Leishmania mexicana centrin knockout parasites promote M1-polarizing metabolic changes

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 LmexCenversus 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.