Simian immunodeficiency virus–induced mucosal interleukin-17 deficiency promotes Salmonella dissemination from the gut

Abstract

Salmonella typhimurium causes a localized enteric infection in immunocompetent individuals, whereas HIV-infected individuals develop a life-threatening bacteremia. Here we show that simian immunodeficiency virus (SIV) infection results in depletion of T helper type 17 (T H 17) cells in the ileal mucosa of rhesus macaques, thereby impairing mucosal barrier functions to S. typhimurium dissemination. In SIV-negative macaques, the gene expression profile induced by S. typhimurium in ligated ileal loops was dominated by T H 17 responses, including the expression of interleukin-17 (IL-17) and IL-22. T H 17 cells were markedly depleted in SIV-infected rhesus macaques, resulting in blunted T H 17 responses to S. typhimurium infection and increased bacterial dissemination. IL-17 receptor-deficient mice showed increased systemic dissemination of S. typhimurium from the gut, suggesting that IL-17 deficiency causes defects in mucosal barrier function. We conclude that SIV infection impairs the IL-17 axis, an arm of the mucosal immune response preventing systemic microbial dissemination from the gastrointestinal tract. A.G. served as consultant for the presentation of NTS bacteremia in African subjects. J.K.K. served as collaborator on studies with Il17ra −/− mice and provided useful comments on the experimental design. S.D. designed and supervised the SIV infections of rhesus macaques, blood sample scheduling, macaque protocols, processing and cell isolations for flow cytometry and DNA microarray analyses. A.J.B. was responsible for the experimental design and supervision of mouse studies, ligated ileal loop experiments in rhesus macaques, macaque protocols and analysis of host responses to Salmonella infection. A.J.B. collected tissue during the ligated ileal loop surgery and was responsible for the final manuscript preparation. A.J.B. and S.D. provided financial support for the study and equally contributed to the experimental design, supervision and data interpretation. Although nontyphoidal Salmonella serotypes (NTS) are common agents causing acute foodborne disease worldwide, it is unusual to isolate them from the blood of adults, because in immunocompetent individuals these pathogens remain localized to the intestine and cause a self-limiting gastroenteritis 1 . However, in people with underlying immunosuppression, NTS may spread beyond the intestine and reach the bloodstream, a serious complication known as NTS bacteremia2. The rise in the number of people with AIDS in sub-Saharan Africa has led to a dramatic increase in the frequency of NTS bacteremia3. In marked contrast to the pre-AIDS era4, NTS is currently a leading cause of hospital admission of adults and among the most common bacterial blood isolates from hospitalized adults in sub-Saharan Africa5, the vast majority of whom are HIV positive 3 . NTS infection in HIV-positive African adults is associated with high acute mortality rates (47%) 6 . Although the occurrence of NTS bacteremia in HIV-positive people is well documented, there are no reports inv...

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“…Mice devoid of IL-17 signaling manifest alterations in their microbiotas and suffer from increased intestinal permeability and bacterial translocation to systemic sites after infectious insults of the gut (15,16,53). Additionally, loss of Th17 populations during infections by either simian virus or HIV has been associated with intestinal dysbiosis, systemic microbial translocation, and disease progression (53)(54)(55). Moreover, SFB confers heterologous protection from the murine enteropathogen C. rodentium (10).…”

Preferential loss of gut-homing α4β7 CD4+ T cells and their circulating functional subsets in acute HIV-1 infection

“…28,29 Numerous studies demonstrated that the loss of gut Th17 cells likely played an important role in microbial translocation during HIV/SIV infection. 11,14 Macal et al demonstrated that the effective recovery of gut CD4 1 T cells paralleled the high level of Th17 cells. 12 However, to our knowledge, few studies investigated guthoming Th17 cells during acute HIV-1 infection.…”

“…[6][7][8][9] HIV/SIV infection also reduces Th17 cells and impairs gut mucosal integrity, which results in microbial translocation and high levels of immune activation and systemic inflammation in HIV/SIV-infected individuals. [10][11][12][13][14] Alterations in Th17:Th1 and Th17:Treg balance also contribute to disease progression in HIV/SIV infection. [15][16][17] The gut-homing receptor integrin a4b7 mediates lymphocyte migration from the circulation to the intestine through interaction with MAdCAM-1 on endothelial cells of gut tissues.…”

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