Sunday, December 22, 2024
12/22/2024
Abstract Infection with the protozoan parasite Trypanosoma cruzi is generally controlled but often not eliminated by host immune responses. In humans and many other hosts, this persistent infection ultimately results in muscle tissue damage known as Chagas disease. It is widely accepted that the early detection and rapid treatment of T. cruzi improves treatment outcomes and reduces the chances of heart damage and that parasitological cure could provide lasting immunity to reinfection and disease. However, there are limited data that specifically support these ideas. In addition to humans, T. cruzi also impacts many other mammalian species, among these dogs, that develop very similar patterns of immune control, disease development, and response to therapy, as humans. The project proposed herein takes advantage of a natural setting of high intensity infection in working dogs in south Texas to address questions of critical importance to the management of infection and disease in humans exposed to infection by T. cruzi. The question of the relative benefit of treatment soon after infection will be explored by comparing treatment outcomes using a new, high rate-of-cure treatment regimen, delivered to dogs either within months of infection, or delayed by several years. Treatment success will be evaluated using parasitological (deeply sampled blood qPCR and hemoculture), immunological (declining antibody titers) and clinical disease (blood cardiac troponin concentration, EKG and echocardiographic changes). In dogs in which parasitological cure is achieved by drug therapy, we will determine the long-term benefits of prior infection exposure by assessing reinfection rates and resistance to cardiac disease for dogs in this setting of high transmission risk. The immunological correlates of increased resistance to infection and disease will be determined by comparing the potency of anti-T. cruzi humoral and cellular immune responses to reinfection potential and ultimate pattern of disease. Lastly, the benefit of a reduced parasite burden, rather than parasitological cure, to disease development will be investigated in this same setting. Overall, this project takes advantage of one of the major benefits of work in Chagas disease, that of the highly similar course of infection and disease in naturally infected non-human mammals, to investigate questions of prime importance to the management of human Chagas disease. The work takes advantage of the cumulative and broad skill set of scientists and clinicians with a long history of work in human and animal Chagas disease and established record of collaboration in this highly accessible, high infection-risk setting. Completion of these studies will provide information that for ethical and infection dynamic reasons is likely unattainable in humans but that is highly relevant to designing strategies for management of T. cruzi infection in humans, including assessment of the need for very early detection and treatment, the requirement or not for parasitologic cure for the prevention of clinical disease, and the likelihood of reinfections and subsequent clinical disease in subjects who have received curative treatments.
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