Differences in innate Intracellular viral suppression competencies may explain variations in morbidity and mortality from SARS-CoV-2 infection

SARS-CoV-2 infection and COVID-19 ravage the world with wide variations in morbidity and mortality that have remained largely unexplained, even by mutations in protein coding regions. In this study, we analyzed available complete SARS-CoV-2 sequences using the CpG index as a signature of Zinc finger antiviral protein (ZAP) activity to examine population variations in innate intracellular antiviral competencies. The result suggests that differential ZAP activity may be a major determinant of the outcome of SARS-CoV-2 infection. SARS-CoV-2 sequences from Africa, Asia, and pools of asymptomatic patients had I_CpG signature evidence of high ZAP activity, while SARS-CoV-2 sequences from North America and Intensive Care Unit or Deceased patients had I_CpG signature of low ZAP activity. ZAP activity is linked to the interferon system. Low ZAP activity may be part of the explanation for the increased morbidity of SARS-CoV-2 in the elderly and with comorbidities like diabetes, obesity, and hypertension. It may also provide some insight into the discrepancies between invitro anti-SARS-CoV-2 activities of candidate therapies and performance in clinical trials. Furthermore, our results suggest that asymptomatic patients may paradoxically shed a more dangerous virus.