Whole-genome sequencing reveals host factors underlying critical COVID-19

Critical COVID-19 is caused by immune-mediated inflammatory lung injury. Host genetic variation influences the development of illness requiring critical care1 or hospitalization2,3,4 after infection with SARS-CoV-2. The GenOMICC (Genetics of Mortality in Critical Care) study enables the comparison of genomes from individuals who are critically ill with those of population controls to find underlying disease mechanisms. Here we use whole-genome sequencing in 7,491 critically ill individuals compared with 48,400 controls to discover and replicate 23 independent variants that significantly predispose to critical COVID-19. We identify 16 new independent associations, including variants within genes that are involved in interferon signalling (IL10RB and PLSCR1), leucocyte differentiation (BCL11A) and blood-type antigen secretor status (FUT2). Using transcriptome-wide association and colocalization to infer the effect of gene expression on disease severity, we find evidence that implicates multiple genes—including reduced expression of a membrane flippase (ATP11A), and increased expression of a mucin (MUC1)—in critical disease. Mendelian randomization provides evidence in support of causal roles for myeloid cell adhesion molecules (SELE, ICAM5 and CD209) and the coagulation factor F8, all of which are potentially druggable targets. Our results are broadly consistent with a multi-component model of COVID-19 pathophysiology, in which at least two distinct mechanisms can predispose to life-threatening disease: failure to control viral replication; or an enhanced tendency towards pulmonary inflammation and intravascular coagulation. We show that comparison between cases of critical illness and population controls is highly efficient for the detection of therapeutically relevant mechanisms of disease

The Ag85B protein of the BCG vaccine facilitates macrophage uptake but is dispensable for protection against aerosol Mycobacterium tuberculosis infection.

Defining the function and protective capacity of mycobacterial antigens is crucial for progression of tuberculosis (TB) vaccine candidates to clinical trials. The Ag85B protein is expressed by all pathogenic mycobacteria and is a component of multiple TB vaccines under evaluation in humans. In this report we examined the role of the BCG Ag85B protein in host cell interaction and vaccine-induced protection against virulent Mycobacterium tuberculosis infection. Ag85B was required for macrophage infection in vitro, as BCG deficient in Ag85B expression (BCG:Delta85B) was less able to infect RAW 264.7 macrophages compared to parental BCG, while an Ag85B-overexpressing BCG strain (BCG:oex85B) demonstrated improved uptake. A similar pattern was observed in vivo after intradermal delivery to mice, with significantly less BCG:Delta85B present in CD64hiCD11bhi macrophages compared to BCG or BCG:oex85B. After vaccination of mice with BCG:Delta85B or parental BCG and subsequent aerosol M. tuberculosis challenge, similar numbers of activated CD4+ and CD8+ T cells were detected in the lungs of infected mice for both groups, suggesting the reduced macrophage uptake observed by BCG:Delta85B did not alter host immunity. Further, vaccination with both BCG:Delta85B and parental BCG resulted in a comparable reduction in pulmonary M. tuberculosis load. These data reveal an unappreciated role for Ag85B in the interaction of mycobacteria with host cells and indicates that single protective antigens are dispensable for protective immunity induced by BCG

Association of early life and acute pollen exposure with lung function and exhaled nitric oxide (FeNO). A prospective study up to adolescence in the GINIplus and LISA cohort.

Background: Pollen exposure has both acute and chronic detrimental effects on allergic asthma, but little is known about its wider effects on respiratory health. This is increasingly important knowledge as ambient pollen levels are changing with the changing global climate. Objective: To assess associations of pollen exposure with lung function and fractional exhaled nitric oxide (FeNO) at age 15 in two prospective German birth cohorts, GINIplus and LISA. Methods: Background city-specific pollen exposure was measured in infancy (during the first three months of life), and contemporary (on the day of and 7 days prior to lung function measurement). Greenness levels within circular buffers (100–3000 m) around the birth and 15-year home addresses were calculated using the satellite-derived Normalized Difference Vegetation Index. Regression models were used to assess the associations of grass and birch pollen with lung function and FeNO, and the modifying effects of residential greenness were explored. Results: Cumulative early life exposure to grass pollen was associated with reduced lung function in adolescence (FEV1: −4.9 mL 95%CI: −9.2, −0.6 and FVC: −5.2 mL 95%CI: −9.8, −0.5 per doubling of pollen count). Acute grass pollen exposure was associated with increased airway inflammation in all children, with higher FeNO increases in children living in green areas. In contrast acute birch pollen exposure was associated with reduced lung function only in children sensitised to birch allergens. Conclusion: This study provides suggestive evidence that early pollen exposure has a negative effect on later lung function, which is in turn influenced by acute pollen exposures

Residential greenness and allergic respiratory diseases in children and adolescents – A systematic review and meta-analysis

Background The aetiology of allergic respiratory disease in children is not yet fully understood. Environmental factors are believed to play a major part. The amount of green vegetation surrounding the home (residential greenness) has been recently identified as a potentially important exposure Objectives Our goal was to provide a systematic review and quantitative summary of the evidence regarding the relationship between residential greenness and allergic respiratory diseases in children. Methods Peer-reviewed literature published prior to 1 March 2017 was systematically searched using nine electronic databases. Meta-analyses were conducted if at least three studies published risk estimates for the same outcome and exposure measures. Results We included 11 articles across broad outcomes of asthma and allergic rhinitis. Reported effects were inconsistent with varying measures to define residential greenness. Only limited meta-analysis could be conducted, with the pooled odds ratios for asthma (OR 1.01 95%CI 0.93, 1.09; I2 68.1%) and allergic rhinitis (OR 0.99 95%CI 0.87, 1.12; I2 72.9%) being significantly heterogeneous. Conclusions Inconsistencies between the studies were too large to accurately assess the association between residential greenness and allergic respiratory disease. A standardised global measure of greenness which accounts for seasonal variation at a specific relevant buffer size is needed to create a more cohesive body of evidence and for future examination of the effect of residential greenness on allergic respiratory diseases