathogen loads in the epithelium during early infection. Although the epithelium-invading S.Tm replicate initially, this intraepithelial replicative niche is restricted by expulsion of infected enterocytes into the lumen. This mechanism is compromised if inflammasome components (NAIP1-6, NLRC4, caspase-1/-11) are deleted, or ablated specifically in the epithelium, resulting in ∼100-fold higher intraepithelial loads and accelerated lymph node colonization. Interestingly, the cytokines downstream of inflammasome activation, interleukin (IL)-1α/β and IL-18, appear dispensable for epithelial restriction of early infection. These data establish the role of an epithelium-intrinsic inflammasome, which drives expulsion of infected cells to restrict the pathogen's intraepithelial proliferation. This may represent a general defense mechanism against mucosal infections.
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Affiliation(s)
- Mikael E Sellin
- Institute of Microbiology, ETH Zürich, 8093 Zürich, Switzerland.
| | - Anna A Müller
- Institute of Microbiology, ETH Zürich, 8093 Zürich, Switzerland
| | - Boas Felmy
- Institute of Microbiology, ETH Zürich, 8093 Zürich, Switzerland
| | | | - Médéric Diard
- Institute of Microbiology, ETH Zürich, 8093 Zürich, Switzerland
| | - Aubry Tardivel
- Department of Biochemistry, University of Lausanne, 1066 Epalinges, Switzerland
| | - Kendle M Maslowski
- Department of Biochemistry, University of Lausanne, 1066 Epalinges, Switzerland; Laboratory for Intestinal Ecosystem, RIKEN Center for Integrative Medical Sciences (IMS), Yokohama 230-0045, Japan
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17
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Maier L, Diard M, Sellin ME, Chouffane ES, Trautwein-Weidner K, Periaswamy B, Slack E, Dolowschiak T, Stecher B, Loverdo C, Regoes RR, Hardt WD. Granulocytes impose a tight bottleneck upon the gut luminal pathogen population during Salmonella typhimurium colitis. PLoS Pathog 2014; 10:e1004557. [PMID: 25522364 PMCID: PMC4270771 DOI: 10.1371/journal.ppat.1004557] [Citation(s) in RCA: 60] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2014] [Accepted: 11/06/2014] [Indexed: 12/22/2022] Open
Abstract
Topological, chemical and immunological barriers are thought to limit infection by enteropathogenic bacteria. However, in many cases these barriers and their consequences for the infection process remain incompletely understood. Here, we employed a mouse model for Salmonella colitis and a mixed inoculum approach to identify barriers limiting the gut luminal pathogen population. Mice were infected via the oral route with wild type S. Typhimurium (S. Tm) and/or mixtures of phenotypically identical but differentially tagged S. Tm strains ("WITS", wild-type isogenic tagged strains), which can be individually tracked by quantitative real-time PCR. WITS dilution experiments identified a substantial loss in tag/genetic diversity within the gut luminal S. Tm population by days 2-4 post infection. The diversity-loss was not attributable to overgrowth by S. Tm mutants, but required inflammation, Gr-1+ cells (mainly neutrophilic granulocytes) and most likely NADPH-oxidase-mediated defense, but not iNOS. Mathematical modelling indicated that inflammation inflicts a bottleneck transiently restricting the gut luminal S. Tm population to approximately 6000 cells and plating experiments verified a transient, inflammation- and Gr-1+ cell-dependent dip in the gut luminal S. Tm population at day 2 post infection. We conclude that granulocytes, an important clinical hallmark of S. Tm-induced inflammation, impose a drastic bottleneck upon the pathogen population. This extends the current view of inflammation-fuelled gut-luminal Salmonella growth by establishing the host response in the intestinal lumen as a double-edged sword, fostering and diminishing colonization in a dynamic equilibrium. Our work identifies a potent immune defense against gut infection and reveals a potential Achilles' heel of the infection process which might be targeted for therapy.
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Affiliation(s)
- Lisa Maier
- Eidgenössische Technische Hochschule Zürich, Institute of Microbiology, Zurich, Switzerland
| | - Médéric Diard
- Eidgenössische Technische Hochschule Zürich, Institute of Microbiology, Zurich, Switzerland
| | - Mikael E. Sellin
- Eidgenössische Technische Hochschule Zürich, Institute of Microbiology, Zurich, Switzerland
| | - Elsa-Sarah Chouffane
- Eidgenössische Technische Hochschule Zürich, Institute of Microbiology, Zurich, Switzerland
| | | | - Balamurugan Periaswamy
- Eidgenössische Technische Hochschule Zürich, Institute of Microbiology, Zurich, Switzerland
| | - Emma Slack
- Eidgenössische Technische Hochschule Zürich, Institute of Microbiology, Zurich, Switzerland
| | - Tamas Dolowschiak
- Eidgenössische Technische Hochschule Zürich, Institute of Microbiology, Zurich, Switzerland
| | - Bärbel Stecher
- Max von Pettenkofer-Institut, München, Germany; German Center for Infection Research (DZIF), partner site Ludwig Maximilian University of Munich, Munich, Germany
| | - Claude Loverdo
- Eidgenössische Technische Hochschule Zürich, Institute of Integrative Biology, Zurich, Switzerland
| | - Roland R. Regoes
- Eidgenössische Technische Hochschule Zürich, Institute of Integrative Biology, Zurich, Switzerland
| | - Wolf-Dietrich Hardt
- Eidgenössische Technische Hochschule Zürich, Institute of Microbiology, Zurich, Switzerland
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18
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Loetscher Y, Wieser A, Lengefeld J, Kaiser P, Schubert S, Heikenwalder M, Hardt WD, Stecher B. Salmonella transiently reside in luminal neutrophils in the inflamed gut. PLoS One 2012; 7:e34812. [PMID: 22493718 PMCID: PMC3321032 DOI: 10.1371/journal.pone.0034812] [Citation(s) in RCA: 54] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2012] [Accepted: 03/05/2012] [Indexed: 01/03/2023] Open
Abstract
BACKGROUND Enteric pathogens need to grow efficiently in the gut lumen in order to cause disease and ensure transmission. The interior of the gut forms a complex environment comprising the mucosal surface area and the inner gut lumen with epithelial cell debris and food particles. Recruitment of neutrophils to the intestinal lumen is a hallmark of non-typhoidal Salmonella enterica infections in humans. Here, we analyzed the interaction of gut luminal neutrophils with S. enterica serovar Typhimurium (S. Tm) in a mouse colitis model. RESULTS Upon S. Tm(wt) infection, neutrophils transmigrate across the mucosa into the intestinal lumen. We detected a majority of pathogens associated with luminal neutrophils 20 hours after infection. Neutrophils are viable and actively engulf S. Tm, as demonstrated by live microscopy. Using S. Tm mutant strains defective in tissue invasion we show that pathogens are mostly taken up in the gut lumen at the epithelial barrier by luminal neutrophils. In these luminal neutrophils, S. Tm induces expression of genes typically required for its intracellular lifestyle such as siderophore production iroBCDE and the Salmonella pathogenicity island 2 encoded type three secretion system (TTSS-2). This shows that S. Tm at least transiently survives and responds to engulfment by gut luminal neutrophils. Gentamicin protection experiments suggest that the life-span of luminal neutrophils is limited and that S. Tm is subsequently released into the gut lumen. This "fast cycling" through the intracellular compartment of gut luminal neutrophils would explain the high fraction of TTSS-2 and iroBCDE expressing intra- and extracellular bacteria in the lumen of the infected gut. CONCLUSION In conclusion, live neutrophils recruited during acute S. Tm colitis engulf pathogens in the gut lumen and may thus actively engage in shaping the environment of pathogens and commensals in the inflamed gut.
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Affiliation(s)
| | - Andreas Wieser
- Max von Pettenkofer Insititute, Ludwig Maximilians University Munich, Munich, Germany
| | | | - Patrick Kaiser
- Institute of Microbiology, ETH Zürich, Zürich, Switzerland
| | - Sören Schubert
- Max von Pettenkofer Insititute, Ludwig Maximilians University Munich, Munich, Germany
| | - Mathias Heikenwalder
- Institute for Virology, Technical University Munich/Helmholtz Center Munich, Munich, Germany
| | | | - Bärbel Stecher
- Institute of Microbiology, ETH Zürich, Zürich, Switzerland
- Max von Pettenkofer Insititute, Ludwig Maximilians University Munich, Munich, Germany
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19
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Peroral ciprofloxacin therapy impairs the generation of a protective immune response in a mouse model for Salmonella enterica serovar Typhimurium diarrhea, while parenteral ceftriaxone therapy does not. Antimicrob Agents Chemother 2012; 56:2295-304. [PMID: 22354292 DOI: 10.1128/aac.05819-11] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022] Open
Abstract
Nontyphoidal Salmonella (NTS) species cause self-limiting diarrhea and sometimes severe disease. Antibiotic treatment is considered only in severe cases and immune-compromised patients. The beneficial effects of antibiotic therapy and the consequences for adaptive immune responses are not well understood. We used a mouse model for Salmonella diarrhea to assess the effects of per os treatment with ciprofloxacin (15 mg/kg of body weight intragastrically 2 times/day, 5 days) or parenteral ceftriaxone (50 mg/kg intraperitoneally, 5 days), two common drugs used in human patients. The therapeutic and adverse effects were assessed with respect to generation of a protective adaptive immune response, fecal pathogen excretion, and the emergence of nonsymptomatic excreters. In the mouse model, both therapies reduced disease severity and reduced the level of fecal shedding. In line with clinical data, in most animals, a rebound of pathogen gut colonization/fecal shedding was observed 2 to 12 days after the end of the treatment. Yet, levels of pathogen shedding and frequency of appearance of nonsymptomatic excreters did not differ from those for untreated controls. Moreover, mice treated intraperitoneally with ceftriaxone developed an adaptive immunity protecting the mice from enteropathy in wild-type Salmonella enterica serovar Typhimurium challenge infections. In contrast, the mice treated intragastrically with ciprofloxacin were not protected. Thus, antibiotic treatment regimens can disrupt the adaptive immune response, but treatment regimens may be optimized in order to preserve the generation of protective immunity. It might be of interest to determine whether this also pertains to human patients. In this case, the mouse model might be a tool for further mechanistic studies.
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20
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Ahmad I, Lamprokostopoulou A, Le Guyon S, Streck E, Barthel M, Peters V, Hardt WD, Römling U. Complex c-di-GMP signaling networks mediate transition between virulence properties and biofilm formation in Salmonella enterica serovar Typhimurium. PLoS One 2011; 6:e28351. [PMID: 22164276 PMCID: PMC3229569 DOI: 10.1371/journal.pone.0028351] [Citation(s) in RCA: 72] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2011] [Accepted: 11/07/2011] [Indexed: 11/21/2022] Open
Abstract
Upon Salmonella enterica serovar Typhimurium infection of the gut, an early line of defense is the gastrointestinal epithelium which senses the pathogen and intrusion along the epithelial barrier is one of the first events towards disease. Recently, we showed that high intracellular amounts of the secondary messenger c-di-GMP in S. typhimurium inhibited invasion and abolished induction of a pro-inflammatory immune response in the colonic epithelial cell line HT-29 suggesting regulation of transition between biofilm formation and virulence by c-di-GMP in the intestine. Here we show that highly complex c-di-GMP signaling networks consisting of distinct groups of c-di-GMP synthesizing and degrading proteins modulate the virulence phenotypes invasion, IL-8 production and in vivo colonization in the streptomycin-treated mouse model implying a spatial and timely modulation of virulence properties in S. typhimurium by c-di-GMP signaling. Inhibition of the invasion and IL-8 induction phenotype by c-di-GMP (partially) requires the major biofilm activator CsgD and/or BcsA, the synthase for the extracellular matrix component cellulose. Inhibition of the invasion phenotype is associated with inhibition of secretion of the type three secretion system effector protein SipA, which requires c-di-GMP metabolizing proteins, but not their catalytic activity. Our findings show that c-di-GMP signaling is at least equally important in the regulation of Salmonella-host interaction as in the regulation of biofilm formation at ambient temperature.
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Affiliation(s)
- Irfan Ahmad
- Department of Microbiology, Tumor and Cell Biology (MTC), Karolinska Institutet, Stockholm, Sweden
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21
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Salmonella typhimurium diarrhea: switching the mucosal epithelium from homeostasis to defense. Curr Opin Immunol 2011; 23:456-63. [PMID: 21726991 DOI: 10.1016/j.coi.2011.06.004] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2011] [Revised: 06/10/2011] [Accepted: 06/14/2011] [Indexed: 12/24/2022]
Abstract
The mammalian intestine is a complex biological system composed of the epithelium, the gut associated immune system, a commensal microbial community of approx. 10(10) cells per gram of content ('microbiota') and an occasional onslaught by pathogens. The mechanisms governing homeostasis and immune defense are of great importance, but incompletely understood. This is explained by the system's sheer complexity. So far, no single study has considered all relevant parameters, that is (i) innate and adaptive mucosal immune responses; (ii) mucosa cell gene expression; (iii) community composition of the microbiota; (iv) microbiota gene expression; (v) genetic profiling of the host; (vi) the virulence complement expressed by the pathogen in vivo. This exquisite complexity explains why simplified model systems have fuelled much recent progress on the system's regulating principles. Here, we focus on one particular model, the streptomycin pretreated mouse model for Salmonella diarrhea, to illustrate novel concepts in microbe-mucosa interaction, that is how this system switches from homeostasis to disease.
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22
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Protective role of Akt2 in Salmonella enterica serovar typhimurium-induced gastroenterocolitis. Infect Immun 2011; 79:2554-66. [PMID: 21555401 DOI: 10.1128/iai.01235-10] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
The Salmonella effector protein SopB has previously been shown to induce activation of Akt and protect epithelial cells from apoptosis in vitro. To characterize the role of Akt2 in host defense against Salmonella enterica serovar Typhimurium infection, wild-type (WT) mice and mice lacking Akt2 (Akt2 knockout [KO] mice) were infected using a Salmonella acute gastroenteritis model. Infected Akt2 KO mice showed a more pronounced morbidity and mortality associated with higher bacterial loads in the intestines and elevated levels of proinflammatory cytokines, including tumor necrosis factor alpha (TNF-α), gamma interferon (IFN-γ), and MCP-1, in the colons at 1 day postinfection compared to those shown in WT mice. Histopathological assessment and immunohistochemical analysis of cecal sections at 1 day postinfection revealed more severe inflammation and higher levels of neutrophil infiltration in the ceca of Akt2 KO mice. Flow cytometry analysis further confirmed an increase in the recruitment of Gr-1(+) CD11b(+) neutrophils and F4/80(+) CD11b(+) macrophages in the intestines of infected Akt2 KO mice. Additionally, enhanced levels of annexin V(+) and terminal transferase dUTP nick end labeling-positive (TUNEL(+)) apoptotic cells in the intestines of infected Akt2 KO mice were also observed, indicating that Akt2 plays an essential role in protection against apoptosis. Finally, the differences in bacterial loads and cecal inflammation in WT and Akt2 KO mice infected with WT Salmonella were abolished when these mice were infected with the sopB deletion mutant, indicating that SopB may play a role in protecting the mice from Salmonella infection through the activation of Akt2. These data demonstrate a definitive phenotypic abnormality in the innate response in mice lacking Akt2, underscoring the important protective role of Akt2 in Salmonella infection.
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23
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Abstract
Gastrointestinal (GI) infections are a major cause of morbidity and mortality worldwide. Although infectious organisms are often recovered by microbiological methods, surgical pathologists play an invaluable role in diagnosis. The lower GI tract, including the appendix, large bowel, and anus, harbors a wide variety of pathogens. Some infections are part of disseminated disease, whereas others produce clinicopathologic scenarios that are specific to the lower GI tract. This review focuses on selected infectious disorders of the lower GI tract that may be encountered by the general surgical pathologist, including viral, bacterial, fungal, and parasitic organisms, and including infections caused by food- and water-borne pathogens. Diagnostic gross and histologic features are discussed, as well as useful clinical features and ancillary diagnostic techniques. Pertinent differential diagnoses are also emphasized, including other inflammatory conditions of the gut (such as ischemia or idiopathic inflammatory bowel disease) that can be mimicked by lower GI infections.
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Affiliation(s)
- Laura W Lamps
- Department of Pathology, University of Arkansas for Medical Sciences, 4301 West Markham Street, Shorey 4S/09, Little Rock, AR 72205, USA.
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24
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Kum WWS, Lee S, Grassl GA, Bidshahri R, Hsu K, Ziltener HJ, Finlay BB. Lack of functional P-selectin ligand exacerbates Salmonella serovar typhimurium infection. THE JOURNAL OF IMMUNOLOGY 2009; 182:6550-61. [PMID: 19414810 DOI: 10.4049/jimmunol.0802536] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
The selectin family of adhesion molecules mediates the recruitment of immune cells to the site of inflammation, which is critical for host survival of infection. To characterize the role of selectins in host defense against Salmonella Typhimurium infection, wild-type (WT) mice and mice lacking P-selectin glycoprotein ligand-1 (PSGL-1), P-, E-, or L-selectin, or the glycosyltransferase C2GlcNAcT-I (core 2) were infected using a Salmonella acute gastroenteritis model. Mice were monitored for survival and assessed for intestinal inflammation at 1 and 4 days postinfection. Infected mice lacking core 2, PSGL-1, or P-selectin showed a more pronounced morbidity and a significantly higher mortality rate associated with higher bacterial load and proinflammatory cytokine production, including that of TNF-alpha, MCP-1, and IL-6, from the colons at 4 days postinfection as compared with WT control. Surprisingly, at 1 day postinfection, more severe inflammation and higher neutrophil infiltration were observed in the ceca of mice lacking core 2, PSGL-1, or P-selectin compared with WT control. Enhanced levels of alpha(4)beta(7)(+) and MAdCAM-1(+) cells were observed in the ceca of infected mice lacking core 2, PSGL-1, or P-selectin. Neutrophil recruitment, cecal inflammation, and mortality rates were dramatically reduced in infected P-selectin knockout mice receiving blocking mAb to alpha(4)beta(7) integrin, indicating that this alternative adhesion molecule may attempt to compensate for the loss of selectins in neutrophil recruitment. These results demonstrate a definitive phenotypic abnormality in mice lacking core 2, PSGL-1, or P-selectin, suggesting that the interaction of functional PSGL-1 with P-selectin is an important process in host defense against Salmonella infection.
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Affiliation(s)
- Winnie W S Kum
- Michael Smith Laboratories, University of British Columbia, Vancouver, British Columbia, Canada
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25
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26
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Lamps LW. Infectious disorders of the upper gastrointestinal tract (excluding Helicobacter pylori ). ACTA ACUST UNITED AC 2008. [DOI: 10.1016/j.mpdhp.2008.07.003] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/01/2022]
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27
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Gordon MA. Salmonella infections in immunocompromised adults. J Infect 2008; 56:413-22. [PMID: 18474400 DOI: 10.1016/j.jinf.2008.03.012] [Citation(s) in RCA: 302] [Impact Index Per Article: 17.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2008] [Revised: 03/25/2008] [Accepted: 03/31/2008] [Indexed: 12/11/2022]
Abstract
Clinical syndromes caused by Salmonella infection in humans are divided into typhoid fever, caused by Salmonella typhi and Salmonella paratyphi, and a range of clinical syndromes, including diarrhoeal disease, caused by a large number of non-typhoidal salmonella serovars (NTS). Typhoid is a human-restricted and highly adapted invasive disease, but shows little association with immunocompromise. In contrast, NTS have a broad vertebrate host range, epidemiology that often involves food animals, and have a dramatically more severe and invasive presentation in immunocompromised adults, in particular in the context of HIV. Immunocompromise among adults, including underlying severe or progressive disease, chronic granulomatous disease, defects or blockade of specific cytokines (particularly IL-12/IL-23/IL-17 and TNF), and HIV, is associated with suppurative foci and with primary bacteraemic disease, which may be recurrent. These patients have markedly increased mortality. Worldwide, invasive recurrent NTS bacteraemia associated with advanced HIV disease is a huge problem, and the epidemiology in this context may be more human-restricted than in other settings. This review will describe the presentation and pathogenesis of NTS in different categories of immunocompromised adults, contrasted to typhoid fever.
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Affiliation(s)
- Melita A Gordon
- Division of Gastroenterology, Henry Wellcome Laboratories, Nuffield Building, Crown Street, Liverpool University L69 3GE, UK.
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28
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Chessa D, Dorsey CW, Winter M, Baümler AJ. Binding Specificity of Salmonella Plasmid-encoded Fimbriae Assessed by Glycomics. J Biol Chem 2008; 283:8118-24. [DOI: 10.1074/jbc.m710095200] [Citation(s) in RCA: 37] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022] Open
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29
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Hapfelmeier S, Müller AJ, Stecher B, Kaiser P, Barthel M, Endt K, Eberhard M, Robbiani R, Jacobi CA, Heikenwalder M, Kirschning C, Jung S, Stallmach T, Kremer M, Hardt WD. Microbe sampling by mucosal dendritic cells is a discrete, MyD88-independent step in DeltainvG S. Typhimurium colitis. ACTA ACUST UNITED AC 2008; 205:437-50. [PMID: 18268033 PMCID: PMC2271026 DOI: 10.1084/jem.20070633] [Citation(s) in RCA: 144] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
Intestinal dendritic cells (DCs) are believed to sample and present commensal bacteria to the gut-associated immune system to maintain immune homeostasis. How antigen sampling pathways handle intestinal pathogens remains elusive. We present a murine colitogenic Salmonella infection model that is highly dependent on DCs. Conditional DC depletion experiments revealed that intestinal virulence of S. Typhimurium SL1344 ΔinvG mutant lacking a functional type 3 secretion system-1 (ΔinvG)critically required DCs for invasion across the epithelium. The DC-dependency was limited to the early phase of infection when bacteria colocalized with CD11c+CX3CR1+ mucosal DCs. At later stages, the bacteria became associated with other (CD11c−CX3CR1−) lamina propria cells, DC depletion no longer attenuated the pathology, and a MyD88-dependent mucosal inflammation was initiated. Using bone marrow chimeric mice, we showed that the MyD88 signaling within hematopoietic cells, which are distinct from DCs, was required and sufficient for induction of the colitis. Moreover, MyD88-deficient DCs supported transepithelial uptake of the bacteria and the induction of MyD88-dependent colitis. These results establish that pathogen sampling by DCs is a discrete, and MyD88-independent, step during the initiation of a mucosal innate immune response to bacterial infection in vivo.
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Abstract
Gastrointestinal infections are a major cause of morbidity and mortality worldwide. Infectious organisms are often recovered by microbiological methods, but surgical pathologists may play a very valuable role in diagnosis. This review will focus on infective disorders of the gastrointestinal tract with an emphasis on enterocolitides caused by food‐ and water‐borne pathogens. Diagnostic histological features of selected enteric infections will be emphasized, including those that mimic other inflammatory conditions of the gut (such as ischaemia or idiopathic inflammatory bowel disease), along with available diagnostic methods that can aid in diagnosis.
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Affiliation(s)
- L W Lamps
- Department of Pathology, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA.
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31
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Abstract
Diverticular disease-associated segmental colitis is a unique variant of chronic colitis limited to segments of the left colon that harbor diverticula. Histologically, this disease mimics chronic idiopathic inflammatory bowel disease and can be indistinguishable from ulcerative colitis or Crohn's colitis on histologic grounds alone. Patients typically present with hematochezia and cramping abdominal pain, and colonoscopic evaluation reveals inflammatory changes limited to the segment of bowel containing the diverticula, with rectal sparing. Although this disease does not appear to be an unusual form of diverticulitis but possibly an immunologically mediated process, many patients respond to treatment directed toward diverticulitis. A subset of patients requires immunosuppressive therapy and/or surgery, and a small subset progresses to develop classic ulcerative colitis. Because of the histologic overlap with ulcerative colitis and occasionally Crohn's colitis, it is essential that endoscopists provide a full description of the macroscopic appearance of the inflammatory changes at endoscopy, such as limitation to a segment of diverticular disease, so that the pathologist can provide a more informative interpretation of the biopsy.
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Affiliation(s)
- Laura W Lamps
- Department of Pathology, University of Arkansas for Medical Sciences, Little Rock, Arkansas 72212, USA.
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32
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Abstract
Salmonella species cause substantial morbidity, mortality and burden of disease globally. Infections with Salmonella species cause multiple clinical syndromes. Central to the pathophysiology of all human salmonelloses is the induction of a strong host innate immune/inflammatory response. Whether this ultimately reflects an adaptive advantage to the host or pathogen is not clear. However, it is evident that both the host and pathogen have evolved mechanisms of triggering host responses that are detrimental to the other. In this review, we explore some of the host and pathogenic mechanisms mobilized in the two predominant clinical syndromes associated with infection with Salmonella enterica species: enterocolitis and typhoid.
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Affiliation(s)
- Bryan Coburn
- Michael Smith Laboratories, University of British Columbia, Vancouver, British Columbia, Canada
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Stecher B, Paesold G, Barthel M, Kremer M, Jantsch J, Stallmach T, Heikenwalder M, Hardt WD. Chronic Salmonella enterica serovar Typhimurium-induced colitis and cholangitis in streptomycin-pretreated Nramp1+/+ mice. Infect Immun 2006; 74:5047-57. [PMID: 16926396 PMCID: PMC1594839 DOI: 10.1128/iai.00072-06] [Citation(s) in RCA: 58] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
Salmonella enterica subspecies 1 serovar Typhimurium is an enteric bacterial pathogen infecting a broad range of hosts. In susceptible Nramp1(-/-) (Slc11alpha1(-/-)) mice, serovar Typhimurium cannot efficiently colonize the intestine but causes a systemic typhoid-like infection. However, after pretreatment with streptomycin, these susceptible (C57BL/6 and BALB/c) mice develop acute serovar Typhimurium-induced colitis (M. Barthel et al., Infect. Immun. 71:2839-2858, 2003). It was not clear whether resistant Nramp1(+/+) (Slc11alpha1(+/+)) mouse strains would similarly develop colitis. Here we compared serovar Typhimurium infection in streptomycin-pretreated susceptible (C57BL/6) and resistant (DBA/2 and 129Sv/Ev) mouse strains: We found that acute colitis (days 1 and 3 postinfection) is strikingly similar in susceptible and resistant mice. In 129Sv/Ev mice we followed the serovar Typhimurium infection for as long as 6 weeks. After the initial phase of acute colitis, these animals developed chronic crypt-destructive colitis, including ulceration, crypt abscesses, pronounced mucosal and submucosal infiltrates, overshooting regeneration of the epithelium, and crypt branching. Moreover, we observed inflammation of the gall duct epithelium (cholangitis) in the 129Sv/Ev mice between days 14 and 43 of infection. Cholangitis was not attributable to side effects of the streptomycin treatment. Furthermore, chronic infection of 129Sv/Ev mice in a typhoid fever model did not lead to cholangitis. We propose that streptomycin-pretreated 129Sv/Ev mice provide a robust murine model for chronic enteric salmonellosis including complications such as cholangitis.
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Affiliation(s)
- Bärbel Stecher
- Institute of Microbiology, ETH Zürich, Wolfgang-Pauli Strasse 10, 8093 Zürich, Switzerland
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Tükel C, Raffatellu M, Chessa D, Wilson RP, Akçelik M, Bäumler AJ. Neutrophil influx during non-typhoidal salmonellosis: who is in the driver's seat? ACTA ACUST UNITED AC 2006; 46:320-9. [PMID: 16553804 DOI: 10.1111/j.1574-695x.2006.00051.x] [Citation(s) in RCA: 33] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
A massive neutrophil influx in the intestine is the histopathological hallmark of Salmonella enterica serovar Typhimurium-induced enterocolitis in humans. Two major hypotheses on the mechanism leading to neutrophil infiltration in the intestinal mucosa have emerged. One hypothesis suggests that S. enterica serovar Typhimurium takes an active role in triggering this host response by injecting proteins, termed effectors, into the host cell cytosol which induce a proinflammatory gene expression profile in the intestinal epithelium. The second hypothesis suggests a more passive role for the pathogen by proposing that bacterial invasion stimulates the innate pathways of inflammation because the pathogen-associated molecular patterns of S. enterica serovar Typhimurium are recognized by pathogen recognition receptors on cells in the lamina propria. A review of the current literature reveals that, while pathogen recognition receptors are clearly involved in eliciting neutrophil influx during S. enterica serovar Typhimurium infection, a direct contribution of effectors in triggering proinflammatory host cell responses cannot currently be ruled out.
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Affiliation(s)
- Cagla Tükel
- Department of Medical Microbiology and Immunology, School of Medicine, University of California at Davis, Davis, CA 95616-8645, USA
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Höner zu Bentrup K, Ramamurthy R, Ott CM, Emami K, Nelman-Gonzalez M, Wilson JW, Richter EG, Goodwin TJ, Alexander JS, Pierson DL, Pellis N, Buchanan KL, Nickerson CA. Three-dimensional organotypic models of human colonic epithelium to study the early stages of enteric salmonellosis. Microbes Infect 2006; 8:1813-25. [PMID: 16730210 DOI: 10.1016/j.micinf.2006.02.020] [Citation(s) in RCA: 80] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2005] [Revised: 02/11/2006] [Accepted: 02/16/2006] [Indexed: 11/28/2022]
Abstract
In vitro cell culture models used to study how Salmonella initiates disease at the intestinal epithelium would benefit from the recognition that organs and tissues function in a three-dimensional (3-D) environment and that this spatial context is necessary for development of cultures that more realistically resemble in vivo tissues/organs. Our aim was to establish and characterize biologically meaningful 3-D models of human colonic epithelium and apply them to study the early stages of enteric salmonellosis. The human colonic cell line HT-29 was cultured in 3-D and characterized by immunohistochemistry, histology, and scanning electron microscopy. Wild-type Salmonella typhimurium and an isogenic SPI-1 type three secretion system (TTSS) mutant derivative (invA) were used to compare the interactions with 3-D cells and monolayers in adherence/invasion, tissue pathology, and cytokine expression studies. The results showed that 3-D culture enhanced many characteristics normally associated with fully differentiated, functional intestinal epithelia in vivo, including better organization of junctional, extracellular matrix, and brush-border proteins, and highly localized mucin production. Wild-type Salmonella demonstrated increased adherence, but significantly lower invasion for 3-D cells. Interestingly, the SPI-I TTSS mutant showed wild-type ability to invade into the 3-D cells but did not cause significant structural changes to these cells. Moreover, 3-D cells produced less interleukin-8 before and after Salmonella infection. These results suggest that 3-D cultures of human colonic epithelium provide valuable alternative models to study human enteric salmonellosis with potential for novel insight into Salmonella pathogenesis.
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Affiliation(s)
- Kerstin Höner zu Bentrup
- Department of Microbiology and Immunology, Program in Molecular Pathogenesis and Immunity, Tulane University Health Sciences Center, New Orleans, LA 70112, USA
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Hapfelmeier S, Hardt WD. A mouse model for S. typhimurium-induced enterocolitis. Trends Microbiol 2005; 13:497-503. [PMID: 16140013 DOI: 10.1016/j.tim.2005.08.008] [Citation(s) in RCA: 162] [Impact Index Per Article: 8.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2005] [Revised: 07/26/2005] [Accepted: 08/12/2005] [Indexed: 12/20/2022]
Abstract
Salmonella typhimurium has emerged as a model pathogen that manipulates host cells in a complex fashion, thus causing disease. In humans, S. typhimurium causes acute intestinal inflammation. Intriguingly, type III secreted virulence proteins have a central role in this process. At the cellular level, the functions of these factors are well characterized; at present, animal models are required for elucidating how these factors trigger inflammatory disease in vivo. Calf infection models have been employed successfully and, recently, a mouse model was identified: in streptomycin-pretreated mice, S. typhimurium causes acute colitis. This mouse model provides a new avenue for research into acute intestinal inflammation because it enables the manipulation and dissection of both the bacterial and host contributions to the disease in unsurpassed detail.
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Affiliation(s)
- Siegfried Hapfelmeier
- Institute of Microbiology, ETH Hönggerberg, Wolfgang-Pauli-Str. 10, 8093 Zürich, Switzerland
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Affiliation(s)
- Rakesh Rao
- Department of Pediatrics, University of Kentucky, Lexington, KY 40536, USA
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Coburn B, Li Y, Owen D, Vallance BA, Finlay BB. Salmonella enterica serovar Typhimurium pathogenicity island 2 is necessary for complete virulence in a mouse model of infectious enterocolitis. Infect Immun 2005; 73:3219-27. [PMID: 15908346 PMCID: PMC1111876 DOI: 10.1128/iai.73.6.3219-3227.2005] [Citation(s) in RCA: 156] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023] Open
Abstract
Salmonella species cause a wide range of disease in multiple hosts. Salmonella enterica serovar Typhimurium causes self-limited intestinal disease in humans and systemic typhoid-like illness in susceptible mice. The prevailing dogma in murine S. enterica serovar Typhimurium pathogenesis is that distinct virulence mechanisms-Salmonella pathogenicity islands 1 and 2 (SPI1 and SPI2)-perform distinct roles in pathogenesis, the former being important for invasion and intestinal disease and the latter important for intracellular survival and systemic persistence and disease. Although evidence from bovine infections has suggested that SPI2 has a role in ileal disease, there is no evidence that SPI2 is important for inflammation in a disease that more closely recapitulates human colitis. Using S. enterica serovar Typhimurium strains that lack functional type III secretion systems, we demonstrate that SPI2 is essential for complete virulence in murine infectious enterocolitis. Using a recently characterized murine model (M. Barthel,S. Hapfelmeier, L. Quintanilla-Martinez, M. Kremer, M. Rohde, M. Hogardt, K. Pfeffer, H. Russmann, and W. D. Hardt, Infect. Immun. 71:2839-2858, 2003), we demonstrate that SPI1 mutants are unable to cause intestinal disease 48 h after infection and that SPI2-deficient bacteria also cause significantly attenuated typhlitis. We show that at the peak of inflammation in the cecum, SPI2 mutants induce diminished intercellular adhesion molecule 1 expression and neutrophil recruitment but that wild-type and mutant Salmonella are similarly distributed in the lumen of the infected organ. Finally, we demonstrate that attenuation of intestinal inflammation is accompanied by resolution of typhlitis in the mutant, but not wild-type, infections. Collectively, these results indicate that SPI2 is needed for enterocolitis, as well as for systemic disease.
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Affiliation(s)
- Bryan Coburn
- Michael Smith Laboratories, University of British Columbia, 2185 East Mall, Vancouver, British Columbia V6T 1Z4, Canada
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Stecher B, Macpherson AJ, Hapfelmeier S, Kremer M, Stallmach T, Hardt WD. Comparison of Salmonella enterica serovar Typhimurium colitis in germfree mice and mice pretreated with streptomycin. Infect Immun 2005; 73:3228-41. [PMID: 15908347 PMCID: PMC1111827 DOI: 10.1128/iai.73.6.3228-3241.2005] [Citation(s) in RCA: 112] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
Salmonella enterica subspecies 1 serovar Typhimurium is a common cause of bacterial enterocolitis. Mice are generally protected from Salmonella serovar Typhimurium colonization and enterocolitis by their resident intestinal microflora. This phenomenon is called "colonization resistance" (CR). Two murine Salmonella serovar Typhimurium infection models are based on the neutralization of CR: (i) in specific-pathogen-free mice pretreated with streptomycin (StrSPF mice) antibiotics disrupt the intestinal microflora; and (ii) germfree (GF) mice are raised without any intestinal microflora, but their intestines show distinct physiologic and immunologic characteristics. It has been unclear whether the same pathogenetic mechanisms trigger Salmonella serovar Typhimurium colitis in GF and StrSPF mice. In this study, we compared the two colitis models. In both of the models Salmonella serovar Typhimurium efficiently colonized the large intestine and triggered cecum and colon inflammation starting 8 h postinfection. The type III secretion system encoded in Salmonella pathogenicity island 1 was essential in both disease models. Thus, Salmonella serovar Typhimurium colitis is triggered by similar pathogenetic mechanisms in StrSPF and GF mice. This is remarkable considering the distinct physiological properties of the GF mouse gut. One obvious difference was more pronounced damage and reduced regenerative response of the cecal epithelium in GF mice. Overall, StrSPF mice and GF mice provide similar but not identical models for Salmonella serovar Typhimurium colitis.
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Affiliation(s)
- Bärbel Stecher
- Institute of Microbiology, ETH Zürich, Wolfgang-Paulistrasse 10, HCI G413, CH-8093 Zürich, Switzerland
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Hapfelmeier S, Stecher B, Barthel M, Kremer M, Müller AJ, Heikenwalder M, Stallmach T, Hensel M, Pfeffer K, Akira S, Hardt WD. The Salmonella pathogenicity island (SPI)-2 and SPI-1 type III secretion systems allow Salmonella serovar typhimurium to trigger colitis via MyD88-dependent and MyD88-independent mechanisms. THE JOURNAL OF IMMUNOLOGY 2005; 174:1675-85. [PMID: 15661931 DOI: 10.4049/jimmunol.174.3.1675] [Citation(s) in RCA: 303] [Impact Index Per Article: 15.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Salmonella typhimurium can colonize the gut, invade intestinal tissues, and cause enterocolitis. In vitro studies suggest different mechanisms leading to mucosal inflammation, including 1) direct modulation of proinflammatory signaling by bacterial type III effector proteins and 2) disruption or penetration of the intestinal epithelium so that penetrating bacteria or bacterial products can trigger innate immunity (i.e., TLR signaling). We studied these mechanisms in vivo using streptomycin-pretreated wild-type and knockout mice including MyD88(-/-) animals lacking an adaptor molecule required for signaling via most TLRs. The Salmonella SPI-1 and the SPI-2 type III secretion systems (TTSS) contributed to inflammation. Mutants that retain only a functional SPI-1 (M556; sseD::aphT) or a SPI-2 TTSS (SB161; DeltainvG) caused attenuated colitis, which reflected distinct aspects of the colitis caused by wild-type S. typhimurium: M556 caused diffuse cecal inflammation that did not require MyD88 signaling. In contrast, SB161 induced focal mucosal inflammation requiring MyD88. M556 but not SB161 was found in intestinal epithelial cells. In the lamina propria, M556 and SB161 appeared to reside in different leukocyte cell populations as indicated by differential CD11c staining. Only the SPI-2-dependent inflammatory pathway required aroA-dependent intracellular growth. Thus, S. typhimurium can use two independent mechanisms to elicit colitis in vivo: SPI-1-dependent and MyD88-independent signaling to epithelial cells and SPI-2-dependent intracellular proliferation in the lamina propria triggering MyD88-dependent innate immune responses.
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Affiliation(s)
- Siegfried Hapfelmeier
- Institute of Microbiology, D-BIOL, Eidgenössiche Technische Hochschule, Zürich, Switzerland
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Tsai CN, Chang CM, Chuang CH, Jin YT, Liu MF, Wang CR. Extended colonic ulcerations in a patient with microscopic polyangiitis. Ann Rheum Dis 2004; 63:1521-2. [PMID: 15479909 PMCID: PMC1754815 DOI: 10.1136/ard.2003.018580] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/03/2022]
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Abstract
Although naturally occurring food-borne pathogens cause more than 76 million illnesses, 325,000 hospitalizations, and 5000 deaths annually in the United States, many more infections are unrecognized and unreported. In addition, mass production and distribution of food, on a global rather than a local scale, make it possible for localized instances of contamination to spread quickly to other states, provinces, and countries. Infectious organisms are often recovered by microbiological methods, but surgical pathologists may play a very valuable role in diagnosis. This review will focus on the diagnosis of food-borne infectious diseases of the gastrointestinal tract, including those that mimic other inflammatory conditions of the gut (such as ischemia or idiopathic inflammatory bowel disease); available diagnostic methods; and gastrointestinal infectious processes that pathologists should be aware of in terms of potential biologic weapons threats.
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Affiliation(s)
- Laura W Lamps
- Department of Pathology, University of Arkansas for Medical Sciences, Little Rock 72205, USA.
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Barthel M, Hapfelmeier S, Quintanilla-Martínez L, Kremer M, Rohde M, Hogardt M, Pfeffer K, Rüssmann H, Hardt WD. Pretreatment of mice with streptomycin provides a Salmonella enterica serovar Typhimurium colitis model that allows analysis of both pathogen and host. Infect Immun 2003; 71:2839-58. [PMID: 12704158 PMCID: PMC153285 DOI: 10.1128/iai.71.5.2839-2858.2003] [Citation(s) in RCA: 809] [Impact Index Per Article: 36.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/20/2023] Open
Abstract
Salmonella enterica subspecies 1 serovar Typhimurium is a principal cause of human enterocolitis. For unknown reasons, in mice serovar Typhimurium does not provoke intestinal inflammation but rather targets the gut-associated lymphatic tissues and causes a systemic typhoid-like infection. The lack of a suitable murine model has limited the analysis of the pathogenetic mechanisms of intestinal salmonellosis. We describe here how streptomycin-pretreated mice provide a mouse model for serovar Typhimurium colitis. Serovar Typhimurium colitis in streptomycin-pretreated mice resembles many aspects of the human infection, including epithelial ulceration, edema, induction of intercellular adhesion molecule 1, and massive infiltration of PMN/CD18(+) cells. This pathology is strongly dependent on protein translocation via the serovar Typhimurium SPI1 type III secretion system. Using a lymphotoxin beta-receptor knockout mouse strain that lacks all lymph nodes and organized gut-associated lymphatic tissues, we demonstrate that Peyer's patches and mesenteric lymph nodes are dispensable for the initiation of murine serovar Typhimurium colitis. Our results demonstrate that streptomycin-pretreated mice offer a unique infection model that allows for the first time to use mutants of both the pathogen and the host to study the molecular mechanisms of enteric salmonellosis.
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Affiliation(s)
- Manja Barthel
- Institute of Microbiology, ETH Zürich, 8092 Zürich, Switzerland
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Chao HC, Chiu CH, Kong MS, Chang LY, Huang YC, Lin TY, Lou CC. Factors associated with intestinal perforation in children's non-typhi Salmonella toxic megacolon. Pediatr Infect Dis J 2000; 19:1158-62. [PMID: 11144376 DOI: 10.1097/00006454-200012000-00008] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
BACKGROUND To evaluate the risk factors for intestinal perforation in children with toxic megacolon caused by non-typhi Salmonella infection. METHODS During an 11-year period we reviewed the records of children treated for non-typhi Salmonella infection. All of the subjects had positive stool culture for non-typhi Salmonella and were treated with intravenous ceftriaxone during hospitalization. Clinical data reviewed included demographic features, clinical manifestations, laboratory findings, radiologic findings, microbiology, therapeutic effect of hydration and rectal tube placement and the operative findings. Patients with toxic megacolon were defined as those having toxic appearance, diarrhea, high fever (>39 degrees C) and marked colon dilatation with maximal diameter > 1.5 times the width of the vertebra body of the first lumbar spine (L1-VB). To define the risk factors for patients with toxic megacolon complicated by intestinal perforation, patients were divided into two groups for analysis: P group, those complicated with intestinal perforation; and NP group, those without intestinal perforation. Differences in age, sex, severity of diarrhea, duration of fever, hemogram and its differential, culture, stool analysis, serum C-reactive protein (CRP), electrolytes, maximal colon diameter, medical therapy and timing of rectal tube insertion between the two groups were analyzed. Statistical analyses were conducted with chi square tests and multiple logistic regression. RESULTS A total of 75 patients (P group, 27 patients; NP group, 48 patients) ages 4 months to 6 years were evaluated. With chi square analysis 7 variables were found to be significantly associated with intestinal perforation: age >1 year; fever >5 days; ratio of immature to total neutrophils >20%; serum CRP >200 mg/l; colon diameter >2.5 times the width of L1-VB; inadequate early hydration; and delay in rectal tube insertion. With multivariate analysis age >1 year, serum CRP >200 mg/l and colon diameter >2.5 times of width of L1-VB, inadequate early hydration and delay in rectal tube insertion were the most significant factors associated with intestinal perforation. CONCLUSION Identification of patients with toxic megacolon associated with non-typhi Salmonella infection at risk for further intestinal perforation is possible. Early effective fluid resuscitation and rectal tube insertion may be helpful to prevent the occurrence of intestinal perforation.
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Affiliation(s)
- H C Chao
- Department of Pediatrics, Chang Gung Children's Hospital, Taoyuan, Taiwan.
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46
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Darwin KH, Miller VL. Molecular basis of the interaction of Salmonella with the intestinal mucosa. Clin Microbiol Rev 1999; 12:405-28. [PMID: 10398673 PMCID: PMC100246 DOI: 10.1128/cmr.12.3.405] [Citation(s) in RCA: 268] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023] Open
Abstract
Salmonella is one of the most extensively characterized bacterial pathogens and is a leading cause of bacterial gastroenteritis. Despite this, we are only just beginning to understand at a molecular level how Salmonella interacts with its mammalian hosts to cause disease. Studies during the past decade on the genetic basis of virulence of Salmonella have significantly advanced our understanding of the molecular basis of the host-pathogen interaction, yet many questions remain. In this review, we focus on the interaction of enterocolitis-causing salmonellae with the intestinal mucosa, since this is the initiating step for most infections caused by Salmonella. Animal and in vitro cell culture models for the interaction of these bacteria with the intestinal epithelium are reviewed, along with the bacterial genes that are thought to affect this interaction. Lastly, recent studies on the response of epithelial cells to Salmonella infection and how this might promote diarrhea are discussed.
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Affiliation(s)
- K H Darwin
- Departments of Pediatrics, Washington University School of Medicine, St. Louis, Missouri 63110, USA
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Gillen D, Wirz AA, Neithercut WD, Ardill JE, McColl KE. Helicobacter pylori infection potentiates the inhibition of gastric acid secretion by omeprazole. Gut 1999; 44:468-75. [PMID: 10075952 PMCID: PMC1727447 DOI: 10.1136/gut.44.4.468] [Citation(s) in RCA: 96] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/01/2023]
Abstract
BACKGROUND Omeprazole has a greater intragastric pH elevating effect in Helicobacter pylori positive than negative subjects. Ammonia production by H pylori has been suggested as a probable mechanism. AIMS To assess the effect of H pylori status on gastric acid secretion during omeprazole treatment, and to examine the possible role of ammonia neutralisation of intragastric acid in increased omeprazole efficacy in infected subjects. METHODS Twenty H pylori positive and 12 H pylori negative healthy volunteers were examined before and six to eight weeks after commencing omeprazole 40 mg/day. On both occasions plasma gastrin and acid output were measured basally and in response to increasing doses of gastrin 17 (G-17). Gastric juice ammonium concentrations were also measured. RESULTS Prior to omeprazole, measurements were similar in the H pylori positive and negative subjects. During omeprazole, median basal intragastric pH was higher in the H pylori positive (7.95) versus negative (3.75) subjects (p<0.002). During omeprazole basal, submaximal (180 pmol/kg/h G-17), and maximal acid outputs (800 pmol/kg/h G-17) were lower in H pylori positive subjects (0.0, 3.6, 6.0 mmol/h respectively) versus negative subjects (0.3, 14.2, 18.6 mmol/h) (p<0.03 for each). This effect was not explained by neutralisation by ammonia. CONCLUSION The presence of H pylori infection leads to a more profound suppression of acid secretion during omeprazole treatment. The effect cannot be explained by neutralisation of intragastric acid by bacterial ammonia production and its precise mechanism has to be explained.
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Affiliation(s)
- D Gillen
- University Department of Medicine and Therapeutics, Western Infirmary, Glasgow G11 6NT, UK
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Huang GT, Haake SK, Park NH. Gingival epithelial cells increase interleukin-8 secretion in response to Actinobacillus actinomycetemcomitans challenge. J Periodontol 1998; 69:1105-10. [PMID: 9802708 DOI: 10.1902/jop.1998.69.10.1105] [Citation(s) in RCA: 29] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
Abstract
Periodontal diseases result from the interaction of bacterial pathogens with the host gingival tissues. The role of gingival epithelial cells in the initiation of host defense mechanisms after encountering oral bacteria has not been investigated. Actinobacillus actinomycetemcomitans is a key periodontal pathogen that adheres to and invades oral epithelial cells. Thus, we examined whether gingival epithelial cells increase secretion of the potent neutrophil chemoattractant interleukin-8 (IL-8) following A. actinomycetemcomitans challenge. Normal human oral keratinocytes (NHOK), isolated from gingival tissue, and 3 oral epithelial cell lines (HOK-18A, HOK-16B-BaP-T1, and HEp-2) were co-cultured with A. actinomycetemcomitans for 2 hours to allow bacteria-epithelial cell interactions. The epithelial cells were then washed, and fresh medium with gentamicin was added to kill extracellular bacteria. Cell cultures were further incubated for 24 hours before the supernatant was collected for IL-8 detection with ELISA. The results showed that IL-8 secretion increased 2- to 7-fold 24 hours after bacterial challenge. The highest IL-8 secretion was at the multiplicity of infection (MOI) of 1,000:1 in bacterial dose response studies using HOK-16B-BaP-T1 cells. Time-course studies revealed that IL-8 secretion rapidly reached a maximum level 6 hours after bacterial challenge and subsequently decreased to basal levels. These data indicate that gingival epithelial cells are capable of upregulating IL-8 expression rapidly in response to A. actinomycetemcomitans challenge and thus may facilitate the recruitment of neutrophils as a host defense mechanism.
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Affiliation(s)
- G T Huang
- Section of Endodontics, UCLA School of Dentistry, Los Angeles, CA 90095-1668, USA.
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Huang GT, Eckmann L, Savidge TC, Kagnoff MF. Infection of human intestinal epithelial cells with invasive bacteria upregulates apical intercellular adhesion molecule-1 (ICAM)-1) expression and neutrophil adhesion. J Clin Invest 1996; 98:572-83. [PMID: 8755670 PMCID: PMC507463 DOI: 10.1172/jci118825] [Citation(s) in RCA: 147] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/02/2023] Open
Abstract
The acute host response to gastrointestinal infection with invasive bacteria is characterized by an accumulation of neutrophils in the lamina propria, and neutrophil transmigration to the luminal side of the crypts. Intestinal epithelial cells play an important role in the recruitment of inflammatory cells to the site of infection through the secretion of chemokines. However, little is known regarding the expression, by epithelial cells, of molecules that are involved in interactions between the epithelium and neutrophils following bacterial invasion. We report herein that expression of ICAM-1 on human colon epithelial cell lines, and on human enterocytes in an in vivo model system, is upregulated following infection with invasive bacteria. Increased ICAM-1 expression in the early period (4-9 h) after infection appeared to result mainly from a direct interaction between invaded bacteria and host epithelial cells since it co-localized to cells invaded by bacteria, and the release of soluble factors by epithelial cells played only a minor role in mediating increased ICAM-1 expression. Furthermore, ICAM-1 was expressed on the apical side of polarized intestinal epithelial cells, and increased expression was accompanied by increased neutrophil adhesion to these cells. ICAM-1 expression by intestinal epithelial cells following infection with invasive bacteria may function to maintain neutrophils that have transmigrated through the epithelium in close contact with the intestinal epithelium, thereby reducing further invasion of the mucosa by invading pathogens.
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Affiliation(s)
- G T Huang
- Laboratory of Mucosal Immunology, Department of Medicine, University of California, San Diego, La Jolla, California, 92093-0623, USA
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Matsumoto T, Iida M, Kimura Y, Fujishima M. Culture of colonoscopically obtained biopsy specimens in acute infectious colitis. Gastrointest Endosc 1994; 40:184-7. [PMID: 8013819 DOI: 10.1016/s0016-5107(94)70164-4] [Citation(s) in RCA: 18] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
To investigate the value of colonoscopy in the diagnosis of acute infectious colitis, we prospectively cultured both feces and biopsy specimens obtained during colonoscopy of patients who, because of clinical features such as the acute onset of abdominal pain and diarrhea, were suspected of having the disease. Of the 20 patients who participated in the study, some causative micro-organism was identified in 13 (Campylobacter in 6 patients, Salmonella in 5 patients, and Yersinia in 2 patients), but not in the remaining 7. In addition, biopsy specimens were more sensitive for culture (positive for Campylobacter in 4 patients, Salmonella in 5 patients, and Yersinia in 1 patient) than were feces samples (positive for Campylobacter in 2 patients and for Yersinia and Salmonella in 1 patient each) (50% versus 20%, p = 0.048). These findings suggest that cultures of biopsy specimens obtained during colonoscopy may be diagnostic in sporadic cases of acute enterocolitis caused by bacteria.
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Affiliation(s)
- T Matsumoto
- Second Department of Internal Medicine, Faculty of Medicine, Kyushu University, Fukuoka, Japan
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