Gene: environment interactions in immune and inflammatory responses to severe acute respiratory syndrome coronavirus 2 infection

Despite its devastating human cost, the rapid spread and global establishment of the severe acute respiratory syndrome coronavirus (SARS-CoV-2) pandemic had the benefit of providing unique insights into the intricate interplay between genetic, environmental, and socioeconomic factors, which collectively impact susceptibility to infection with SARS-CoV-2. Preceding the implementation of broad vaccination programs and assuming the absence of significant acquired immunity, examining the innate vulnerability to the virus becomes essential. There is indeed considerable heterogeneity observed at both the population and individual levels for various SARS-CoV-2 infection phenotypes, including emergence, progression, and survival from the coronavirus disease 2019 (COVID-19) syndrome. Particularly intriguing is the seemingly milder course of COVID-19 disease reported for the African continent early during the pandemic. This was characterized by significantly lower mortality rates in SARS-CoV-2 patients compared with the European and American continents and globally. We will discuss some of the demographic and socioeconomic factors that may have contributed to these observations. We review the mapped COVID-19 genetic architecture, including the remarkable association of type I interferon as a single protective mechanism and a major determinant of susceptibility. Furthermore, we speculate on potential ‘environmental’ modulators of penetrance and expressivity of intrinsic vulnerability factors, with a focus on the microbiome and associated metabolomes. Additionally, this review explores the potential immunomodulatory contribution of helminth parasites to the human host immune and inflammatory responses to respiratory viral infections.