Sex Differences in Cardiac Pathology of SARS-CoV2 Infected and Trypanosoma cruzi Co-infected Mice

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.

Susceptibility of Fat Tissue to SARS-CoV-2 Infection in Female hACE2 Mouse Model

“…Earlier, we demonstrated that SARS-CoV-2 infection alters pulmonary pathology in hACE2 mice differently in males and females [ 30 ]. In particular, we showed a significantly increased viral load and infiltration of immune cells in the lungs of infected male mice compared to female mice at 10 DPI [ 30 ]. However, both male and female mice showed decreased body weight compared to control mice.…”

“…However, both male and female mice showed decreased body weight compared to control mice. Our earlier studies suggest that decreased body weight is likely caused by a loss of body fat mass [ 30 ]. Therefore, we investigated the role of adipose tissue in CoV-2 infection using white adipose tissue (WAT) of infected and uninfected control mice (10 DPI) as detailed in the Materials and Methods section.…”

“…ACE2 protein is a well-recognized receptor for CoV-2 entry into the host cell [ 33 , 34 ]. Earlier we showed by Western blotting that CoV-2 infection increases the expression levels of ACE2 protein in the lungs of hACE2 mice [ 30 ]. The levels of ACE2 were significantly higher in the lungs of both male ( p ≤ 0.0001) and female ( p ≤ 0.01) mice infected with SARS-CoV-2 compared to sex-matched uninfected (control) mice [ 30 ].…”

“…Earlier we showed by Western blotting that CoV-2 infection increases the expression levels of ACE2 protein in the lungs of hACE2 mice [ 30 ]. The levels of ACE2 were significantly higher in the lungs of both male ( p ≤ 0.0001) and female ( p ≤ 0.01) mice infected with SARS-CoV-2 compared to sex-matched uninfected (control) mice [ 30 ]. Here, we analyzed whether CoV-2 infection also alters the levels of ACE2 in WAT.…”

“…We analyzed the viral loads in the lung and WAT by qPCR analysis. Lung viral loads were significantly greater in male CoV-2-infected mice compared to female CoV-2-infected mice ( Figure 2 b), which may be due to increased ACE2 levels in male mice [ 30 ]. However, qPCR analysis demonstrated significantly higher levels of viral load in the WAT of female CoV-2 infected mice (64-fold, p ≤ 0.005) compared to male CoV-2 infected mice, although the levels of ACE2 were not significantly increased ( Figure 2 c).…”