Distinct contributions of the innate immune receptors TLR2 and RP105 to formation and architecture of structured lung granulomas in mice infected with Mycobacterium tuberculosis

Abstract

Granulomas are key histopathological features of Mycobacterium tuberculosis (Mtb) infection, with complex roles in pathogen control and dissemination. Thus, understanding drivers and regulators of granuloma formation is important for improving tuberculosis diagnosis, treatment, and prevention. Yet, molecular mechanisms underpinning granuloma formation and dynamics remain poorly understood. Here we used low‐dose Mtb infection of C57BL/6 mice, which elicits structured lung granulomas composed of central macrophage clusters encased by a lymphocyte mantle, alongside the disorganized lymphocyte and macrophage clusters commonly observed in Mtb‐infected mice. Using gene‐deficient mice, we observed that Toll‐like receptor (TLR) 2 and the TLR‐related Radioprotective 105 kDa protein (RP105) contributed to the extent and spatial positioning of pathology in infected lung tissues, consistent with functional cooperation between TLR2 and RP105 in the innate immune recognition of Mtb. In mice infected with the highly virulent Mtb clinical isolate HN878, TLR2, but not RP105, positively regulated the extent of central macrophage regions within structured granulomas. Moreover, RP105, but not TLR2, promoted the formation of structured lung granulomas, suggesting that the functions of RP105 as an innate immune sensor for Mtb reach beyond its roles as TLR2 co‐receptor. TLR2 and RP105 contributions to lung pathology are governed by Mtb biology, as neither receptor affected the frequency or architecture of structured granulomas in mice infected with the reference strain Mtb H37Rv. Thus, by revealing distinctive as well as cooperative functions of TLR2 and RP105 in lung pathology, our data identify TLRs as molecular determinants of TB granuloma formation and architecture, and expand understanding of how interactions between innate immune receptors and Mtb shape TB disease manifestation.

Predicting the Progress of Tuberculosis by Inflammatory Response-Related Genes Based on Multiple Machine Learning Comprehensive Analysis

“…TLR are recognition molecules for a variety of pathogens, including bacteria, viruses, fungi, and parasites [ 54 ]. In TB, TLR2 contributes to the pathological scope and spatial localization of infected lung tissue [ 55 ].…”

“…TLR are recognition molecules for a variety of pathogens, including bacteria, viruses, fungi, and parasites [54]. In TB, TLR2 contributes to the pathological scope and spatial localization of infected lung tissue [55]. In order to elucidate the role of characteristic genes in TB progression, we conducted a series of analyses of characteristic genes.…”

Animal models for COVID-19 and tuberculosis

“…Upon ULD, mice develop single, structured lesions upon inhalation of 1-3 Mtb CFU of the laboratory strain H37Rv. Organized granulomas have also been reported in C57BL/6 mice challenged with low-dose hypervirulent HN878 Mtb ( 24 , 58 ). These murine models mirror, to some extent, human TB lesions, have organized granuloma-like lesions which contain foamy macrophages, develop central necrosis, yet still miss certain cellular components such as multinucleated giant cells and do not show fibrosis and calcification.…”

“…Mtb lineages and virulence factors, impact as well on the course of TB. For instance, aerogenic exposure to the East/Asian Beijing strain HN878, in contrast to infection with the reference Euro-American strain H37Rv, triggers heightened susceptibility in C57BL/6 mice ( 23 ) and granulomatous lesions resembling human-like pathology ( 24 ). Various Mtb strains differ in propensity to infect myeloid cells ( 25 ), disseminate ( 26 ) or trigger inflammation ( 27 ).…”

Initial immune response after exposure to Mycobacterium tuberculosis or to SARS-COV-2: similarities and differences

“…The primed T (and likely B) lymphocytes can then move to the site of infection and contribute to the formation of the organized granuloma that consists of modified macrophages as epithelioid cells and multinucleated giant cells accompanied by neutrophils and DCs in the center, infiltrated immune cells including granulocytes, antigen-specific T cells and few B cells in the periphery, with variable degrees of fibrosis or central caseous necrosis ( Figure 2 ) ( 272 , 273 ). Although the mechanisms driving protection and pathology within the granuloma microenvironments are still poorly understood, such mechanisms can be very important for the prognosis, and outcome of the disease ( 52 ).…”