Muco-cutaneous leishmaniasis in the New World: the ultimate subversion

Abstract

Infection by the human protozoan parasite Leishmania can lead, depending primarily on the parasite species, to either cutaneous or mucocutaneous lesions, or fatal generalized visceral infection. In the New World, Leishmania (Viannia) species can cause mucocutaneous leishmaniasis (MCL). Clinical MCL involves a strong hyper-inflammatory response and parasitic dissemination (metastasis) from a primary lesion to distant sites, leading to destructive metastatic secondary lesions especially in the nasopharyngal areas. Recently, we reported that metastasizing, but not non-metastatic strains of Leishmania (Viannia) guyanensis, have high burden of a non-segmented dsRNA virus, Leishmania RNA Virus (LRV). Viral dsRNA is sensed by the host Toll-like Receptor 3 (TLR3) thereby inducing a pro-inflammatory response and exacerbating the disease. The presence of LRV in Leishmania opens new perspectives not only in basic understanding of the intimate relation between the parasite and LRV, but also in understanding the importance of the inflammatory response in MCL patients.

Figure 1

Model of the signaling cascade in response to the release of dsRNA from LRV particles, production of IFNβ and secretion of proinflammatory cytokines and chemokines. The main pathway involved in this process is highlighted in bold. (1) Phagocytosis of LRV infected promastigotes by phagocytes (macrophages); (2) promastigotes differentiate into amatigotes, which reside in phagolysosomes; (3) death of some parasites (promastigotes and amastigotes), release of LRV and of dsRNA, which binds to TLR3; (4) activation of TLR3 via TRIF and signal transmission via the transcription factors IRF3 and NFκB; (5) activation and secretion of IFNβ; (6) binding of IFNβ to its receptor and activation of pro-inflammatory cytokines and chemokines genes (autocrine loop); (7) synthesis and secretion of pro-inflammatory cytokines and chemokines such as TNFα, IL-6, CCL and CXCL10 leading to increased parasitemia and pathology.