Abstract
Leishmaniasis is a disease caused by the protozoan parasite Leishmania and is known to affect millions of individuals worldwide. In recent years, we have established the critical role played by Leishmania zinc-metalloprotease GP63 in the modulation of host macrophage signalling and functions, favouring its survival and progression within its host. Leishmania major lacking 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 upon Leishmania inoculation within mice and establish whether Leishmania GP63 influences this initial inflammatory response. Experimentally, L. major WT (L. majorWT), L. major GP63 knockout (L. majorKO), or L. major GP63 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 that Leishmania GP63 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 fewer L. majorKO amastigotes 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 during L. major infection and further establish the prominent role of the virulence factor GP63 to provide favourable conditions for host cell infection.
Highlights
The host immune response is a significant determinant in the outcome of the disease leishmaniasis
Clear bands were only observed in the lanes containing L. majorWT and L. majorR, indicating the presence of active GP63 [28]
Cutaneous leishmaniasis (CL) caused by L. major remains a major public health concern to people living in endemic areas, as lesions can be acute or become chronic and slow healing [1]
Summary
The host immune response is a significant determinant in the outcome of the disease leishmaniasis. Many mice studies indicate that the adaptive immune response is responsible for the outcome of disease [2, 3]. It is the ability of the Leishmania to infect cells that determine whether or not disease will manifest. This is dependent on the host’s early innate immune response, and how the parasite can evade or exploit it. Leishmania express a variety of virulence factors that mediate the initial interaction between the parasite and the host cell to promote infection [4]
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