The COVID-19 pandemic has highlighted how one respiratory RNA virus can induce a tremendous diversity of
host outcomes. While we have made progress in understanding clinical, cellular, and molecular correlates of
disease severity, few studies have assessed if or how specific factors present at baseline may induce severe
disease. There is a tremendous knowledge gap in whether correlates of disease severity represent causal factors
(i.e. if presence at baseline lead to more severe infection), or may actually represent generally beneficial attempts
at restoring tissue function (i.e. a resilience mechanism), that are detrimental only in select host contexts. Despite
distinct biology of SARS-CoV-2 and influenza, epidemiological studies have noted that overweight and obese
individuals are at greater risk for severe infection, implicating lipid metabolism, and further genetic studies have
found mutations in the Type I/III interferon system in severe cases. Importantly, treating the underlying causes
of severe viral respiratory diseases will require a deeper understanding of the epithelial cell states that contribute
to diverse outcomes to design host-directed therapies that complement vaccination campaigns and avoid long-
lasting damage to the respiratory and cardiovascular systems.
Recently through single-cell RNA-sequencing (scRNA-seq) of nasopharyngeal swabs, we have discovered that
a muted interferon antiviral response combined with an increase in intracellular cholesterol biosynthesis potential
in respiratory epithelial cells characterizes severe vs. mild-moderate COVID-19. In this same study, we also
revealed diversified subsets of secretory and goblet cells with uncharacterized functional potential, overlapping
with subsets we had previously identified in a study of seasonal influenza. Our published data, together with that
of our colleagues, mandate further investigation into how pre-existing antiviral and cholesterol biosynthetic cell
states in human respiratory epithelial cells dictate host outcomes to respiratory viral infection.
In light of these findings, we hypothesize that baseline cholesterol biosynthesis in respiratory epithelial cells is
a critical host resilience mechanism which becomes pathogenic in the absence of effective antiviral resistance
mechanisms. This overarching hypothesis can only be tested through a shift in the conceptual and experimental
approaches we traditionally deploy (New Research Direction). Successfully testing our hypothesis will address
(Aim 1) whether cholesterol biosynthesis dictates the maximum potential interferon response in airway epithelial
cells, or whether a muted interferon response underlies enhanced cholesterol biosynthesis in mice. Furthermore,
it will identify novel contributions of airway epithelial cells to local and organismal lipid metabolism. Our work will
also test (Aim 2) the stability of metabolic and antiviral cellular phenotypes in human epithelial progenitor cells.
Successful completion of our plan will lead to the development of non-invasive screening approaches to better
ascertain risk of susceptible populations to respiratory viruses, and of prophylactic and therapeutic strategies to
achieve optimal balance of host defense strategies in the respiratory tract.