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 first occurrence of an avian-style respiratory infection in a non-avian dinosaur

Other than repaired fractures, osteoarthritis, and periosteal reaction, the vertebrate fossil record has limited evidence of non-osseous diseases. This difficulty in paleontological diagnoses stems from (1) the inability to conduct medical testing, (2) soft-tissue pathologic structures are less likely to be preserved, and (3) many osseous lesions are not diagnostically specific. However, here reported for the first time is an avian-style respiratory disorder in a non-avian dinosaur. This sauropod presents irregular bony pathologic structures stemming from the pneumatic features in the cervical vertebrae. As sauropods show well-understood osteological correlates indicating that respiratory tissues were incorporated into the post-cranial skeleton, and thus likely had an ‘avian-style’ form of respiration, it is most parsimonious to identify these pathologic structures as stemming from a respiratory infection. Although several extant avian infections produce comparable symptoms, the most parsimonious is airsacculitis with associated osteomyelitis. From actinobacterial to fungal in origin, airsacculitis is an extremely prevalent respiratory disorder in birds today. While we cannot pinpoint the specific infectious agent that caused the airsacculitis, this diagnosis establishes the first fossil record of this disease. Additionally, it allows us increased insight into the medical disorders of dinosaurs from a phylogenetic perspective and understanding what maladies plagued the “fearfully great lizards”

GENOMIC SIGNATURES OF TYPE-2 INFLAMMATION IN COPD

Pathogenesis and treatment of chronic pulmonary disease

Crosstalk between TGF-β1 and complement activation augments epithelial injury in pulmonary fibrosis

The epithelial complement inhibitory proteins (CIPs) cluster of differentiation 46 and 55 (CD46 and CD55) regulate circulating immune complex-mediated complement activation in idiopathic pulmonary fibrosis (IPF). Our previous studies demonstrated that IL-17A mediates epithelial injury via transforming growth factor beta 1 (TGF-beta 1) and down-regulates CIPs. In the current study, we examined the mechanistic role of TGF-beta 1 in complement activation-mediated airway epithelial injury in IPF pathogenesis. We observed lower epithelial CIP expression in IPF lungs compared to normal lungs, associated with elevated levels of complement component 3a and 5a (C3a and C5a), locally and systemically. In normal primary human small airway epithelial cells (SAECs) treated with TGF-beta 1 (10 ng/ml), C3a, or C5a (100 nM), we observed loss of CIPs and increased poly(ADP-ribose) polymerase (PARP) activation [also observed with RNA interference (RNAi) of CD46/CD55]. TGF-beta 1-mediated loss of CIPs and Snail induction [SNAI1; a transcriptional repressor of E-cadherin (E-CAD)] was blocked by inhibiting mitogen-activated protein kinase (p38MAPK; SB203580) and RNAi silencing of SNAI1. C3a- and C5a-mediated loss of CIPs was also blocked by p38MAPK inhibition. While C3a upregulated TGFb transcripts, both C3a and C5a down-regulated SMAD7 (negative regulator of TGF-beta), and whereas TGF-beta 1 induced C3a/C5a receptor (C3aR/C5aR) expression, pharmacologic C3aR/C5aR inhibition protected against C3a- /C5a-mediated loss of CIPs. Taken together, our results suggest that epithelial injury in IPF can be collectively amplified as a result of TGF-beta 1-induced loss of CIPs leading to complement activation that down-regulates CIPs and induces TGF-beta 1 expression