SIVmac239 infection dysregulates anti-mycobacterial immunity at the granuloma level and contributes to severe tuberculosis in cynomolgus macaques

Abstract Tuberculosis (TB) is a global pandemic caused by Mycobacterium tuberculosis (Mtb) infection that is characterized by formation of lung lesions called granulomas. TB has a synergistic relationship with HIV and TB often occurs in HIV-infected individuals with near normal CD4+ T cell counts. Despite the importance of this co-infection to public health, interactions between HIV and lesion-level immunity remain poorly understood. To address this issue, we used SIVmac239-infected or SIV-negative Mauritian cynomolgus macaques with active TB to identify which cell types are infected in granulomas and how SIV modulates local immunity. Using RNAscope and immunohistochemistry, we found that CD11c+ macrophages were the most-commonly infected cell type in granulomas. To identify how viral infection changes the immune landscape in granulomas, we performed a transcriptional analysis on RNA isolated from lung granulomas. We found that SIV infection downregulated large numbers of macrophage-activating cytokines and receptors, toll-like receptors, and T cell activation markers. In contrast, anti-viral responses including type 1 interferons and receptors expressed by NK cells were upregulated. IL-10 was among the genes that were not differentially regulated. Pathway analysis indicated that many pathways were downregulated, including pathways associated with Th1-, Th2-, and NFkB-mediated responses. These data suggest that SIV infection deactivates protective responses in granulomas but activates antiviral responses that are counterproductive in TB while leaving detrimental IL-10 expression intact. We hypothesize that this disequilibrium leads to an inability to kill bacteria and restrict dissemination that exacerbates TB.