C-type lectin receptor dysregulation in HIV and Mycobacterium tuberculosis co-infection

Abstract Infection with Mycobacterium tuberculosis (Mtb) is a serious and potentially life-threatening condition, especially in people with HIV (PWH). According to the WHO, there were 10.6 million new tuberculosis (TB) cases in 2021, and 700,000 of those cases were among PWH. Macrophages are a host cell for both pathogens and play an important innate immune role in determining the outcome of disease. C-type lectin receptors (CLR) are pattern recognition receptors (PRR) abundantly expressed on the macrophage surface that orchestrate the innate immune response to microbial insults. We previously identified a role for the macrophage galactose-type lectin receptor (MGL) CLR in protection against TB. In subsequent studies, we observed suppression of MGL in tissues of HIV-infected decedents and in human macrophages following in vitro infection with HIV. In human THP-1 cells and a humanized mouse model, we observe that HIV infection markedly impairs activation of MGL by mycobacteria in comparison to other CLRs with defined roles in antimycobacterial immunity including DC-SIGN and Dectin 1. We further determine roles for TLR2/6 heterodimer, TLR4, and TGF-β signaling pathways for transcriptional regulation of MGL. Importantly, these pathways have roles in innate immunity and pathogenesis following Mtb or HIV infections. These findings advance our understanding of MGL regulation as part of the CLR repertoire, as well as its role in the response to Mtb and to Mtb/HIV co-infection. NIH R31AI138328, R61AI138328