Respiratory influenza virus infection induces intestinal immune injury via microbiota-mediated Th17 cell-dependent inflammation

Jian Wang; Fengqi Li; Haiming Wei; Zhe-Xiong Lian; Rui Sun; Zhigang Tian

doi:10.1084/jem.20140625

Respiratory influenza virus infection induces intestinal immune injury via microbiota-mediated Th17 cell-dependent inflammation

J Exp Med. 2014 Nov 17;211(12):2397-410. doi: 10.1084/jem.20140625. Epub 2014 Nov 3.

Authors

Jian Wang¹, Fengqi Li¹, Haiming Wei², Zhe-Xiong Lian², Rui Sun², Zhigang Tian³

Affiliations

¹ Institute of Immunology and CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life Sciences and Medical Center, University of Science and Technology of China, Hefei, Anhui 230027, China.
² Institute of Immunology and CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life Sciences and Medical Center, University of Science and Technology of China, Hefei, Anhui 230027, China Hefei National Laboratory for Physical Sciences at Microscale, Hefei, Anhui 230027, China.
³ Institute of Immunology and CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life Sciences and Medical Center, University of Science and Technology of China, Hefei, Anhui 230027, China Hefei National Laboratory for Physical Sciences at Microscale, Hefei, Anhui 230027, China Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang 310003, China tzg@ustc.edu.cn.

Abstract

Influenza in humans is often accompanied by gastroenteritis-like symptoms such as diarrhea, but the underlying mechanism is not yet understood. We explored the occurrence of gastroenteritis-like symptoms using a mouse model of respiratory influenza infection. We found that respiratory influenza infection caused intestinal injury when lung injury occurred, which was not due to direct intestinal viral infection. Influenza infection altered the intestinal microbiota composition, which was mediated by IFN-γ produced by lung-derived CCR9(+)CD4(+) T cells recruited into the small intestine. Th17 cells markedly increased in the small intestine after PR8 infection, and neutralizing IL-17A reduced intestinal injury. Moreover, antibiotic depletion of intestinal microbiota reduced IL-17A production and attenuated influenza-caused intestinal injury. Further study showed that the alteration of intestinal microbiota significantly stimulated IL-15 production from intestinal epithelial cells, which subsequently promoted Th17 cell polarization in the small intestine in situ. Thus, our findings provide new insights into an undescribed mechanism by which respiratory influenza infection causes intestinal disease.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Antibodies, Neutralizing / immunology
Antibodies, Neutralizing / pharmacology
CD4-Positive T-Lymphocytes / immunology
CD4-Positive T-Lymphocytes / metabolism
Chemokines, CC / immunology
Chemokines, CC / metabolism
Epithelial Cells / immunology
Epithelial Cells / metabolism
Flow Cytometry
Host-Pathogen Interactions / immunology
Humans
Inflammation / genetics
Inflammation / immunology*
Influenza A Virus, H1N1 Subtype / immunology*
Influenza A Virus, H1N1 Subtype / physiology
Interleukin-15 / immunology
Interleukin-15 / metabolism
Interleukin-17 / genetics
Interleukin-17 / immunology*
Interleukin-17 / metabolism
Intestines / drug effects
Intestines / immunology*
Intestines / microbiology
Lung / immunology
Lung / microbiology
Male
Mice, Inbred C57BL
Mice, Knockout
Microbiota / immunology*
Orthomyxoviridae Infections / genetics
Orthomyxoviridae Infections / immunology*
Orthomyxoviridae Infections / virology
Receptors, CCR / immunology
Receptors, CCR / metabolism
Reverse Transcriptase Polymerase Chain Reaction
Th17 Cells / immunology*
Th17 Cells / metabolism

Substances

Antibodies, Neutralizing
CC chemokine receptor 9
Ccl25 protein, mouse
Chemokines, CC
Interleukin-15
Interleukin-17
Receptors, CCR