Aging-dependent responses to human systemic protozoosis: proof of pronciple in an experimental model of trypanossoma cruzi infection

Abstract

Immunosenescence, a process that develops throughout aging, is characterized by decline in the phenotype and function of organs and cells of the immune system. In general, the increased susceptibility of elderly organisms to infectious diseases has been related to immunosenescence. Although extreme age groups are more susceptible to pathogenic microorganisms, especially bacteria and virus, the impact of parasitic infections in elderly organisms is poorly understood. Therefore, we developed an integrated model based on systematic review and preclinical studies to compare the evolution of systemic protozooses in young and elderly organisms. In the first approach based on systematic review, we investigated preclinical models of human systemic protozooses (Chagas disease, Leishmaniasis, Malaria, Sleeping sickness, Toxoplasmosis). In this study, we identified the evidence that throughout aging, parasitemia and mortality were reduced in Chagas disease and malaria, but similar or increased in Leishmaniasis and highly variable in Toxoplasmosis. While a humoral response in older animals was protective in Chagas disease, a cellular Th1 response was protective against Plasmodium infections. In Leishmaniasis, the most severe infections were related to the imbalance between Th1 and Th2 phenotypes. To reinforce the evidence found in the systematic review, we used a preclinical model (in vitro and in vivo) to compare the evolution of T. cruzi infection in young (8 weeks-old) and elderly (72 weeks-old) mice. Our findings indicate that young and elderly mice infected by T. cruzi express divergent parasitic control and myocarditis severity, which is potentially related to differences in cytokine expression and activation of Arg-1 and iNOS pathways. The severe myocarditis identified in elderly animals was consistent with higher parasitemia and parasitic load, indicating that the upregulated IgG2b and IL-17 production was unable to counteract heart parasitism and damage. Thus, the higher susceptibility of elderly mice to T. cruzi infection was related to differential activation of Arg-1 and iNOS pathways. Therefore, our findings indicated that the aging of immune cells is associated with an attenuated response to antigenic stimulation, in which iNOS downregulation and increased activation of the arginase pathway creates favourable conditions for heart parasitism and myocarditis development.