Immunization with a Trypanosoma cruzi cyclophilin-19 deletion mutant protects against acute Chagas disease in mice

Abstract

Human infection with the protozoan parasite Trypanosoma cruzi causes Chagas disease for which there are no prophylactic vaccines. Cyclophilin 19 is a secreted cis-trans peptidyl isomerase expressed in all life stages of Trypanosoma cruzi. This protein in the insect stage leads to the inactivation of insect anti-parasitic peptides and parasite transformation whereas in the intracellular amastigotes it participates in generating ROS promoting the growth of parasites. We have generated a parasite mutant with depleted expression of Cyp19 by removal of 2 of 3 genes encoding this protein using double allelic homologous recombination. The mutant parasite line failed to replicate when inoculated into host cells in vitro or in mice indicating that Cyp19 is critical for infectivity. The mutant parasite line also fails to replicate in or cause clinical disease in immuno-deficient mice further validating their lack of virulence. Repeated inoculation of mutant parasites into immuno-competent mice elicits parasite-specific trypanolytic antibodies and a Th-1 biased immune response and challenge of mutant immunized mice with virulent wild-type parasites is 100% effective at preventing death from acute disease. These results suggest that parasite Cyp19 may be candidate for small molecule drug targeting and that the mutant parasite line may warrant further immunization studies for prevention of Chagas disease.

Vaccination with parasite-specific TcTASV proteins combined with recombinant baculovirus as a delivery platform protects against acute and chronic Trypanosoma cruzi infection

“…Several vaccines against T. cruzi have been pre-clinically tested in animal models, using different antigens and platforms. Most assayed antigens are well-characterized parasite virulence factors belonging to large multigene families, such as trans -sialidase, ASP-2, and cruzipain ( Tzelepis et al., 2008 ; Haolla et al., 2009 ; Bontempi et al., 2015 , 2017 ; Cerny et al., 2020 ; Moraschi et al., 2021 ; Castro et al., 2023 ; Jha et al., 2023 ). However, to date, none antigen-defined vaccines have been able to induce an immune response that avoids an initial infection with the parasite.…”

“…In recent years, special attention has been paid to the use of glycoantigens, chimeric antigens, novel adjuvants, and live platforms ( Nogueira et al., 2013 ; Sanchez Alberti et al., 2017 ; Portillo et al., 2019 ; Bivona et al., 2020 ; Lokugamage et al., 2021 ; Rodrigues da Cunha et al., 2021 ; Cai et al., 2022 ; Pacini et al., 2022 ). Recently, Jha et al. (2023) demonstrated that a parasite attenuated by the deletion of cyclophilin-19 completely prevents T. cruzi infection.…”

“…In recent years, special attention has been paid to the use of glycoantigens, chimeric antigens, novel adjuvants, and live platforms (Nogueira et al, 2013;Sanchez Alberti et al, 2017;Portillo et al, 2019;Bivona et al, 2020;Lokugamage et al, 2021;Rodrigues da Cunha et al, 2021;Cai et al, 2022;Pacini et al, 2022). Recently, Jha et al (2023) demonstrated that a parasite attenuated by the deletion of cyclophilin-19 completely prevents T. cruzi infection. Although this study showed that sterilizing immunity against T. cruzi can be achieved by immunization, the use of live parasites as vaccines still requires additional work to evaluate its safety.…”

Insights Into Peptidyl-Prolyl Cis-Trans Isomerases From Clinically Important Protozoans: From Structure to Potential Biotechnological Applications

“…Most CyPs from T. vaginalis retain the aa residues essential for catalytic activity within the highly conserved CLD identified in TvCyP19 (referred to as TvCyP1 by Hsu et al, 2014) [26]: H 62 , R 63 , F 68 , M 69 , Q 71 , G 80 , A 109 , N 110 , A 111 , Q 119 , F 121 , W 129 , L 130 , and H 134 . Exceptions to this pattern were observed in TvCyP21, TvCyP37, and TvCyP44 (Supplementary Figure S2).…”

“…TcCyP19 is also involved in the modulation of ROS production during infection, promoting T. cruzi proliferation [78]. Recently, TcCyP19 has been identified as a promising target of treatment for this disease [134] and seems to be a promising biomarker for evaluating trypanocidal therapies and diagnosing the disease [135].…”