Abstract
Coronavirus disease-2019 (COVID-19) caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2; CoV2) is a deadly contagious infectious disease. For those who survive COVID-19, post-COVID cardiac damage greatly increases the risk of cardiomyopathy and heart failure. Currently, the number of COVID-related cases are increasing in Latin America, where a major COVID comorbidity is Chagas' heart disease, which is caused by the parasite Trypanosoma cruzi. However, the interplay between indeterminate Chagas disease and COVID-19 is unknown. We investigated the effect of CoV2 infection on heart pathology in T. cruzi infected mice (coinfected with CoV2 during the indeterminate stage of T. cruzi infection). We used transgenic human angiotensin-converting enzyme 2 (huACE2/hACE2) mice infected with CoV2, T. cruzi, or coinfected with both in this study. We found that the viral load in the hearts of coinfected mice is lower compared to the hearts of mice infected with CoV2 alone. We demonstrated that CoV2 infection significantly alters cardiac immune and energy signaling via adiponectin (C-ApN) and AMP-activated protein kinase (AMPK) signaling. Our studies also showed that increased β-adrenergic receptor (b-AR) and peroxisome proliferator-activated receptors (PPARs) play a major role in shifting the energy balance in the hearts of coinfected female mice from glycolysis to mitochondrial β-oxidation. Our findings suggest that cardiac metabolic signaling may differently regulate the pathogenesis of Chagas cardiomyopathy (CCM) in coinfected mice. We conclude that the C-ApN/AMPK and b-AR/PPAR downstream signaling may play major roles in determining the progression, severity, and phenotype of CCM and heart failure in the context of COVID.
Highlights
COVID-19 illness, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV2; CoV2), results in debilitating disease manifestations in many infected people and increases mortality in people with comorbidities, including heart disease [1–6]
We found no significant difference in the parasite load in the hearts between male and female, and T. cruzi infected and coinfected mice
We observed vascular leakage and neutrophilic alveolitis in the lungs in CoV2/coinfected mice. These analyses demonstrated that: (i) the pulmonary pathology in coinfection is reduced compared to CoV2 infection alone; and (ii) males are more susceptible to severe pulmonary CoV2 infection in general, in the context of T. cruzi coinfection females are more susceptible to severe pulmonary CoV2 infection compared to males
Summary
COVID-19 illness, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV2; CoV2), results in debilitating disease manifestations in many infected people and increases mortality in people with comorbidities, including heart disease [1–6]. CD is caused by the parasite Trypanosoma cruzi, which infects an estimated eight million people in Latin America and is increasingly found in nonendemic countries, including 300,000 infected individuals in the United States [15] Of these chronically infected individuals, 30% will develop chronic Chagas cardiomyopathy (CCM) and congestive heart failure, which are significant causes of morbidity and mortality [16]. The authors reported that COVID-19 infected CD patients (n = 2) presented with a rapid disease progression, and despite all efforts of the medical team, both patients died [18] These authors suggested that COVID-19 may lead to lymphopenia, which could curb the anti–T. cruzi immune response and increase the risk of death in coinfected patients [18]. There is limited clinical data or information from animal models on the interplay between indeterminate/asymptomatic CD and COVID susceptibility, severity, risk of mortality, and long-term effects on heart pathology in post-COVID CD patients
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