Defects in macrophage galactose-type lectin (MGL) signaling and pathogenesis of Mycobacterium tuberculosis and Human Immunodeficiency virus co-infection

Abstract

Abstract Mycobacterium tuberculosis (Mtb) and Human Immunodeficiency virus (HIV) are important causes of death in infected patients worldwide, and act synergistically to worsen disease in those with co-infection. C-type lectin receptors (CLRs) are an important component of innate immunity that can recognize and respond to pathogen-associated signals. The macrophage galactose-type lectin (MGL, CLEC10) has been described as an immunomodulatory CLR associated with M2 macrophages and regulation of inflammation following infection. Our lab previously identified an important antibacterial role of murine MGL-1 in host immunity to Mtb. More recently we observed that human peripheral blood mononuclear cell-derived macrophages, and THP-1 cells, upregulated MGL following in vitro exposure to Mtb, Mycobacterium bovis BCG, and TLR2 agonists. Silencing of MGL in primary human macrophages permitted greater intracellular Mtb replication. Interestingly, we observed that MGL is suppressed by HIV in differential transcriptome analysis of lung from HIV-infected humanized mice, in lung and spleen of autopsy specimens from HIV-infected decedents, and upon in vitro infection of human macrophages. Using a recombinant human MGL/Fc chimeric molecule we observed that Mtb, and not HIV, directly bound MGL. MGL surface expression was reduced in lung of mice with chronic HIV infection compared to those with Mtb, and variable in co-infected animals. These results indicate that human MGL is an important CLR for pathogen recognition and initiation of protective immunity by host macrophages to Mtb. The suppression of MGL due to HIV may increase susceptibility to Mtb in people with HIV or exacerbate disease progression in those with co-infection. Supported by grants from NIH (R33 AI138328, R61 AI138328, U24 MH100930)