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Novel Role for Macrophage Galactose-Type Lectin-1 to Regulate Innate Immunity against Mycobacterium tuberculosis.

ABSTRACT: Tuberculosis (TB) caused by infection with Mycobacterium tuberculosis is characterized by inflammatory pathology and poorly understood mechanisms of innate immunity. Pattern recognition receptors, expressed on the surface of macrophages, determine the balance of inflammatory and antimicrobial functions that influence disease outcome. Carbohydrate moieties displayed by mycobacteria can serve as pattern recognition receptor ligands for some members of the C-type lectin receptor (CLR) family, interactions that mediate a variety of incompletely understood immune outcomes. This work identifies a novel role for the CLR macrophage galactose-type lectin (MGL)-1 in a mouse model (C57BL/6 and MGL-1^-/-) of experimental TB. Murine macrophages upregulated MGL-1 following in vitro exposure to M. tuberculosis, whereas MGL⁺ cells accumulated at sites of mycobacteria-driven inflammation in the lung. Pulmonary macrophages from MGL-1-deficient mice displayed increased production of proinflammatory cytokines (IL-1β, IL-6, and IFN-γ) that were associated with greater lipid accumulation, following M. tuberculosis infection. Surprisingly, for a CLR, we also observed MGL-1-dependent antimycobacterial activity as evidenced by greater M. tuberculosis proliferation in bone marrow-derived macrophages, and the lung, of MGL-1-deficient mice. Differential transcriptome analysis further revealed that loss of MGL-1 perturbs the activation of various genes involved in the regulation of inflammation and lipid metabolism in the setting of M. tuberculosis infection. These results identify MGL-1 signaling as an important mechanism that regulates innate immunity against M. tuberculosis and indicates the potential for the MGL pathway as a novel therapeutic target for anti-TB immunity.

SUBMITTER: Naqvi KF

PROVIDER: S-EPMC8702441 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis (TB), infects one third of the world's population. Among these infections, clinical isolates belonging to the W-Beijing appear to be emerging, representing about 50% of Mtb isolates in East Asia, and about 13% of all Mtb isolates worldwide. In animal models, infection with W-Beijing strain, Mtb HN878, is considered "hypervirulent" as it results in increased mortality and causes exacerbated immunopathology in infected animals. We had previously shown the Interleukin (IL) -17 pathway is dispensable for primary immunity against infection with the lab adapted Mtb H37Rv strain. However, it is not known whether IL-17 has any role to play in protective immunity against infection with clinical Mtb isolates. We report here that lab adapted Mtb strains, such as H37Rv, or less virulent Mtb clinical isolates, such as Mtb CDC1551, do not require IL-17 for protective immunity against infection while infection with Mtb HN878 requires IL-17 for early protective immunity. Unexpectedly, Mtb HN878 induces robust production of IL-1β through a TLR-2-dependent mechanism, which supports potent IL-17 responses. We also show that the role for IL-17 in mediating protective immunity against Mtb HN878 is through IL-17 Receptor signaling in non-hematopoietic cells, mediating the induction of the chemokine, CXCL-13, which is required for localization of T cells within lung lymphoid follicles. Correct T cell localization within lymphoid follicles in the lung is required for maximal macrophage activation and Mtb control. Since IL-17 has a critical role in vaccine-induced immunity against TB, our results have far reaching implications for the design of vaccines and therapies to prevent and treat emerging Mtb strains. In addition, our data changes the existing paradigm that IL-17 is dispensable for primary immunity against Mtb infection, and instead suggests a differential role for IL-17 in early protective immunity against emerging Mtb strains.

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Novel Role for Macrophage Galactose-Type Lectin-1 to Regulate Innate Immunity against Mycobacterium tuberculosis.

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