Leishmania major centrin knock-out parasites reprogram tryptophan metabolism to induce a pro-inflammatory response

Timur Oljuskin; Nazli Azodi; Greta Volpedo; Parna Bhattacharya; Hannah L Markle; Shinjiro Hamano; Greg Matlashewski; Abhay R Satoskar; Sreenivas Gannavaram; Hira L Nakhasi

doi:10.1016/j.isci.2023.107593

Leishmania major centrin knock-out parasites reprogram tryptophan metabolism to induce a pro-inflammatory response

iScience. 2023 Aug 29;26(9):107593. doi: 10.1016/j.isci.2023.107593. eCollection 2023 Sep 15.

Authors

Affiliations

¹ Animal Parasitic Diseases Laboratory, Agricultural Research Service, USDA, Beltsville, MD 20705, USA.
² Division of Emerging and Transfusion Transmitted Diseases, CBER, FDA, Silver Spring, MD 20993, USA.
³ Department of Microbiology, The Ohio State University, Columbus, OH 43210, USA.
⁴ Department of Parasitology, Institute of Tropical Medicine (NEKKEN), The Joint Usage/Research Center on Tropical Disease, Nagasaki University, Nagasaki, Japan.
⁵ Nagasaki University Graduate School of Biomedical Sciences Doctoral Leadership Program, Nagasaki, Japan.
⁶ Department of Microbiology and Immunology, McGill University, Montreal, QC, Canada.
⁷ Department of Pathology, Wexner Medical Center, The Ohio State University, Columbus, OH 43210, USA.

Abstract

Leishmaniasis is a parasitic disease that is prevalent in 90 countries, and yet no licensed human vaccine exists against it. Toward control of leishmaniasis, we have developed Leishmania major centrin gene deletion mutant strains (LmCen^-/-) as a live attenuated vaccine, which induces a strong IFN-γ-mediated protection to the host. However, the immune mechanisms of such protection remain to be understood. Metabolomic reprogramming of the host cells following Leishmania infection has been shown to play a critical role in pathogenicity and shaping the immune response following infection. Here, we applied untargeted mass spectrometric analysis to study the metabolic changes induced by infection with LmCen^-/- and compared those with virulent L. major parasite infection to identify the immune mechanism of protection. Our data show that immunization with LmCen^-/- parasites, in contrast to virulent L. major infection promotes a pro-inflammatory response by utilizing tryptophan to produce melatonin and downregulate anti-inflammatory kynurenine-AhR and FICZ-AhR signaling.

Keywords: Immunology; Metabolomics; Parasitology.