Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) causes enhanced mortality in people with metabolic and cardiovascular diseases. Other highly infectious RNA viruses have demonstrated dependence on glucose transport and utilization, so we hypothesized that SARS-CoV-2 infection could lead to alterations in cellular and whole-body glucose metabolism. Twenty-four healthy domestic cats were intratracheally inoculated with B.1.617.2 (delta) SARS-CoV-2 and samples were collected at 4- and 12-days post-inoculation (dpi). Blood glucose and circulating cortisol concentrations were elevated at 4 and 12 dpi. Serum insulin concentration was statistically significantly decreased, while angiotensin 2 concentration was elevated at 12 dpi. SARS-CoV-2 RNA was detected in the pancreas and skeletal muscle at low levels; however, no change in the number of insulin-producing cells or proinflammatory cytokines was observed in the pancreas of infected cats through 12 dpi. SARS-CoV-2 infection statistically significantly increased GLUT protein expression in both the heart and lungs, correlating with increased AMPK expression. In brief, SARS-CoV-2 increased blood glucose concentration and cardio-pulmonary GLUT expression through an AMPK-dependent mechanism, without affecting the pancreas, suggesting that SARS-CoV-2 induces the reprogramming of host glucose metabolism. A better understanding of host cell metabolism and virus crosstalk could lead to the discovery of novel metabolic therapeutic targets for patients affected by COVID-19.

Human alpha-herpesvirus 1 (HSV-1) acute infection culminates in life-long latency in sensory neurons in trigeminal ganglia and certain neurons in the central nervous system. Previously, E2F family members and glucocorticoid receptor (GR) were shown to stimulate HSV-1 and bovine herpesvirus 1 (BoHV-1) replication. Consequently, we hypothesized GR and E2F family members activate certain HSV-l promoters. To test this hypothesis, we determined if four HSV-1 ICP0 cis-regulatory modules (CRM) upstream of the ICP0 promoter were activated by E2F. GR and E2F2, but not E2F1, E2F3a, or E2F3b, cooperatively transactivate the ICP0 CRM-C, but not CRM-A, -B, or -D fragments upstream of a minimal promoter in a luciferase reporter construct. CRM-C sequences contain two E2F consensus binding sites, a GC-rich motif that E2F2 can bind, and a consensus ½ GR response element (GRE) adjacent to the consensus E2F #2 binding site. Mutating the ½ GRE or the 3 E2F binding sites significantly reduced GR- and E2F2-mediated transactivation. Chromatin immunoprecipitation studies revealed E2F2 occupied ICP0 CRM-C sequences during productive infection and mutating the E2F binding sites prevented E2F2 binding. These studies reveal GR and E2F2 transactivate ICP0-promoter activity, which may enhance viral replication in certain cell types.