Cysteine Protease B of Leishmania mexicana Inhibits Host Th1 Responses and Protective Immunity

Abstract

C3H mice infected with Leishmania mexicana fail to develop a protective Th1 response, and are unable to cure. In this study, we show that L. mexicana cysteine proteases suppress the antileishmanial immune response. Previous studies demonstrated that deletion of the entire multicopy cysteine protease B (CPB) gene array in L. mexicana is associated with decreased parasite virulence, potentially attributable to factors related to parasite fitness rather than to direct effects on the host immune response. We now show that C3H mice infected with the L. mexicana deletion mutant (Δcpb) initially develop lesions that grow at rates comparable to those of wild-type L. mexicana-infected mice. However, in contrast to controls, Δcpb-induced lesions heal with an accompanying Th1 immune response. Lesion resolution was Th1 dependent, as Δcpb-infected IL-12p40−/− and STAT4−/− mice developed high parasite burdens and progressive disease. Moreover, when L. major was transfected with a cosmid expressing multiple L. mexicana CPB genes, this parasite induced a significantly lower IFN-γ response compared with wild-type L. major. These data indicate that cysteine proteases of L. mexicana are critical in suppressing protective immune responses and that inhibition of CPB may prove to be a valuable immunomodulatory strategy for chronic forms of leishmaniasis.

An Effect of Parasite-Encoded Arginase on the Outcome of Murine Cutaneous Leishmaniasis

“…The course of murine infection with L. major has been shown to be under genetically determined immunoregulatory controls that are different from those associated with L. mexicana infection (37)(38)(39). Whereas a majority of inbred mouse strains develop self-healing lesions when infected s.c. with L. major, virtually all mice develop rapidly growing large nonhealing lesions full of parasites following s.c. L. mexicana infection (40,41). BALB/c mice are an exception in that both parasites cause progressive disease (3,4,40,41).…”

“…Whereas a majority of inbred mouse strains develop self-healing lesions when infected s.c. with L. major, virtually all mice develop rapidly growing large nonhealing lesions full of parasites following s.c. L. mexicana infection (40,41). BALB/c mice are an exception in that both parasites cause progressive disease (3,4,40,41).…”

Prolyl oligopeptidase-like deficient Trypanosoma evansi parasites are associated with reduced interleukin-10 concentrations in vivo and in vitro

“…Future experiments are required to ascertain which sub-type of T cells produce regulatory IL-10 and further elucidate which role parasite POP-like protease plays in host IL-10 production. Other parasite peptidases that have also been shown to inhibit Th1 responses during infection include a cysteine protease B from Leishmania mexicana and cathepsin B from Leishmania chagasi, that cleave human TGF-β, a cytokine that regulates IL-10 and thereby affecting immunosuppression (Somanna et al 2002;Buxbaum et al 2003;Buxbaum, 2015). In classical trypanosome infections, initial pro-inflammatory type I immune responses mediated by IFN-γ, nitric oxide (NO) and TNF are necessary for controlling the first wave of parasitaemia (Namangala et al 2001b;Stijlemans et al 2007;Baral, 2010).…”

Manipulación genética y el estudio del parásito protozoario Leishmania.

“…En otro estudio observaron que las lesiones inducidas por parásitos mutantes lmcpb -se curan acompañadas de respuesta inmune Th1 a diferencia de las inducidas por parásitos de tipo silvestre lo que sugiere que las cisteína proteinasas de L. mexicana suprimen la respuesta inmune antileishmania (82). Además, cuando L. major fue transfectada con un cósmido que expresa múltiples genes de CPB de L. mexicana, estos parásitos indujeron una respuesta IFNγ significativamente inferior comparada con L. major silvestre.…”