C type Lectin Pathway Regulates Macrophage Immune Metabolism in Mtb-Infected Lung - ABSTRACT Pathogen recognition receptors (PRR) pathways are critical for integrating the complex microbial stimuli encountered by innate immune cells to direct the appropriate host response. Among these PRR systems, the C type lectin (CLR) responses are the least understood. CLRs are abundantly expressed by many myeloid cell populations and perform a growing list of roles in recognition, internalization, and inflammatory response regulation following host exposure to microbial insult. These recognition pathways are further complicated in the setting of co-infections such as HIV where conflicting or synergist signaling can drive dysfunctional outcomes including inflammation. Understanding how CLRs recognize and respond to microbial ligands to orchestrate immune outcomes thus represents an important gap for understanding immune events and development of host directed therapies. We identified a novel antimycobacterial role for the macrophage galactose type lectin (MGL, CLEC10a), a CLR previously associated with alternatively activated (M2) macrophage outcomes in tumor microenvironments. In preliminary outcomes, we have further identified that MGL is suppressed by Human Immunodeficiency Virus (HIV) and loss of MGL leads to changes in the lipid response to Mtb associated with defects in PPAR pathways. Our overall hypothesis is CLR signaling through MGL promotes metabolic reprogramming of lung M through PPAR- pathways that alter lipid signatures and limit inflammation in TB. Pulmonary M populations will be investigated to determine how MGL regulates the activation state and functional response after Mtb infection. Our aims are to 1) Identify role of MGL to orchestrate the host lipid response by pulmonary M populations following Mtb infection, 2) Demonstrate role of MGL pathways in determining M polarization in response to mycobacteria, and 3) Identify the mechanism whereby MGL pathways in lung M regulate Mtb-driven inflammation. We will employ mass spectrometry imaging, spatial transcriptomics, lipidomics, and spectral imaging approaches in experiments with Mtb infected WT and gene deleted mice. We expect our results to identify how MGL shifts myeloid cell metabolism toward an M2 activation state to limit inflammation and regulate lipid accumulation. Long term, our findings are important for understanding M activation states as affected by mycobacterial infections. Given our observations that MGL is susceptible to HIV- mediated suppression, our results may further identify opportunities to augment myeloid cell function in those with co-infections through host directed therapies.
