Disease Tolerance and Pathogen Resistance Genes May Underlie Trypanosoma cruzi Persistence and Differential Progression to Chagas Disease Cardiomyopathy

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.

Keywords: Tripanosoma cruzi; chagas cardiomyopathy; disease tolerance gene; interferon gamma; pathogen resistance genes.

Figure 1

Central role of IFN-γ in protection against T. cruzi and potential host cell damage by peroxynitrite. IFN-γ, interferon-gamma; TLR, Toll-like receptor, IL12R, IL-12 receptor; IFNγR, IFN-γ receptor; JAK, Janus Associated Kinase; NO, nitric oxide; ONOO-, peroxynitrite; IRF, Interferon regulatory factor; STAT, Signal Transducer And Activator Of Transcription; ROS, reactive oxygen species.

Figure 2

Immune profile of CCC patients revolves around the IFN-γ axis. CCC patients display increased production of PRGs IFN-γ and TNF-α, and decreased levels of IFN-γ/Th1 suppressive factors as compared with ASY patients. IL-10 and Ebi3/IL-27p28 are DTGs and IL-17, also reduced in CCC, is included here as the DTG IL17RA signaling showed to suppress the IFN-γ/Th1 axis. CCC, Chagas disease cardiomyopathy; PRG, pathogen resistance gene; ASY, asymptomatic; DTG, disease tolerance gene; IFN-γ, interferon-gamma; TNF-α, tumor necrosis factor alpha; IL, interleukin; Ebi3, Epstein-Barr virus induced gene 3; IL17RA, interleukin 17 receptor A.

Figure 3

Interplay between IFN-γ and DTG determines the fate of mitochondria. IFN-γ/TNF-α strongly activate NF-kB signaling. Unchecked NF-kB activation leads to mitochondrial dysfunction, including decreased MMP, increased ROS production and reduced ATP production. IFN-γ-lowering DTG can reduce IFN-γ/TNF-α activation of NF-kB and shift the balance favoring SIRT1, Nrf2, and AMPK. Agonists can protect mitochondria and myocardial damage by reverting NF-kB activity in experimental CCC. DTG, DISEASE tolerance gene; IFN-γ, interferon-gamma; TNF-α, tumor necrosis factor alpha; NF-kB, nuclear factor kappa B; SIRT1, Sirtuin-1; Nrf2, nuclear respiratory factor 2; AMPK, 5′ adenosine monophosphate-activated protein kinase; MMP, mitochondrial membrane potential; ROS, reactive oxygen species; ATP, adenosine triphosphate.

Figure 4

Inflammation-induced mitochondrial dysfunction starts a positive feedback loop. Inflammation in CCC can trigger mitochondrial dysfunction and damage, leading to release of mtROS and other mitochondrial DAMPs which can trigger inflammation cascades themselves, using several pathways. Such mitochondrial DAMP-induced inflammation can perpetuate inflammation and promote further mitochondrial dysfunction in a positive feedback loop. “Sterile” cardiac inflammation mediated by mitochondrial damage could thus perpetuate and/or potentiate inflammation in the hearts or CCC patients. CCC, Chagas disease cardiomyopathy; DAMPs, damage-associated molecular patterns; mtROS, mitochondrial reactive oxygen species; mtDNA, mitochondrial DNA; TFAM, transcription factor A, mitochondrial; cGAS, Cyclic GMP-AMP Synthase; NRLP3, NLR family pyrin domain containing 3; TLR9, toll-like receptor 9; MyD88, myeloid differentiation primary response 88; STING, stimulator of interferon genes protein; TBK1, TANK binding kinase 1; IRF, interferon regulatory factor; NF-kB, nuclear factor kappa B; IFN, interferon; TNF-α, tumor necrosis factor alpha.