Leishmania mexicana promotes pain-reducing metabolomic reprogramming in cutaneous lesions
Greta Volpedo,
Timur Oljuskin,
Blake Cox,
Yulian Mercado,
Candice Askwith,
Nazli Azodi,
Matthew Bernier,
Hira L. Nakhasi,
Sreenivas Gannavaram,
Abhay R. Satoskar
Affiliations
Greta Volpedo
Department of Microbiology, The Ohio State University, Columbus, OH 43210, USA; Department of Pathology, Wexner Medical Center, The Ohio State University, Columbus, OH 43210, USA
Timur Oljuskin
Animal Parasitic Disease Lab, Agricultural Research Service, USDA, Beltsville, MD, USA
Blake Cox
Department of Pathology, Wexner Medical Center, The Ohio State University, Columbus, OH 43210, USA
Yulian Mercado
Department of Pathology, Wexner Medical Center, The Ohio State University, Columbus, OH 43210, USA
Candice Askwith
Department of Neuroscience, The Ohio State University, Columbus, OH 43210, USA
Nazli Azodi
Division of Emerging and Transfusion Transmitted Diseases, CBER, FDA, Silver Spring, MD, USA
Matthew Bernier
Mass Spectrometry and Proteomics Facility, The Ohio State University, Columbus, OH 43210, USA
Hira L. Nakhasi
Division of Emerging and Transfusion Transmitted Diseases, CBER, FDA, Silver Spring, MD, USA
Sreenivas Gannavaram
Division of Emerging and Transfusion Transmitted Diseases, CBER, FDA, Silver Spring, MD, USA
Abhay R. Satoskar
Department of Microbiology, The Ohio State University, Columbus, OH 43210, USA; Department of Pathology, Wexner Medical Center, The Ohio State University, Columbus, OH 43210, USA; Corresponding author
Summary: Cutaneous leishmaniasis (CL) is characterized by extensive skin lesions, which are usually painless despite being associated with extensive inflammation. The molecular mechanisms responsible for this analgesia have not been identified. Through untargeted metabolomics, we found enriched anti-nociceptive metabolic pathways in L. mexicana-infected mice. Purines were elevated in infected macrophages and at the lesion site during chronic infection. These purines have anti-inflammatory and analgesic properties by acting through adenosine receptors, inhibiting TRPV1 channels, and promoting IL-10 production. We also found arachidonic acid (AA) metabolism enriched in the ear lesions compared to the non-infected controls. AA is a metabolite of anandamide (AEA) and 2-arachidonoylglycerol (2-AG). These endocannabinoids act on cannabinoid receptors 1 and 2 and TRPV1 channels to exert anti-inflammatory and analgesic effects. Our study provides evidence of metabolic pathways upregulated during L. mexicana infection that may mediate anti-nociceptive effects experienced by CL patients and identifies macrophages as a source of these metabolites.
