A2A Receptor Activation Restores Lipid and Mitochondrial Homeostasis, Limiting Mycobacterium leprae Persistence in Human Monocytes.

Background/

Objectives

Leprosy is a chronic infection caused by Mycobacterium leprae that, in addition to Schwann cells, macrophages, and adipocytes, also infects human peripheral blood monocytes and subverts their metabolism in its favor. Infection is marked by cholesterol and fatty acid accumulation in lipid droplets (LDs), and a reduction in mitochondrial membrane potential (Δψm). Previous studies showed that M. leprae downregulates adenosine receptor A2A (A2AR) expression in Schwann cells, while activation reduces LD accumulation and bacterial viability. Since A2AR controls immunometabolic response, we investigated whether A2AR signaling restrains M. leprae-driven reprogramming in monocytes.

Methods

Peripheral blood mononuclear cells from healthy donors were enriched for monocytes and infected with M. leprae in the presence or absence of adenosinergic modulators (5'AMP, adenosine (ADO), A2AR agonist CGS21680, the antagonist ZM241385, or A2BR antagonist, MRS1754). We used flow cytometry, fluorescence microscopy, and RT-qPCR to evaluate purinergic components expression and bacillary viability. LDs and Δψm were measured by fluorescence microscopy, and extracellular levels of inosine (INO) and hypoxanthine (HPX) by LC-MS/MS.

Results

The results show that infection increased CD39, ADA, A2AR and A3R expression, decreased ENT1, A1R and A2BR, and raised extracellular INO and HPX. In addition, 5'AMP, ADO and CGS21680 reversed infection-induced LD accumulation. CGS21680 also restored Δψm and decreased intracellular M. leprae viability.

Conclusions

Our data suggest that M. leprae suppresses A2AR signaling to favor its survival in monocytes, indicating that the extracellular ADO-A2AR pathway may be a potential target to limit early M. leprae infection.