Immunity Against Leishmania major Infection: Parasite-Specific Granzyme B Induction as a Correlate of Protection

Abstract

Zoonotic cutaneous leishmaniasis (ZCL) caused by Leishmania (L.) major infection is characterized by different clinical presentations which depend in part on the host factors. In attempt to investigate the impact of the host's immune response in the outcome of the disease, we conducted a prospective study of 453 individuals living in endemic foci of L. major transmission in Central Tunisia. Several factors were assessed at the baseline including (i) the presence of typical scars of ZCL, (ii) in vivo hypersensitivity reaction to leishmanin, and (iii) the in vitro release of granzyme B (Grz B) by peripheral blood mononuclear cells (PBMC) in response to stimulation with live L. major promastigotes. After one season of parasite's transmission, repeated clinical examinations allowed us to diagnose the new emerging ZCL cases. Heterogeneity was observed in terms of number of lesions developed by each individual as well as their size and spontaneous outcome, which led us to establish the parameter “severity of the disease.” The efficacy of the presence of typical ZCL scar, the leishmanin skin test (LST) positive reactivity and the high levels of Grz B (≥2 ng/ml), in the protection against the development of ZCL were 29, 15, and 22%, respectively. However, these factors were more efficient against development of intermediate or severe forms of ZCL. Levels of Grz B >2 ng/ml showed the best efficacy of protection (equals to 72.8%) against development of these forms of ZCL. The association of such parameter with the positivity of the LST exhibited a better efficacy (equals to 83.6%). In conclusion, our results support the involvement of Leishmania-specific cytotoxic cellular immune response in host protection against Leishmania-infection. This factor could be of great interest in monitoring the success of vaccination against human leishmaniasis.

Unraveling the Role of Immune Checkpoints in Leishmaniasis

“…(43,44). Protection takes place by production of nitric oxide (NO) by the inducible NO synthase (iNOS) in macrophages in order to kill the amastigotes (45)(46)(47)(48).…”

“…IFN-γ levels collectively produced by CD4 + Th1 and other activated cells types, such as CD8 + T cells and natural killer (NK) cells, is, so far, known as the best correlate of protection in leishmaniasis ( 43 , 44 ). Protection takes place by production of nitric oxide (NO) by the inducible NO synthase (iNOS) in macrophages in order to kill the amastigotes ( 45 – 48 ).…”

Design of multi-epitope peptides containing HLA class-I and class-II-restricted epitopes derived from immunogenic Leishmania proteins, and evaluation of CD4+ and CD8+ T cell responses induced in cured cutaneous leishmaniasis subjects

“…GrB, is a proapoptotic protease that has been associated with both tissue damage and good prognosis in CL and VL patients [28-32, 95, 96]. It was recently reported that GrB constitutes a good correlate for protection against severe forms of CL [33].…”

“…CD8+ T cells are also important in the healing mainly through IFN-γ production [24][25][26]. These cells have also been involved in pathogenesis, trough Granzyme B (GrB) production [27][28][29][30], while other studies showed that an increase of GrB activity was associated with a good prognosis in patients with CL [31][32][33].…”

Intestinal helminthiasis as a relevant factor on immunological markers status of cutaneous leishmaniasis patients

“…Likewise, the American tegumentary leishmaniasis also stimulates complex immune and inflammatory responses at local level in the skin with production of IL-4, IL-6 and IL-22 by cells Th17 [13,14]. However, the chronic mucous form of the infection is characterized by an immune response oriented towards Th2 favouring a persistent inflammation at local and/or systemic level [15,16,17].…”