Leishmania mexicana centrin knockout parasites promote M1-polarizing metabolic changes

Greta Volpedo; Thalia Pacheco-Fernandez; Timur Oljuskin; Hannah L Markle; Nazli Azodi; Shinjiro Hamano; Greg Matlashewski; Sreenivas Gannavaram; Hira L Nakhasi; Abhay R Satoskar

doi:10.1016/j.isci.2023.107594

Leishmania mexicana centrin knockout parasites promote M1-polarizing metabolic changes

iScience. 2023 Aug 29;26(9):107594. doi: 10.1016/j.isci.2023.107594. eCollection 2023 Sep 15.

Authors

Greta Volpedo^{1

2}, Thalia Pacheco-Fernandez^{2

3}, Timur Oljuskin³, Hannah L Markle³, Nazli Azodi³, Shinjiro Hamano^{4

5}, Greg Matlashewski⁶, Sreenivas Gannavaram³, Hira L Nakhasi³, Abhay R Satoskar^{1

2}

Affiliations

¹ Department of Microbiology, The Ohio State University, Columbus, OH 43210, USA.
² Department of Pathology, Wexner Medical Center, The Ohio State University, Columbus, OH 43210, USA.
³ Division of Emerging and Transfusion Transmitted Diseases, CBER, FDA, Silver Spring, MD, 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, Canada.

Abstract

Leishmaniasis is a tropical disease prevalent in 90 countries. Presently, there is no approved vaccine for human use. We developed a live attenuated L. mexicana Cen^-/-(LmexCen^-/-) strain as a vaccine candidate that showed excellent efficacy, characterized by reduced Th2 and enhanced Th1 responses in C57BL/6 and BALB/c mice, respectively, compared to wild-type L. mexicana (LmexWT) infection. Toward understanding the immune mechanisms of protection, we applied untargeted mass spectrometric analysis to LmexCen^-/- and LmexWT infections. Data showed enrichment of the pentose phosphate pathway (PPP) in ears immunized with LmexCen^-/-versus naive and LmexWT infection. PPP promotes M1 polarization in macrophages, suggesting a switch to a pro-inflammatory phenotype following LmexCen^-/- inoculation. Accordingly, PPP inhibition in macrophages infected with LmexCen^-/- reduced the production of nitric oxide and interleukin (IL)-1β, hallmarks of classical activation. Overall, our study revealed the immune regulatory mechanisms that may be critical for the induction of protective immunity.

Keywords: Immunology; Metabolomics; Parasitology.