The role of Leishmania GP63 in the modulation of innate inflammatory response to Leishmania major infection

Leishmaniasis is a disease caused by the protozoan parasiteLeishmaniaand is known to affect millions of individuals worldwide. In recent years, we have established the critical role played byLeishmaniazinc-metalloprotease GP63 in the modulation of host macrophage signalling and functions, favouring its survival and progression within its host.Leishmania majorlacking GP63 was reported to cause limited infection in mice, however, it is still unclear how GP63 may influence the innate inflammatory response and parasite survival in an in vivo context. Therefore, we were interested in analyzing the early innate inflammatory events uponLeishmaniainoculation within mice and establish whetherLeishmaniaGP63 influences this initial inflammatory response. Experimentally,L.majorWT (L.majorWT),L.majorGP63 knockout (L.majorKO), orL.majorGP63 rescue (L.majorR) were intraperitoneally inoculated in mice and the inflammatory cells recruited were characterized microscopically and by flow cytometry (number and cell type), and their infection determined. Pro-inflammatory markers such as cytokines, chemokines, and extracellular vesicles (EVs, e.g. exosomes) were monitored and proteomic analysis was performed on exosome contents. Data obtained from this study suggest thatLeishmaniaGP63 does not significantly influence the pathogen-induced inflammatory cell recruitment, but rather their activation status and effector function. Concordantly, internalization of promastigotes during early infection could be influenced by GP63 as fewerL.majorKOamastigotes were found within host cells and appear to maintain in host cells over time. Collectively this study provides a clear analysis of innate inflammatory events occurring duringL.majorinfection and further establish the prominent role of the virulence factor GP63 to provide favourable conditions for host cell infection.