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

Abstract

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.

Keywords: Mtb reinfection; granuloma; homeostasis; inflammation; natural immunity.

Graphical abstract

Figure 1

A model for granuloma outcomes Host-intrinsic and -extrinsic factors modulate the relative magnitude of host inflammatory response and the relative success of Mtb, from elimination to persistence and dissemination. Following primary Mtb infection, most immunocompetent individuals have the intrinsic capacity to control or clear Mtb through harmonized and protective inflammatory responses, as indicated by the dotted black line and pale blue solid line. Others infected may develop persistent infections (i.e., LTBI) that may lead to tolerogenic immunity (solid yellow line). Immunosuppressed individuals, such as persons living with HIV and those receiving anti-PD-1 or anti-TNF treatment are susceptible to an aberrant inflammatory response that may surpass a given granuloma’s ideal or stable set point leading to disease progression. In both tolerogenic and aberrant inflammatory processes, there may be the formation of alternate stable states such as continued neutrophil recruitment in the absence of CD4⁺ T cells within the granuloma and lung, as indicated by the circular arrows; thus, these alternate stable states require an opposing harmonizing effector function(s) to restore the granuloma’s optimal set point, one that mitigates tissue damage and bacterial growth. In the event of reinfection, immunity generated during primary infection or the persistence of infection, such as LTBI, can provide protection against reinfection, leading to sterilizing immunity (dotted gray line). Reinfection granulomas that do form can have a growth restrictive phenotype (solid gray line) and may feature enhanced bacterial killing relative to primary infection lesions. Recent reinfection data from murine and NHP systems suggest that the relative amplitude of the host proinflammatory response is rapid and followed by immunomodulation to mitigate maladaptive inflammation.

Figure 2

Bacterial dissemination Primary Mtb infection is associated with the formation of primary complexes. Data across biological systems and scales have demonstrated that bacilli from primary infection granulomas disseminate within the lung and to thoracic lymph nodes and sometimes to extrapulmonary sites. The dashed line indicates the potential for extrapulmonary dissemination to sites such as the spleen; the latter is infrequent in NHPs and relatively absolute in mice. Natural immunity, conferred by a concurrent or prior Mtb infection, can prevent or slow the formation of new primary complexes and lymphadenitis following reinfection and greater protection against disseminated TB and extrapulmonary organ infection.