Abstract
Chagas disease is caused by infection with the protozoan Trypanosoma cruzi and affects over 8 million people worldwide. In spite of a powerful innate and adaptive immune response in acute infection, the parasite evades eradication, leading to a chronic persistent infection with low parasitism. Chronically infected subjects display differential patterns of disease progression. While 30% develop chronic Chagas disease cardiomyopathy (CCC)—a severe inflammatory dilated cardiomyopathy—decades after infection, 60% of the patients remain disease-free, in the asymptomatic/indeterminate (ASY) form, and 10% develop gastrointestinal disease. Infection of genetically deficient mice provided a map of genes relevant for resistance to T. cruzi infection, leading to the identification of multiple genes linked to survival to infection. These include pathogen resistance genes (PRG) needed for intracellular parasite destruction, and genes involved in disease tolerance (protection against tissue damage and acute phase death—DTG). All identified DTGs were found to directly or indirectly inhibit IFN-γ production or Th1 differentiation. We hypothesize that the absolute need for DTG to control potentially lethal IFN-γ PRG activity leads to T. cruzi persistence and establishment of chronic infection. IFN-γ production is higher in CCC than ASY patients, and is the most highly expressed cytokine in CCC hearts. Key DTGs that downmodulate IFN-γ, like IL-10, and Ebi3/IL27p28, are higher in ASY patients. Polymorphisms in PRG and DTG are associated with differential disease progression. We thus hypothesize that ASY patients are disease tolerant, while an imbalance of DTG and IFN-γ PRG activity leads to the inflammatory heart damage of CCC.
Highlights
Chagas disease is caused by infection with Trypanosoma cruzi, an obligatory intracellular parasite in the mammalian host
pathogen resistance genes (PRG) were defined as genes essential for control of T. cruzi parasitism and needed for survival of infection; operationally, we identified as PRG those genes whose knockout led to increased pathogen load and mortality
We found that 7 genes with polymorphisms associated with chronic Chagas disease cardiomyopathy (CCC) or severe CCC were defined as PRG or Disease tolerance genes (DTG) in mouse knockout infection studies (Table 2)
Summary
Chagas disease is caused by infection with Trypanosoma cruzi, an obligatory intracellular parasite in the mammalian host. Disease tolerance genes (DTG)—which do not limit infection, but reduce its fitness costs—operate to minimize tissue damaging effects of the pathogen, leading to stress and damage reduction responses; DTG can operate by counteracting excessive, tissue-damaging PRG activity [1, 3, 4]. One such stress response pathways involved in disease tolerance is the oxidative stress response, whose master regulator is nuclear respiratory factor 2 (Nrf2) [3]. We will provide evidence supporting both hypotheses
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