High-resolution epigenome analysis in nasal samples derived from children with respiratory viral infections reveals striking changes upon SARS-CoV-2 infection (preprint)

Background: DNA methylation patterns of the human genome can be modified by environmental stimuli and provide dense information on gene regulatory circuitries. We studied genome-wide DNA methylation in nasal samples from infants (<6 months) applying whole-genome bisulfite sequencing (WGBS) to characterize epigenome response to 10 different respiratory viral infections including SARS-CoV-2. Results: We identified virus-specific differentially methylated regions (vDMR) with human metapneumovirus (hMPV) and SARS-CoV-2 followed by Influenza B (Flu B) causing the weakest vs. strongest epigenome response with 496 vs. 78541 and 14361 vDMR, respectively. We found a strong replication rate of FluB (52%) and SARS-CoV-2 (42%) vDMR in independent samples indicating robust epigenome perturbation upon infection. Among the FluB and SARS-CoV-2 vDMRs, around 70% were hypomethylated and significantly enriched among epithelial cell-specific regulatory elements whereas the hypermethylated vDMRs for these viruses mapped more frequently to immune cell regulatory elements, especially those of the myeloid lineage. The hypermethylated vDMRs were also enriched among genes and genetic loci in monocyte activation pathways and monocyte count, suggesting that suppression or underdevelopment of these gene networks may trigger viral colonization in airway epithelium. We further mapped FluB and SARS-CoV-2 epigenome response in children across ages (0-5 years) and found different profiles of epigenome across the early lifespan. Finally, we perform single-cell RNA-sequencing characterization of nasal mucosa in response to these two viruses to functionally analyze the epigenome perturbations. Conclusions: All together, we find evidence indicating genetic predisposition to innate immune response upon a respiratory viral infection. Our genome-wide monitoring of infant viral response provides first catalogue of associated host regulatory elements. Assessing epigenetic variation in individual patients may reveal evidence for viral triggers of childhood disease.

Immune cell residency in the nasal mucosa and COVID-19 severity across the age range (preprint)

Severe coronavirus disease of 2019 (COVID-19) positively correlates with age (Centers for Disease Control), develops after progression of infection from the upper airway to the lower respiratory tract (LRT), and can worsen into acute respiratory distress syndrome (ARDS). Why children seem to be less likely to develop severe disease remains unclear. As the nasal mucosa (NM) is the first site of contact and defense for respiratory pathogens such as SARS-CoV-2 before dissemination to the LRT, we hypothesized that differences in this tissue across the age range may help explain the disparity in COVID-19 severity. To this end, we profiled NM samples across the lifespan in health and disease. We find that global transcriptomic changes including the expression of SARS-CoV-2 and coronavirus-associated receptors and factors are not correlated with age or the novel virus type, since pediatric NM cells mount similar antiviral response to both SARS-CoV-2 or Influenza B. Rather, we find immune cell residency in NM decreases dramatically with age especially cells of the innate immune system. This includes a resident-memory-like T cell subset with antiviral properties. These observations give plausible biological explanation to the observed clinical differences in disease spectrum and provide a foundation for future experimental studies.