Abstract
Chagas disease, the clinical presentation of T. cruzi infection, is a major human health concern. While the acute phase of Chagas disease is typically asymptomatic and self-resolving, chronically infected individuals suffer numerous sequelae later in life. Cardiomyopathies in particular are the most severe consequence of chronic Chagas disease and cannot be reversed solely by parasite load reduction. To prioritize new therapeutic targets, we unbiasedly interrogated the host signaling events in heart tissues isolated from a Chagas disease mouse model using quantitative, multiplexed proteomics. We defined the host response to infection at both the proteome and phospho-proteome levels. The proteome showed an increase in the immune response and a strong repression of several mitochondrial proteins. Complementing the proteome studies, the phospho-proteomic survey found an abundance of phospho-site alterations in plasma membrane and cytoskeletal proteins. Bioinformatic analysis of kinase activity provided substantial evidence for the activation of NDRG2 and JNK/p38 kinases during Chagas disease. A significant activation of DYRK2 and AMPKA2 and the inhibition of casein family kinases were also predicted. We concluded our analyses by linking the diseased heart proteome profile to known therapeutic interventions, uncovering a potential to target mitochondrial proteins, secreted immune effectors and core kinases for the treatment of chronic Chagas disease. Together, this study provides molecular insight into host proteome and phospho-proteome responses to T. cruzi infection in the heart for the first time, highlighting pathways that can be further validated for functional contributions to disease and suitability as drug targets.
Highlights
Chagas disease is the manifestation of an infection by the protozoan parasite Trypanosoma cruzi
This study reveals new signaling pathways modulated during chronic Chagas disease that expand the understanding of molecular mechanisms of pathogenesis and inform rational drug design
We noted a decrease in most of the NADH dehydrogenases (NDUFs) (Fig 3G) and coenzyme A-containing proteins (Fig 3H) detected in our experiments. These findings are in-line with previous reports of decreased mitochondrial function[33] and identify the major protein families affected. These analyses demonstrate that chronic Chagas disease drives an IFN-mediated immune response and suppresses mitochondrial pathways in murine hearts
Summary
Chagas disease is the manifestation of an infection by the protozoan parasite Trypanosoma cruzi. First described in 1909 by a Brazilian physician, Carlos Chagas[1], this disease is a significant health concern, in areas with low socio-economic status. Facilitated by human population flow, Chagas disease has spread out of endemic areas into more developed countries, with more than 100,000 cases in Europe[2] and 200,000–300,000 in the United States[3, 4] reported. Infected insect vectors and congenital transmission are the most common means of disease spread, accounting for up to ~96% of recorded cases (70% insect vectors, 26% congenital); blood transfusion, organ transplantation and consumption of contaminated foods contribute to T. cruzi dissemination[5]. Chagas disease is a major human health concern that causes significant morbidity and mortality worldwide
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