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

Expression of immune response genes in peripheral blood of cattle infested with Rhipicephalus microplus

The bovine tick Rhipicephalus microplus is responsible for severe economic losses in tropical cattle production. Bos indicus breeds are more resistant to tick infestations than are Bos taurus breeds, and the understanding of the physiological mechanisms involved in this difference is important for the development of new methods of parasite control. We evaluated differences in the transcript expression of genes related to the immune response in the peripheral blood of cattle previously characterized as resistant or susceptible to tick infestation. Crossbreed F2 Gir x Holstein animals (resistant, N = 6; susceptible, N = 6) were artificially submitted to tick infestation. Blood samples were collected at 0, 24, and 48 h after tick infestation and evaluated for transcript expression of the CD25, CXCL8, CXCL10, FoxP3, interleukin (IL)-10, and tumor necrosis factor alpha (TNFα) genes. Gene expression of CD25 (6.00, P < 0.01), IL-10 (31.62, P < 0.01), FoxP3 (35.48, P < 0.01), and CXCL10 (3.38, P < 0.05) was altered in the resistant group at 48 h compared with samples collected before infestation. In the susceptible group, CXCL8 (-2.02, P < 0.05) and CXCL10 (2.20, P < 0.05) showed altered expression 24 h after infestation. CXCL8 (-5.78, P < 0.05) also showed altered expression at 48 h after infestation when compared with samples collected before infestation. We detected a correlation between T γδ cell activity and the immunological mechanisms that result in a higher resistance to R. microplus in cattle