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

Predator-prey body size, interaction strength and the stability of a real food web.

1. We examined the empirical relationship between predator–prey body size ratio and interaction strength in the Ythan Estuary food web. 2. We have refined a previously published version of the food web and explored how size-based predatory effects might affect food web dynamics. To do so, we used four predatory species Crangon crangon (Linnaeus), Carcinus maenas (Linnaeus), Pomatoschistus microps (Krøyer) and Platichthys flesus (Linnaeus) and one common prey species Corophium volutator (Pallas) from the food web. 3. All predators and prey were sorted into small, medium and large size classes and placed into mesocosms in all possible pairwise combinations of size and species identity to determine per capita effects of predators on prey (aij). 4. Using Lotka–Volterra dynamics the empirical body size relationships obtained from these experiments and other relationships already available for the Ythan Estuary, we parameterized a food web model for this system. The local stability properties of the resulting food web models were then determined. 5. We found that by choosing interaction strengths using an empirically defined scaling law, the resulting food web models are always dynamically stable, despite the residual uncertainties in the modelling approach. This contrasts with the statistical expectation that random webs with random parameters have a vanishingly improbable chance of stability. 6. The patterning of predator and prey body sizes in real ecosystems affects the arrangement of interaction strengths, which in turn determines food web stability

An observational study to assess the effectiveness of 4CMenB against meningococcal disease and carriage and gonorrhea in adolescents in the Northern Territory, Australia—study protocol

Invasive meningococcal disease (IMD) causes significant morbidity and mortality worldwide with serogroup B being the predominant serogroup in Australia and other countries for the past few decades. The licensed 4CMenB vaccine is effective in preventing meningococcal B disease. Emerging evidence suggests that although 4CMenB impact on carriage is limited, it may be effective against gonorrhoea due to genetic similarities between Neisseria meningitidis and Neisseria gonorrhoeae. This study protocol describes an observational study that will assess the effect of the 4CMenB vaccine against meningococcal carriage, IMD and gonorrhoea among adolescents in the Northern Territory (NT). All 14–19-year-olds residing in the NT with no contraindication for 4CMenB vaccine will be eligible to participate in this cohort study. Following consent, two doses of 4CMenB vaccine will be administered two months apart. An oropharyngeal swab will be collected at baseline and 12 months to detect pharyngeal carriage of Neisseria meningitidis by PCR. The main methodological approaches to assess the effect of 4CMenB involve a nested case control analysis and screening method to assess vaccine effectiveness and an Interrupted Time Series regression analysis to assess vaccine impact. Research ethics approvals have been obtained from Menzies and Central Australian Human Research Ethics Committees and the Western Australian Aboriginal Health Ethics Committee. Results will be provided in culturally appropriate formats for NT remote and regional communities and published in international peer reviewed journals. ClinicalTrials.gov Identifier: NCT04398849.Helen S. Marshall, Prabha H. Andraweera, James Ward, John Kaldor, Ross Andrews, Kristine Macartney, Peter Richmond, Vicki Krause, Ann Koehler, David Whiley , Lynne Giles, Rosalind Webby, Heather D’Antoine, Jonathan Karnon, Rob Baird, Andrew Lawrence, Helen Petousis-Harris, Philippe De Wals, Belinda Greenwood-Smith, Michael Binks and Lisa Who