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Investigating the Role of the Lung and Gut Microbiota in HIV-associated Bacterial Pneumonia

Abstract

In the era of highly active antiretroviral therapy (HAART), human immunodeficiency virus (HIV) infected patients are living longer, healthier lives, yet pulmonary infections still pose a common and frequently fatal co-morbidity in this population. Despite the frequency and severity of this disease, particularly within HIV and TB co-endemic regions of Africa, little is known about factors that determine patient endotypes, disease severity, and outcomes. Advanced HIV infection is known to compromise mucosal barrier defense, lead to macrophage dysfunction, and shift lung and gut microbiota composition. Hence we hypothesized that distinct pathogenic microbiota exist on these mucosal surfaces and relate to patient immune and disease endotypes in HIV infected patients with bacterial pneumonia. We initially profiled 16S rRNA in bronchoalveolar lavage (BAL) from a large cohort (n=182) of Ugandan HIV-pneumonia patients and identified three lower airway community states that repeated across the population and differentially related to microbiological, immunological, and clinical factors. Patients with the lowest mortality rate possessed Gammaproteobacteria-dominated communities, while patients with the highest mortality rate were colonized by Prevotellaceae-dominated communities, expressed more T-helper 2 (Th2) and Th17 cytokines within their lower airways, and were more frequently administered the antibiotic ceftriaxone. Building on these observations, we examined bacterial and fungal microbiota composition in paired BAL and stool samples from an independent cohort (n=120) and validated these airway microbiota states. Additionally, we demonstrated that gut microbiota composition is related to circulating CD4 count, airway microbiota composition, and patient outcomes. Gut microbiota from patients with the lowest CD4 counts were enriched for microbes shared with patient airways (based on identical 16S rRNA sequences) and were depleted of traditional gut-associated microbes. Compared to patients with high CD4 counts, sterile microbial products from patients with low CD4 counts induced fewer activated and CD206+IL-10+ tissue repair macrophages and more IL-1b+ pro-inflammatory macrophages in vitro. Overall, we demonstrate that there are a small number of distinct lower airway and gut microbiota within HIV infected patients with bacterial pneumonia that are differentially related to immune and patient outcomes. Stratifying patients based on lung and gut microbial communities may allow for more effective endotyping, leading to novel, tailored patient treatments.

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