SARS-CoV-2 E protein reduces PPARA activity in colonic and pulmonary epithelial cells, driving diarrhea and pneumonia in COVID-19

Although diarrhea is common in COVID-19, its underlying mechanisms remain unclear. Using clinical data from 3023 patients and single-cell RNA sequencing of colonic tissues, we found that diarrhea was associated with higher disease severity and mortality. scRNA-seq (n = 1 COVID-19 patient with diarrhea) of colonic tissue from deceased patient, and experimental validation to elucidate the mechanisms of SARS-CoV-2-induced diarrhea and identify potential therapeutic targets. Clinical analysis revealed that diarrhea was associated with more severe disease and higher mortality rates. scRNA-seq identified significant downregulation of membrane transporters (SLC9A3, SLC26A3, and SPINT2) in colonic epithelial cells of colonic tissue from one deceased COVID-19 patient. Gene regulon network analysis pinpointed PPARA as a master regulator of these proteins, with its activity suppressed post-infection. Further experiments confirmed that E protein stimulation reduced PPARA activity and the expression of membrane transporters, leading to a diarrheal phenotype (OR = 3.33 for diarrhea as risk factor) in vitro cell culture models. Interestingly, we found PPARA activity was also decreased in SARS-CoV-2-infected lung epithelial cells, where it regulated CFTR expression, contributing to pneumonia. Treatment with PPARA agonists rescued the expression of these proteins, mitigating both diarrheal and pneumonia phenotypes. Our findings reveal a common mechanism by which the SARS-CoV-2 E protein inhibits PPARA activity in both colonic and lung epithelial cells, leading to severe clinical outcomes. PPARA agonists may represent a novel therapeutic strategy for COVID-19-associated diarrhea and pneumonia in vitro cell culture models.