Comparative proteomic analysis reveals activation of mucosal innate immune signaling pathways during cholera.

Abstract

Vibrio cholerae O1 is a major cause of acute watery diarrhea in over 50 countries. Evidence suggests that V. cholerae O1 may activate inflammatory pathways, and a recent study of a Bangladeshi population showed that variants in innate immune genes play a role in mediating susceptibility to cholera. We analyzed human proteins present in the small intestine of patients infected with V. cholerae O1 to characterize the host response to this pathogen. We collected duodenal biopsy specimens from patients with acute cholera after stabilization and again 30 days after initial presentation. Peptides extracted from biopsy specimens were sequenced and quantified using label-free mass spectrometry and SEQUEST. Twenty-seven host proteins were differentially abundant between the acute and convalescent stages of infection; the majority of these have known roles in innate defense, cytokine production, and apoptosis. Immunostaining confirmed that two proteins, WARS and S100A8, were more abundant in lamina propria cells during the acute stage of cholera. Analysis of the differentially abundant proteins revealed the activation of key regulators of inflammation by the innate immune system, including Toll-like receptor 4, nuclear factor kappa-light-chain-enhancer of activated B cells, mitogen-activated protein kinases, and caspase-dependent inflammasomes. Interleukin-12β (IL-12β) was a regulator of several proteins that were activated during cholera, and we confirmed that IL-12β was produced by lymphocytes recovered from duodenal biopsy specimens of cholera patients. Our study shows that a broad inflammatory response is generated in the gut early after onset of cholera, which may be critical in the development of long-term mucosal immunity against V. cholerae O1.

• Authors: Crystal N Ellis, Regina C LaRocque, Taher Uddin, Bryan Krastins, Leslie M Mayo-Smith, David Sarracino, Elinor K Karlsson, Atiqur Rahman, Tahmina Shirin, Taufiqur R Bhuiyan, Fahima Chowdhury, Ashraful Islam Khan, Edward T Ryan, Stephen B Calderwood, Firdausi Qadri, Jason B Harris
• Journal: Infection and immunity (Infect Immun) Vol. 83 Issue 3 Pg. 1089-103 (Mar 2015) ISSN: 1098-5522 [Electronic] United States
• PMID: 25561705 (Publication Type: Comparative Study, Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2015, American Society for Microbiology. All Rights Reserved.

Chemical References

• Calgranulin A
• Inflammasomes
• Interleukin-12 Subunit p40
• TLR4 protein, human
• Toll-Like Receptor 4
• Tryptophan-tRNA Ligase
• WARS1 protein, human

Topics

• Acute Disease
• Apoptosis (immunology)
• Biopsy
• Calgranulin A (genetics, immunology)
• Cholera (genetics, immunology, microbiology, pathology)
• Convalescence
• Duodenum (immunology, microbiology, pathology)
• Gene Expression Profiling
• Gene Expression Regulation
• Host-Pathogen Interactions
• Humans
• Immunity, Mucosal
• Inflammasomes (genetics, immunology)
• Interleukin-12 Subunit p40 (genetics, immunology)
• Proteomics
• Signal Transduction (immunology)
• Toll-Like Receptor 4 (genetics, immunology)
• Tryptophan-tRNA Ligase (genetics, immunology)
• Vibrio cholerae O1 (growth & development, immunology, pathogenicity)