Treatment outcome requirements for disease prevention in Chagas disease - 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.
