Gut-associated lymphoid tissue (GALT) harbors the majority of T lymphocytes in the body

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...

SUMMARY Salmonella enterica serotype Typhimurium thrives in the lumen of the acutely inflamed intestine, which suggests that this pathogen is resistant to antimicrobials encountered in this environment. However, the identity of these antimicrobials and the corresponding bacterial resistance genes remains elusive. Here we show that enteric infection with S. Typhimurium evoked marked interleukin (IL)–22/IL-17 mediated induction in intestinal epithelial cells of lipocalin-2, an antimicrobial protein that prevents bacterial iron acquisition. Lipocalin-2 accumulated in the intestinal lumen of rhesus macaques during S. Typhimurium infection. Resistance to lipocalin-2, mediated by the iroBCDE iroN locus, conferred a competitive advantage upon the S. Typhimurium wild-type in colonizing the inflamed intestine of wild-type, but not of lipocalin-2 deficient mice. These data support that resistance to lipocalin-2 defines a specific adaptation to growth in the inflamed intestine.

Although anti-retroviral therapy (ART) is highly effective in suppressing HIV replication, it fails to eradicate the virus from HIV-infected individuals. Stable latent HIV reservoirs are rapidly established early after HIV infection. Therefore, effective strategies for eradication of the HIV reservoirs are urgently needed. We report that ingenol-3-angelate (PEP005), the only active component in a previously FDA approved drug (PICATO) for the topical treatment of precancerous actinic keratosis, can effectively reactivate latent HIV in vitro and ex vivo with relatively low cellular toxicity. Biochemical analysis showed that PEP005 reactivated latent HIV through the induction of the pS643/S676-PKCδ/θ-IκBα/ε-NF-κB signaling pathway. Importantly, PEP005 alone was sufficient to induce expression of fully elongated and processed HIV RNAs in primary CD4+ T cells from HIV infected individuals receiving suppressive ART. Furthermore, PEP005 and the P-TEFb agonist, JQ1, exhibited synergism in reactivation of latent HIV with a combined effect that is 7.5-fold higher than the effect of PEP005 alone. Conversely, PEP005 suppressed HIV infection of primary CD4+ T cells through down-modulation of cell surface expression of HIV co-receptors. This anti-cancer compound is a potential candidate for advancing HIV eradication strategies.