Host-intrinsic and host-extrinsic factors modulate immunity to Mtb infection, reinfection, and noncanonical vaccination routes.

Tuberculosis (TB) disease states and outcomes are highly heterogeneous. While this makes TB difficult to diagnose, monitor, and treat, it also presents opportunities to identify correlates of protection or disease severity that can be used as biomarkers and help inform future interventions. Immunological priming due to primary Mycobacterium tuberculosis (Mtb) infection can protect against subsequent reinfection; thus, comparing primary infection with reinfection can provide insights into features associated with host control. Here, we examine paradigms of natural and vaccine-induced immunity and examine how host-intrinsic and -extrinsic factors modulate the immune response to protect against infection and reinfection. We propose that the TB granuloma is a quasi-homeostatic system, building this model on findings from Mtb reinfection and successful prophylactics, which suggest that protective immunity depends on a balance of pro- and anti-inflammatory cellular phenotypes and that this balance can mitigate pathophysiological processes at the tissue and organismal level.