Vaginal microbiome-hormonal contraceptive interactions associate with the mucosal proteome and HIV acquisition.

Alterations to the mucosal environment of the female genital tract, such as genital inflammation, have been associated with increased HIV acquisition in women. As the microbiome and hormonal contraceptives can affect vaginal mucosal immunity, we hypothesized these components may interact in the context of HIV susceptibility. Using previously published microbiome data from 685 women in the CAPRISA-004 trial, we compared relative risk of HIV acquisition in this cohort who were using injectable depot medroxyprogesterone acetate (DMPA), norethisterone enanthate (NET-EN), and combined oral contraceptives (COC). In women who were Lactobacillus-dominant, HIV acquisition was 3-fold higher in women using DMPA relative to women using NET-EN or COC (OR: 3.27; 95% CI: 1.24-11.24, P = 0.0305). This was not observed in non-Lactobacillus-dominant women (OR: 0.95, 95% CI: 0.44-2.15, P = 0.895) (interaction P = 0.0686). Higher serum MPA levels associated with increased molecular pathways of inflammation in the vaginal mucosal fluid of Lactobacillus-dominant women, but no differences were seen in non-Lactobacillus dominant women. This study provides data suggesting an interaction between the microbiome, hormonal contraceptives, and HIV susceptibility.

B cell heterogeneity in human tuberculosis highlights compartment-specific phenotype and functional roles.

B cells are important in tuberculosis (TB) immunity, but their role in the human lung is understudied. Here, we characterize B cells from lung tissue and matched blood of patients with TB and found they are decreased in the blood and increased in the lungs, consistent with recruitment to infected tissue, where they are located in granuloma associated lymphoid tissue. Flow cytometry and transcriptomics identify multiple B cell populations in the lung, including those associated with tissue resident memory, germinal centers, antibody secretion, proinflammatory atypical B cells, and regulatory B cells, some of which are expanded in TB disease. Additionally, TB lungs contain high levels of Mtb-reactive antibodies, specifically IgM, which promotes Mtb phagocytosis. Overall, these data reveal the presence of functionally diverse B cell subsets in the lungs of patients with TB and suggest several potential localized roles that may represent a target for interventions to promote immunity or mitigate immunopathology.

Failure to decrease HbA1c levels following TB treatment is associated with elevated Th1/Th17 CD4+ responses.

Introduction: The rising global burden of metabolic disease impacts the control of endemic tuberculosis (TB) in many regions, as persons with diabetes mellitus (DM) are up to three times more likely to develop active TB than those without DM. Active TB can also promote glucose intolerance during both acute infection and over a longer term, potentially driven by aspects of the immune response. Identifying patients likely to have persistent hyperglycemia following TB treatment would enable closer monitoring and care, and an improved understanding of underlying immunometabolic dysregulation. Methods: We measured the relationship of plasma cytokine levels, T cell phenotypes and functional responses with the change in hemoglobin A1c (HbA1c) before and after treatment of pulmonary TB in a prospective observational cohort in Durban, South Africa. Participants were stratified based on stable/increased HbA1c (n = 16) versus decreased HbA1c (n = 46) levels from treatment initiation to 12 month follow-up. Results: CD62 P-selectin was up- (1.5-fold) and IL-10 downregulated (0.85-fold) in plasma among individuals whose HbA1c remained stable/increased during TB treatment. This was accompanied by increased pro-inflammatory TB-specific IL-17 production (Th17). In addition, Th1 responses were upregulated in this group, including TNF-α production and CX3CR1 expression, with decreased IL-4 and IL-13 production. Finally, the TNF-α+ IFNγ+ CD8+ T cells were associated with stable/increased HbA1c. These changes were all significantly different in the stable/increased HbA1c relative to the decreased HbA1c group. Discussion: Overall, these data suggest that patients with stable/increased HbA1c had an increased pro-inflammatory state. Persistent inflammation and elevated T cell activity in individuals with unresolved dysglycemia following TB treatment may indicate failure to fully resolve infection or may promote persistent dysglycemia in these individuals, and further studies are needed to explore potential mechanisms.