Figure 3.

Pathways targeted by the Leishmania virulence factors. LmCPb and GP63 proteases are Leishmania virulence factors secreted via the exosome route and found inside the host cell cytoplasm where they can alter numerous signaling pathways. The best studied Leishmania protease is GP63, which proteolytically cleaves and activates host phosphatases (such as PTP1B, PTP-PEST, TCPTP, and SHP-1) or the NF-κB subunit p65/RelA. Once activated, SHP-1 downregulates the macrophage response to interferon-γ by interacting with the kinase JAK2, modulates the pathways induced by pathogen recognition receptors (e.g., toll-like and lectin receptor) and also targets signaling kinases such as mitogen-activated protein kinase. In addition, Leishmania proteases contribute to this general downregulation of the host cell response by degrading proteins of the actin cytoskeleton, mTOR (leading to repression of host cell translation), transcription factors (like STAT1 or AP-1), and components of the NLPR3 inflammasome (thereby blocking the generation of IL-1β).