Type I Interferon confers susceptibility to Mycobacterium tuberculosis infection within granulomas of SIV co-infected non-human primates

Abstract

Abstract Mycobacterium tuberculosis (Mtb) co-infection with human immunodeficiency virus (HIV) typically results in poor disease outcome for tuberculosis (TB). While the loss of CD4+ T cells due to HIV is known to cause increased TB disease susceptibility, the mechanisms which govern the loss of disease control in co-infected individuals are not well understood particularly within the lung granulomas that keep TB contained. This study aims to profile the transcriptional patterns of lung granulomas from non-human primates (NHP) co-infected with Mtb and simian immunodeficiency virus (SIV) as a model for TB-SIV co-infection in humans. We compared the transcriptional profiles of granulomas from four Mauritian cynomolgus macaques that were infected with SIV for six months and then co-infected with Mtb for eight weeks against animals that were infected with Mtb for eight weeks. Granulomas from co-infected animals were found to have generally elevated transcripts involved in Type I interferon pathways (IFIT1), anti-bacterial effectors (defensin A, cathepsin G) and evidence of increased neutrophilic inflammation compared to Mtb-only control lung granulomas. Pathways that were downregulated in co-infected animals were related to Type II interferon signaling (IRF8). These results suggest that SIV infection alters the host immune response in ways that may be advantageous to Mtb growth by lowering IFNγ responsiveness and promoting myeloid cell-associated inflammation. We hypothesize this leads to a more permissive and less antibacterial environment that promotes bacterial survival, dissemination, and ultimately leads to increased susceptibility of co-infected individuals towards TB disease.