Cilia-related gene signature in the nasal mucosa correlates with disease severity and outcomes in critical respiratory syncytial virus bronchiolitis.

Background: Respiratory syncytial virus (RSV) can cause life-threatening respiratory failure in infants. We sought to characterize the local host response to RSV infection in the nasal mucosa of infants with critical bronchiolitis and to identify early admission gene signatures associated with clinical outcomes. Methods: Nasal scrape biopsies were obtained from 33 infants admitted to the pediatric intensive care unit (PICU) with critical RSV bronchiolitis requiring non-invasive respiratory support (NIS) or invasive mechanical ventilation (IMV), and RNA sequencing (RNA-seq) was performed. Gene expression in participants who required shortened NIS ( 3 days), and IMV was compared. Findings: Increased expression of ciliated cell genes and estimated ciliated cell abundance, but not immune cell abundance, positively correlated with duration of hospitalization in infants with critical bronchiolitis. A ciliated cell signature characterized infants who required NIS for > 3 days while a basal cell signature was present in infants who required NIS for

Age-related Differences in the Nasal Mucosal Immune Response to SARS-CoV-2.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has infected more than 180 million people since the onset of the pandemic. Despite similar viral load and infectivity rates between children and adults, children rarely develop severe illness. Differences in the host response to the virus at the primary infection site are among the mechanisms proposed to account for this disparity. Our objective was to investigate the host response to SARS-CoV-2 in the nasal mucosa in children and adults and compare it with the host response to respiratory syncytial virus (RSV) and influenza virus. We analyzed clinical outcomes and gene expression in the nasal mucosa of 36 children with SARS-CoV-2, 24 children with RSV, 9 children with influenza virus, 16 adults with SARS-CoV-2, and 7 healthy pediatric and 13 healthy adult controls. In both children and adults, infection with SARS-CoV-2 led to an IFN response in the nasal mucosa. The magnitude of the IFN response correlated with the abundance of viral reads, not the severity of illness, and was comparable between children and adults infected with SARS-CoV-2 and children with severe RSV infection. Expression of ACE2 and TMPRSS2 did not correlate with age or presence of viral infection. SARS-CoV-2-infected adults had increased expression of genes involved in neutrophil activation and T-cell receptor signaling pathways compared with SARS-CoV-2-infected children, despite similar severity of illness and viral reads. Age-related differences in the immune response to SARS-CoV-2 may place adults at increased risk of developing severe illness.

Immune response to SARS-CoV-2 in the nasal mucosa in children and adults.

RATIONALE: Despite similar viral load and infectivity rates between children and adults infected with SARS-CoV-2, children rarely develop severe illness. Differences in the host response to the virus at the primary infection site are among the proposed mechanisms. OBJECTIVES: To investigate the host response to SARS-CoV-2, respiratory syncytial virus (RSV), and influenza virus (IV) in the nasal mucosa in children and adults. METHODS: Clinical outcomes and gene expression in the nasal mucosa were analyzed in 36 children hospitalized with SARS-CoV-2 infection, 24 children with RSV infection, 9 children with IV infection, 16 adults with mild to moderate SARS-CoV-2 infection, and 7 healthy pediatric and 13 healthy adult controls. RESULTS: In both children and adults, infection with SARS-CoV-2 leads to an interferon response in the nasal mucosa. The magnitude of the interferon response correlated with the abundance of viral reads and was comparable between symptomatic children and adults infected with SARS-CoV-2 and symptomatic children infected with RSV and IV. Cell type deconvolution identified an increased abundance of immune cells in the samples from children and adults with a viral infection. Expression of ACE2 and TMPRSS2 - key entry factors for SARS-CoV-2 - did not correlate with age or presence or absence of viral infection. CONCLUSIONS: Our findings support the hypothesis that differences in the immune response to SARS-CoV-2 determine disease severity, independent of viral load and interferon response at the primary infection primary site.