Human alveolar macrophage function is impaired in tuberculosis contacts with diabetes

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BACKGROUND: Tuberculosis (TB) remains a leading cause of morbidity and mortality worldwide. Individuals with type 2 diabetes (T2D) are at increased risk of developing active TB, tend to present with more severe disease and experience adverse treatment outcomes compared to individuals without T2D co-morbidity. However, the underlying mechanisms responsible for increased susceptibility of patients with T2D to TB remain poorly understood. METHODS: We performed bronchoscopies and collected bronchoalveolar lavage fluid (BAL) from TB contacts with and without T2D in South Africa and obtained paired human alveolar macrophages (HAMs) and monocyte-derived macrophages (MDMs) for transcriptomic, epigenetic and functional assays. FINDINGS: Following ex vivo infection with Mycobacterium tuberculosis (Mtb), T2D-HAMs had increased Mtb growth (p = 0.034) and elevated TNF production (p = 0.033). BAL fluid from patients with T2D contained fewer neutrophils (p = 0.018), with neutrophil frequency inversely correlating with Mtb growth in HAMs. Both T2D-HAMs (p = 0.0206) and T2D-MDMs (p = 0.0465) expressed less CD32 compared to control cells, with patients with T2D having fewer M1-like MDMs (p = 0.0072). Mtb-induced gene expression in T2D-HAMs was delayed, but genes involved in negative regulation of neutrophil migration were upregulated (FDR = 0.035), consistent with the reduced neutrophil recruitment to the lung. Epigenetic profiling revealed hypermethylation in T2D-HAM DNA compared to control HAMs, except for hypomethylated TNF signalling genes, aligning with increased TNF production. INTERPRETATION: Our findings demonstrate that T2D alters early HAM responses to Mtb, characterised by delayed gene transcription, epigenetically driven cytokine dysregulation and impaired neutrophil recruitment-collectively facilitating enhanced Mtb growth. This study provides the first comprehensive investigation of the diabetic HAM phenotype in the context of recent TB exposure, offering mechanistic insights into the increased TB susceptibility observed in patients with T2D. FUNDING: Research reported in this publication was supported by the National Institute of Allergy and Infectious Diseases (NIAID) of the National Institutes of Health (NIH) and the South African Medical Research Council (SAMRC) under the US-South African Program for Collaborative Biomedical Research, the National Research Foundation of South Africa, the National Health and Medical Research Council of Australia and the Mater Foundation. The Translational Research Institute is supported by the Australian Government. RNA-seq data was generated in the Genome Sequencing Facility, which is supported by UT Health San Antonio, the NIH and a CPRIT Core Facility Award.

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