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Abstract
Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb), is the leading infectious cause of death. Clinical outcomes of Mtb infection have been described as active TB (symptomatic) or latent infection (asymptomatic), but a spectrum of outcomes is now recognized. We used a non-human primate (NHP) model of Mtb infection and HIV/Mtb co-infection using SIV as a surrogate, which recapitulates human infection. To characterize the spectrum of latent Mtb infection, we used this model to understand clinical, microbiologic, and radiographic patterns associated with developing latent Mtb infection. Four patterns were identified: “controllers” had normal erythrocyte sedimentation rate (ESR) without Mtb growth in bronchoalveolar lavage or gastric aspirate, “early subclinicals” showed transient ESR elevation and/or Mtb growth for 60 days post-infection, “mid subclinicals” were positive for 90 days, and “late subclinicals” were positive intermittently despite the absence of clinical disease. Variability was noted regarding granuloma formation, lung/lymph node metabolic activity, lung/lymph node bacterial burden, gross pathology, and extrapulmonary disease. This highlights the heterogeneity associated with establishment of latent infection, underscoring the need to understand the clinical spectrum and risk factors associated with severe disease.
The most important risk factor for active TB is co-infection with HIV. Seventy percent of people living with HIV are on antiretroviral therapy (ART) but remain at higher TB risk. The hallmark of TB is a granuloma, a collection of immune cells with a lymphocyte ring around a macrophage region with central necrosis. We used spatial transcriptomics to assess cell dynamics in the inner and outer regions of granulomas from NHPs infected with Mtb or SIV/Mtb in the presence or absence of ART. Within each treatment group, differential gene expression was observed in macrophages from the inner versus outer rings, which may affect how these macrophages interact with lymphocytes. Gene expression in Mtb granulomas was spatially differentiated, with the inner core dominated by expression of metabolic pathways. SIV/Mtb granulomas were more inflammatory overall, especially within the inner core. SIV/ART/Mtb granulomas had an intermediate phenotype, skewing closer to Mtb NHPs. Understanding how HIV alters dynamics within granulomas to drive increased TB disease will be critical for vaccine and therapeutics development.