Geographical sequence variation in the Leishmania major virulence factor P46

- L. major P46 shows sequence variations correlating with geographical origin.
- P46 sequence variants are differentially selected in experimental hosts.
- P46 null mutants show attenuated infectivity.
- P46 is a non-essential payload protein of L. major exosomes.

Cutaneous leishmaniasis as caused by Leishmania major is a zoonotic infection with wide epidemiological impact. The L. major P46 virulence gene was shown to boost the parasite's virulence and extends its range of experimental hosts. Here we show that P46 is subject to significant geographical sequence variations that may reflect the adaption to different reservoir hosts. This view is supported by the results of passage experiments using P46 variants in different experimental hosts. Conversely, loss of P46 expression leads to attenuation both in vitro and in BALB/c mice. Although part of the L. major exosomal protein payload, P46 is not required for exosome-mediated immune modulation.