Leishmania major centrinknock-out parasites alter the kynurenine- aryl hydrocarbon receptor signaling to produce a pro-inflammatory response

Abstract

Leishmaniasis is a parasitic disease that is prevalent in approximately 88 countries, and yet no licensed human vaccine exists against it. Towards control of leishmaniasis, we have developed Leishmania major Centrin gene deletion mutant strains (LmCen-/-) as a live attenuated vaccine, which induces a strong Th1 response to provide 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 with virulent L. major parasite infection to identify the immune mechanism of protection. Our data shows that immunization with LmCen-/- parasites, in contrast to virulent L. major infection, alters tryptophan metabolism to down-regulate Kynurenine-AhR signaling and promote a pro-inflammatory response.

Leishmania mexicana centrin knockout parasites promote M1-polarizing metabolic changes

“… 12 An analogous analysis of LmCen −/− infected ear tissue at the identical time point following immunization revealed that tryptophan metabolism is significantly altered between LmCen −/− and LmWT infections, while PPP remained unaltered, suggesting that similarly attenuated parasite strains utilize distinct metabolic immunoregulatory circuits. 59 …”