Partial Redundancy of the Pattern Recognition Receptors, Scavenger Receptors, and C-Type Lectins for the Long-Term Control of Mycobacterium tuberculosis Infection

Abstract

Mycobacterium tuberculosis is recognized by multiple pattern recognition receptors involved in innate immune defense, but their direct role in tuberculosis pathogenesis remains unknown. Beyond TLRs, scavenger receptors (SRs) and C-type lectins may play a crucial role in the sensing and signaling of pathogen motifs, as well as contribute to M. tuberculosis immune evasion. In this study, we addressed the relative role and potential redundancy of these receptors in the host response and resistance to M. tuberculosis infection using mice deficient for representative SR, C-type lectin receptor, or seven transmembrane receptor families. We show that a single deficiency in the class A SR, macrophage receptor with collagenous structure, CD36, mannose receptor, specific ICAM-3 grabbing nonintegrin-related, or F4/80 did not impair the host resistance to acute or chronic M. tuberculosis infection in terms of survival, control of bacterial clearance, lung inflammation, granuloma formation, and cytokine and chemokine expression. Double deficiency for the SRs class A SR types I and II plus CD36 or for the C-type lectins mannose receptor plus specific ICAM-3 grabbing nonintegrin-related had a limited effect on macrophage uptake of mycobacteria and TNF response and on the long-term control of M. tuberculosis infection. By contrast, mice deficient in the TNF, IL-1, or IFN-γ pathway were unable to control acute M. tuberculosis infection. In conclusion, we document a functional redundancy in the pattern recognition receptors, which might cooperate in a coordinated response to sustain the full immune control of M. tuberculosis infection, in sharp contrast with the nonredundant, essential role of the TNF, IL-1, or IFN-γ pathway for host resistance to M. tuberculosis.

Autophagy in the Fight Against Tuberculosis

“…tuberculosis and all other species of mycobacteria, many of which are opportunistic intracellular pathogens, owe much of their resilience to a distinctive lipid-rich cell envelope that not only protects the cells against harsh environments but also contains many molecules that are immune effectors crucial in evading the host immune response (Briken et al, 2004;Ishikawa et al, 2009;Schafer et al, 2009;Court et al, 2010;Ehlers, 2010;Philips and Ernst, 2012;Lang, 2013;Nobre et al, 2014). Besides glycolipids and glucans that constitute most of the M. tuberculosis cell envelope, several secreted proteins have been identified and shown to also play fundamental roles in M. tuberculosis survival and proliferation within the host (Abdallah et al, 2007;Philips, 2008;Philips and Ernst, 2012).…”

Mycobacterial Trehalose Dimycolate Reprograms Macrophage Global Gene Expression and Activates Matrix Metalloproteinases

“…Recent in vivo infection studies, however, have shown that neither MARCO nor Mincle is required for control of M. tuberculosis infection in the mouse model (51,52), suggesting that there are redundant pathways through which M. tuberculosis stimulates the host immune response. Upregulation of several cytokines (TNF-␣, IL-1␤, and IL-10) and chemokines (CCL3, CCL4, CCL7, CCL12, CXCL1, CXCL2, and CXCL10) important in the response to TB at least partially explains the ability of TDM to induce many of the lesions and symptoms observed during TB (4,5,(53)(54)(55)(56)(57)(58).…”

The Role of Non-Phagocytic Cells in Mycobacterial Infections

“…With respect to SR-A, this receptor can also bound TDM, nevertheless, this recognition diminishes TNF-/MIP-1-production by activated macrophages, suggesting that SR-A have an important role in the suppression of the excessive inflammatory response presented during mycobacterial infection (Ozeki et al, 2006). Recent evidence suggest that scavenger receptors along with C-type lectins, cooperate to maintain controlled the immune response established in vivo against the mycobacterial infection (Court et al, 2010).…”