Dysregulation of C-type lectin receptor pathways due to Mycobacterium tuberculosis (Mtb) and HIV coinfection revealed in a humanized mouse model

Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb), remains one of the leading causes of death due to infectious disease globally, and is also the leading cause of death among people with HIV (PWH). Myeloid C-type lectin receptors (CLRs) are an import pathogen recognition receptor of the innate immune system which bind to conserved carbohydrate structures and modulate antigen processing and presentation, inflammation, and adaptive immune responses. We previously described a protective role of macrophage galactose-type lectin receptor (MGL) for immunity to Mtb and observed abundant MGL in human lung TB granulomas. More recently we observed that HIV infection suppresses MGL in human cell lines and in peripheral blood mononuclear cells of PWH.  To determine how in vivo HIV and Mtb mono- or dual-infections affect MGL and other members of the CLR repertoire in the lung compartment, we employed a humanized immune system (HIS) mouse model. Preliminary assessment of lung using flow cytometric approaches demonstrated both similar and disparate activation patterns for MGL compared to other CLRs such as Dectin-1 and DC-SIGN in the settings of Mtb or Mtb/HIV co-infections.  RNASeq analysis further demonstrated suppression of CLR signaling pathways activated by Mtb due to HIV in co-infected lung. Our findings suggest that HIV-mediated defects in the signals that orchestrate CLR responses as mechanisms influencing disease outcomes in co-infected persons.