Host genetics is a key determinant of COVID-19 outcomes. Previously, the COVID-19 Host Genetics Initiative genome-wide association study used common variants to identify multiple loci associated with COVID-19 outcomes. However, variants with the largest impact on COVID-19 outcomes are expected to be rare in the population. Hence, studying rare variants may provide additional insights into disease susceptibility and pathogenesis, thereby informing therapeutics development. Here, we combined whole-exome and whole-genome sequencing from 21 cohorts across 12 countries and performed rare variant exome-wide burden analyses for COVID-19 outcomes. In an analysis of 5,085 severe disease cases and 571,737 controls, we observed that carrying a rare deleterious variant in the SARS-CoV-2 sensor toll-like receptor TLR7 (on chromosome X) was associated with a 5.3-fold increase in severe disease (95% CI: 2.75–10.05, p = 5.41x10-7). This association was consistent across sexes. These results further support TLR7 as a genetic determinant of severe disease and suggest that larger studies on rare variants influencing COVID-19 outcomes could provide additional insights.

Rhinoviruses (RV) and inhaled allergens, such as house dust mite (HDM) are the major agents responsible for asthma onset, its life-threatening exacerbations and progression to severe disease. The role of severe acute respiratory syndrome coronavirus (SARS-CoV-2) in exacerbations of asthma or the influence of preexisting viral or allergic airway inflammation on the development of coronavirus disease 2019 (COVID-19) is largely unknown. To address this, we compared molecular mechanisms of HDM, RV and SARS-CoV-2 interactions in experimental RV infection in patients with asthma and healthy individuals. RV infection was sensed via retinoic acid-inducible gene I (RIG-I) helicase, but not via NLR family pyrin domain containing 3 (NLRP3), which led to subsequent apoptosis-associated speck like protein containing a caspase recruitment domain (ASC) recruitment, oligomerization and RIG-I inflammasome activation. This phenomenon was augmented in bronchial epithelium in patients with asthma, especially upon pre-exposure to HDM, which itself induced a priming step, pro-IL-1β release and early inhibition of RIG-I/TANK binding kinase 1/IκB kinase ε /type I/III interferons (RIG-I/TBK1/IKKε/IFN-I/III) responses. Excessive activation of RIG-I inflammasomes was partially responsible for the alteration and persistence of type I/III IFN responses, prolonged viral clearance and unresolved inflammation in asthma. RV/HDM-induced sustained IFN I/III responses initially restricted SARS- CoV-2 replication in epithelium of patients with asthma, but even this limited infection with SARS-CoV-2 augmented RIG-I inflammasome activation. Timely inhibition of the epithelial RIG-I inflammasome and reduction of IL-1β signaling may lead to more efficient viral clearance and lower the burden of RV and SARS- CoV-2 infection.

Host genetics is a key determinant of COVID-19 outcomes. Previously, the COVID-19 Host Genetics Initiative genome-wide association study used common variants to identify multiple loci associated with COVID-19 outcomes. However, variants with the largest impact on COVID-19 outcomes are expected to be rare in the population. Hence, studying rare variants may provide additional insights into disease susceptibility and pathogenesis, thereby informing therapeutics development. Here, we combined whole-exome and whole-genome sequencing from 21 cohorts across 12 countries and performed rare variant exome-wide burden analyses for COVID-19 outcomes. In an analysis of 5,048 severe disease cases and 571,009 controls, we observed that carrying a rare deleterious variant in the SARS-CoV-2 sensor toll-like receptor TLR7 (on chromosome X) was associated with a 5.3-fold increase in severe disease (95% CI: 2.75-10.05, p=5.41×10-7). These results further support TLR7 as a genetic determinant of severe disease and suggest that larger studies on rare variants influencing COVID-19 outcomes could provide additional insights.

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Background: The aim of the study was to investigate the impact of COVID-19 on the pulmonary function tests (PFT) in COVID-19 convalescents six months after recovery. Additionally, the research question was whether PFT should be performed routinely in post-COVID-19 patients. Methods: A total of 39 patients with a history of COVID-19 6 months prior to the study were included in the study (Group I). Individuals were hospitalized or treated in the outpatients department. The control group (Group II) consisted of 39 healthy patients without a COVID-19 history. Each subject completed a questionnaire interview and underwent laboratory and pulmonary function examinations. Results: Six months after COVID-19 recovery, patients mainly complained about cough (46%, n = 18), shortness of breath (23%, n = 9), weakness (13%, n = 5), and memory/concentration disorders (8%, n = 3). In the group of patients complaining of persistent cough present 6 months after COVID-19, the following PFT parameters were decreased: FEV1, FVC, FRC, TLC, and DLCO (p < 0.05) in comparison with patients without this symptom. Conclusions: Persistent shortness of breath is not necessarily associated with pulmonary function impairment in patients 6 months after SARS-CoV-2 infection, and hence it requires appropriate differential diagnosis. Patients with a cough persisting 6 months after the acute phase of COVID-19 may benefit from PFT.