Impact of Leishmania metalloprotease GP63 on macrophage signaling

Abstract

The intramacrophage protozoan parasites of Leishmania genus have developed sophisticated ways to subvert the innate immune response permitting their infection and propagation within the macrophages of the mammalian host. Several Leishmania virulence factors have been identified and found to be of importance for the development of leishmaniasis. However, recent findings are now further reinforcing the critical role played by the zinc-metalloprotease GP63 as a virulence factor that greatly influence host cell signaling mechanisms and related functions. GP63 has been found to be involved not only in the cleavage and degradation of various kinases and transcription factors, but also to be the major molecule modulating host negative regulatory mechanisms involving for instance protein tyrosine phosphatases (PTPs). Those latter being well recognized for their pivotal role in the regulation of a great number of signaling pathways. In this review article, we are providing a complete overview about the role of Leishmania GP63 in the mechanisms underlying the subversion of macrophage signaling and functions.

Keywords: GP63; Leishmania; host-pathogen interaction; innate immunity; macrophage; signaling.

Figure 1

Impact of Leishmania GP63 on macrophage signaling and innate immune response. Before parasite entries into the host macrophage, GP63 provides parasite resistance to the complement-mediated lysis and facilitate promastigote engulfment by macrophages. Within the host macrophage, GP63 is responsible for the activation of protein tyrosine phosphatases (PTPs; SHP-1, PTP1B, and TCPTP) that lead to the alteration of JAK, MAP, and IRAK-1 kinase pathways. GP63 is also able to down regulate host macrophage protein synthesis by altering mTORC1-dependent signaling. In the nucleus, inactivation of transcription factors, such as AP-1 and NF-κB, involve specific cleavage and degradation of subunits by GP63. Altogether, this signaling inactivation mediated by GP63 inhibits important antimicrobial, thus favoring the survival and propagation of the parasite.

Figure 2

Temperature shift (25–37°C) induces formation of exosomes at the surface of Leishmania mexicana promastigotes. (Arrows point at emerging exosomes). Hassani and Olivier (unpublished).