MGL/CLEC10a pathways are differentially activated in response to pathogenic and non-pathogenic mycobacteria 4725

Abstract Description Macrophage galactose-type lectin (MGL) is a C-type lectin receptor expressed on myeloid-derived cells. We have previously demonstrated that MGL is upregulated in response to Mycobacterium tuberculosis (Mtb) infection and contributes non-redundantly to host defense. However, it is still unclear by what mechanism MGL expression is activated during infection and the pathways that are used to modulate host immunity. We have observed that in vitro exposure to lipid extracts from slow-growing, pathogenic mycobacteria led to significantly greater MGL expression in comparison with lipids from fast-growing, non-pathogenic M. smegmatis. Assessment of cellular metabolism using extracellular flux and lactate bioassays further showed that the metabolic response of MGL-1 deficient macrophages to infection with the vaccine strain M. bovis BCG differs to that of virulent Mtb H37Rv. This suggests that MGL expression and signaling relies on a cell wall component or protein that is present in slow-growing, pathogenic mycobacteria and less abundant or absent in fast-growing, non-pathogenic species. The two murine homologs of MGL, MGL-1 and MGL-2, are also differentially expressed in response to stimulation with pathogenic and non-pathogenic mycobacterial lipids and cell wall components, implying potentially non-redundant functionality in pathogen pattern recognition. To address this, we have generated novel MGL-2 and total MGL knockout mice, which better model the single human MGL. Funding Sources Supported by NIH/NIAID R61AI138328; NIH/NIAID R33AI138328; Predoctoral Fellowship: UTMB Inst. for Human Infection and Immunity Topic Categories Microbial, Parasitic, and Fungal Immunology (MPF)