A Role For Epithelial Cells In Mucosal Transmission Of Hiv

Author : Tiffany Hensley-McBain
Publisher :
ISBN 13 :
Total Pages : 113 pages
Book Rating : 4.:/5 (11 download)

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Download or read book Mechanisms of Mucosal Dysfunction in HIV Infection and Potential Therapeutic Strategies written by Tiffany Hensley-McBain and published by . This book was released on 2017 with total page 113 pages. Available in PDF, EPUB and Kindle. Book excerpt: HIV and pathogenic SIV infection are characterized by chronic gastrointestinal (GI) mucosal dysfunction, which contributes to morbidities and mortality. This includes damage to the epithelial barrier, loss of Th17 cells, microbial translocation and local and systemic inflammation and immune activation. The mechanisms underlying mucosal damage have not been fully elucidated. The broad purpose of this thesis was to address several unanswered questions relating to mechanisms and potential therapies for GI mucosal dysfunction in HIV infection. We aimed to address three main objectives: 1) longitudinally assess the kinetics of GI neutrophil accumulation and reduced neutrophil antimicrobial function in relation to mucosal dysfunction, immune activation, and Th17 cell depletion in acute SIV infection; 2) investigate increased neutrophil lifespan as a mechanism for GI neutrophil accumulation in chronic, treated HIV infection and a potential role for HIV altered mucosal bacteria; and 3) assess the safety and efficacy of fecal microbial transplantation (FMT) as a potential therapeutic for mucosal dysfunction in SIV infection. The role of neutrophils in HIV gastrointestinal mucosal dysfunction is one major theme of the studies described herein. Neutrophils are important for containment of pathogens, but can also contribute to tissue damage due to their release of reactive oxygen species and other potentially harmful effector molecules. Here, we demonstrate that immune alterations such as Th17 loss, prolonged intestinal neutrophil accumulation, and decreased neutrophil functionality occur after the onset of peripheral and mucosal T cell activation and evidence of microbial translocation, and are thus unlikely to be drivers of initial damage. We additionally demonstrate that neutrophils are recruited to the site of lentivirus infection, maintain antimicrobial function in acute infection, and may therefore participate in the antiviral immune response. In chronic treated HIV infection, we report that reduced homeostatic neutrophil apoptosis contributes to neutrophil accumulation in the gastrointestinal tissues, thus implicating neutrophil lifespan as a new therapeutic target for mucosal inflammation in HIV infection. Microbial dysbiosis in HIV infection is a second major underlying theme of this thesis. During HIV infection, the delicate balance of healthy bacterial communities is perturbed, and this dysbiosis associates with T cell activation and disease progression. Here, we report differential effects of HIV-altered mucosal bacteria on neutrophil survival, suggesting that dysbiosis may contribute to GI neutrophil accumulation in treated HIV. We also provide evidence that Lactobacillus species increase neutrophil apoptosis and decrease neutrophil frequency in vitro, which could have important therapeutic implications for reducing neutrophil-driven inflammation in HIV and other chronic inflammatory conditions. Finally, we demonstrate the safety of FMT in primates infected with lentivirus and examine the relationships between alterations to the microbiome and immunological parameters. We observed increased Th17 and Th22 cells as well as decreased activation of CD4+ T cells post-FMT, and these changes correlated most strongly across all sampling time points with lower abundance genera in the colon. Taken together, the data presented in this thesis improves our understanding of the mechanisms contributing to mucosal dysfunction and potential therapies that can be further investigated to improve overall health in HIV-infected individuals.