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.

The cGAS-STING pathway: The role of self-DNA sensing in inflammatory lung disease.

The presence of DNA in the cytosol is usually a sign of microbial infections, which alerts the host innate immune system to mount a defense response. Cyclic GMP-AMP synthase (cGAS) is a critical cytosolic DNA sensor that elicits robust innate immune responses through the production of the second messenger, cyclic GMP-AMP (cGAMP), which binds and activates stimulator of interferon genes (STING). However, cGAS binds to DNA irrespective of DNA sequence, therefore, self-DNA leaked from the nucleus or mitochondria can also serve as a cGAS ligand to activate this pathway and trigger extensive inflammatory responses. Dysregulation of the cGAS-STING pathway is responsible for a broad array of inflammatory and autoimmune diseases. Recently, evidence has shown that self-DNA release and cGAS-STING pathway over-activation can drive lung disease, making this pathway a promising therapeutic target for inflammatory lung disease. Here, we review recent advances on the cGAS-STING pathway governing self-DNA sensing, highlighting its role in pulmonary disease.

Age-Dependent Differences in T-Cell Responses to Influenza A Virus.

Respiratory infections from influenza A virus (IAV) cause substantial morbidity and mortality in children relative to adults. T cells play a critical role in the host response to IAV by supporting the innate and humoral responses, mediating cytotoxic activity, and promoting recovery. There are age-dependent differences in the number, subsets, and localization of T cells, which impact the host response to pathogens. In this article, we first review how T cells recognize IAV and examine differences in the resting T-cell populations between juveniles and adults. Next, we describe how the juvenile CD4+, CD8+, and regulatory T-cell responses compare with those in adults and discuss the potential physiologic and clinical consequences of the differences. Finally, we explore the roles of two unconventional T-cell types in the juvenile response to influenza, natural-killer T cells and γδ T cells. A clear understanding of age-dependent differences in the T-cell response is essential to developing therapies to prevent or reverse the deleterious effects of IAV in children.