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Comparative Study of SARS-CoV-2, SARS-CoV-1, MERS-CoV, HCoV-229E and Influenza Host Gene Expression in Asthma: Importance of Sex, Disease Severity, and Epithelial Heterogeneity.

ABSTRACT: Epithelial characteristics underlying the differential susceptibility of chronic asthma to SARS-CoV-2 (COVID-19) and other viral infections are currently unclear. By revisiting transcriptomic data from patients with Th2 low versus Th2 high asthma, as well as mild, moderate, and severe asthmatics, we characterized the changes in expression of human coronavirus and influenza viral entry genes relative to sex, airway location, and disease endotype. We found sexual dimorphism in the expression of SARS-CoV-2-related genes ACE2, TMPRSS2, TMPRSS4, and SLC6A19. ACE2 receptor downregulation occurred specifically in females in Th2 high asthma, while proteases broadly assisting coronavirus and influenza viral entry, TMPRSS2, and TMPRSS4, were highly upregulated in both sexes. Overall, changes in SARS-CoV-2-related gene expression were specific to the Th2 high molecular endotype of asthma and different by asthma severity and airway location. The downregulation of ACE2 (COVID-19, SARS) and ANPEP (HCoV-229E) viral receptors wascorrelated with loss of club and ciliated cells in Th2 high asthma. Meanwhile, the increase in DPP4 (MERS-CoV), ST3GAL4, and ST6GAL1 (influenza) was associated with increased goblet and basal activated cells. Overall, this study elucidates sex, airway location, disease endotype, and changes in epithelial heterogeneity as potential factors underlying asthmatic susceptibility, or lack thereof, to SARS-CoV-2.

SUBMITTER: Coden ME

PROVIDER: S-EPMC8226441 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Four coronaviruses (HCoV-OC43, HCoV-HKU1, HCoV-NL63, and HCoV-229E) are endemic in human populations. All these viruses are seasonal and generate short-term immunity. Like the highly pathogenic coronaviruses, the endemic coronaviruses have zoonotic origins. Thus, understanding the evolutionary dynamics of these human viruses might provide insight into the future trajectories of SARS-CoV-2 evolution. Because the zoonotic sources of HCoV-OC43 and HCoV-229E are known, we applied a population genetics-phylogenetic approach to investigate which selective events accompanied the divergence of these viruses from the animal ones. Results indicated that positive selection drove the evolution of some accessory proteins, as well as of the membrane proteins. However, the spike proteins of both viruses and the hemagglutinin-esterase (HE) of HCoV-OC43 represented the major selection targets. Specifically, for both viruses, most positively selected sites map to the receptor-binding domains (RBDs) and are polymorphic. Molecular dating for the HCoV-229E spike protein indicated that RBD Classes I, II, III, and IV emerged 3-9 years apart. However, since the appearance of Class V (with much higher binding affinity), around 25 years ago, limited genetic diversity accumulated in the RBD. These different time intervals are not fully consistent with the hypothesis that HCoV-229E spike evolution was driven by antigenic drift. An alternative, not mutually exclusive possibility is that strains with higher affinity for the cellular receptor have out-competed strains with lower affinity. The evolution of the HCoV-OC43 spike protein was also suggested to undergo antigenic drift. However, we also found abundant signals of positive selection in HE. Whereas such signals might result from antigenic drift, as well, previous data showing co-evolution of the spike protein with HE suggest that optimization for human cell infection also drove the evolution of this virus. These data provide insight into the possible trajectories of SARS-CoV-2 evolution, especially in case the virus should become endemic.

Dataset Information

Comparative Study of SARS-CoV-2, SARS-CoV-1, MERS-CoV, HCoV-229E and Influenza Host Gene Expression in Asthma: Importance of Sex, Disease Severity, and Epithelial Heterogeneity.

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