MUCOSAL IMMUNOLOGY Sick of the Flu

RESEARCH HIGHLIGHTS

Nature Reviews Immunology | AOP, published online 14 November 2014; doi:10.1038/nri3773

MUCOSAL IMMUNOLOGY Sick of the flu

Respiratory infection with influ- In support of an indirect effect The lung-derived CD4+CCR9+ enza virus is often associated with of influenza virus on the intestines, effector T cells secrete interferon-γ gastroenteritis-like symptoms such Wang et al. showed that there in the intestines, which disrupts as vomiting and diarrhoea. This was a decrease in the numbers of homeostasis of the microbiota. study provides a mechanism for such segmented filamentous bacteria, As no intestinal injury was symptoms by showing that CD4+ Lactobacilli and Lactococci, and observed in PR8‑infected mice defi- T cells from the respiratory mucosa an increase in the number of cient for interleukin‑17A (IL‑17A),

are recruited to the intestinal mucosa Enterobacteriaceae (including the authors propose that TH17 cells during influenza virus infection, where Escherichia coli), after intranasal might be involved in the injurious they induce dysbiosis that stimulates PR8 infection. In mice treated with effect of intestinal dysbiosis. Indeed,

T helper 17 (TH17) cell-mediated streptomycin (an antibiotic to which the number of TH17 cells, as well influenza intestinal injury. E. coli is sensitive), the intestines as the expression of IL‑17A and of

virus infection In mice infected intranasally were protected from PR8‑associated the TH17 cell-specific transcription mediates with the A/Puerto Rico/8/34 (PR8) intestinal injury. Also, transferring factor RORγt, increased in the small influenza virus strain, both the lung the intestinal microbiota from intestine after intranasal PR8 infec- intestinal and small intestine, but not nonmu- PR8‑infected mice to non-infected tion. Treatment with streptomycin injury by cosal liver and kidney tissue, showed mice caused intestinal injury in the or an IL‑17A‑specific neutralizing altering the signs of severe injury. Influenza virus absence of influenza virus infection. antibody reduced IL‑17A expression composition of could not be detected in the small Hence, respiratory influenza virus and intestinal injury, respectively, intestine of intranasally infected infection mediates intestinal injury which shows that IL‑17A production the intestinal mice, and mice infected intra by altering the composition of the occurs downstream of intestinal microbiota gastrically with PR8 did not have intestinal microbiota, particularly dysbiosis. The final missing link injury to the small intestine; there- the levels of E. coli. between PR8‑induced intestinal

fore, influenza virus So what causes intestinal dysbio- dysbiosis and TH17 cell-mediated does not directly sis in response to respiratory influ- intestinal injury came from the dem- cause injury to the enza virus infection? The authors onstration that the altered intestinal intestinal mucosa. showed that treating PR8‑infected microbiota of PR8‑infected mice mice with a neutralizing antibody induced IL‑15 expression by IECs,

specific for CC-chemokine ligand 25 which in turn promoted TH17 cell (CCL25), which is expressed by polarization in the small intestine. intestinal epithelial cells (IECs), These findings show that cross- prevented intestinal dysbiosis talk between the respiratory and and reduced intestinal injury. intestinal mucosae can occur through Also, the number of CD4+ T cells the specific recruitment of CD4+ expressing the CCL25 receptor T cells. This interplay of immune CCR9 was increased in the lamina cells between different mucosal sites propria of PR8‑infected mice. lends support to the concept of a These CCR9+ cells were shown to ‘common mucosal immune system’. be induced in the lungs in response Kirsty Minton to PR8‑mediated expression of the ORIGINAL RESEARCH PAPER Wang, J. et al. enzyme ALDH1A2 (which regulates Respiratory influenza virus infection induces production of the CCR9‑inducing intestinal immune injury via microbiota-mediated factor retinoic acid) and they were Th17 cell-dependent inflammation. J. Exp. Med. S.Bradbrook/NPG http://dx.doi.org/10.1084/jem.20140625 (2014) then recruited to the intestines.

NATURE REVIEWS | IMMUNOLOGY VOLUME 14 | DECEMBER 2014