This is a PDF file of a peer-reviewed paper that has been accepted for publication. Although unedited, the content has been subjected to preliminary formatting. Nature is providing this early version of the typeset paper as a service to our authors and readers. The text and figures will undergo copyediting and a proof review before the paper is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers apply.

Pathologic immune hyperactivation is emerging as a key feature of critical illness in COVID-19, but the mechanisms involved remain poorly understood. We carried out proteomic profiling of plasma from cross-sectional and longitudinal cohorts of hospitalized patients with COVID-19 and analyzed clinical data from our health system database of more than 3300 patients. Using a machine learning algorithm, we identified a prominent signature of neutrophil activation, including resistin, lipocalin-2, hepatocyte growth factor, interleukin-8, and granulocyte colony-stimulating factor, which were the strongest predictors of critical illness. Evidence of neutrophil activation was present on the first day of hospitalization in patients who would only later require transfer to the intensive care unit, thus preceding the onset of critical illness and predicting increased mortality. In the health system database, early elevations in developing and mature neutrophil counts also predicted higher mortality rates. Altogether, these data suggest a central role for neutrophil activation in the pathogenesis of severe COVID-19 and identify molecular markers that distinguish patients at risk of future clinical decompensation.

Highlights-Severe acute respiratory virus-2 (SARS-CoV2), the infection responsible for coronavirus disease-2019 (COVID-19), has spread globally leading to a devastating loss of life. In a few short months, the clinical and scientific communities have rallied to rapidly evolve our understanding of the mechanism(s) of disease and potential therapeutics. -This review discusses the current understanding of the basis virology of SARS-CoV2 and the epidemiology, clinical manifestations, including cardiovascular, and mortality of COVID-19. A detailed review of the viral life cycle and putative mechanism(s) of injury frames the discussion of possible preventative and therapeutic strategies. -The ongoing, unprecedented collective effort will, without a doubt, advance our ability to prevent the spread and optimally care for patients suffering from COVID-19. SummaryThe coronavirus disease-2019 (COVID-19), a contagious disease caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV2), has reached pandemic status. As it spreads across the world, it has overwhelmed healthcare systems, strangled the global economy and led to a devastating loss of life. Widespread efforts from regulators, clinicians and scientists are driving a rapid expansion of knowledge of the SARS-CoV2 virus and the COVID-19 disease.We review the most current data with a focus on our basic understanding of the mechanism(s) of disease and translation to the clinical syndrome and potential therapeutics. We discuss the basic virology, epidemiology, clinical manifestation, multi-organ consequences, and outcomes. With a focus on cardiovascular complications, we propose several mechanisms of injury. The virology and potential mechanism of injury form the basis for a discussion of potential disease-modifying therapies.

No abstract

The discovery of genetic loci associated with complex diseases has outpaced the elucidation of mechanisms of disease pathogenesis. Here we conducted a genome-wide association study (GWAS) for coronary artery disease (CAD) comprising 181,522 cases among 1,165,690 participants of predominantly European ancestry. We detected 241 associations, including 30 new loci. Cross-ancestry meta-analysis with a Japanese GWAS yielded 38 additional new loci. We prioritized likely causal variants using functionally informed fine-mapping, yielding 42 associations with less than five variants in the 95% credible set. Similarity-based clustering suggested roles for early developmental processes, cell cycle signaling and vascular cell migration and proliferation in the pathogenesis of CAD. We prioritized 220 candidate causal genes, combining eight complementary approaches, including 123 supported by three or more approaches. Using CRISPR–Cas9, we experimentally validated the effect of an enhancer in MYO9B, which appears to mediate CAD risk by regulating vascular cell motility. Our analysis identifies and systematically characterizes >250 risk loci for CAD to inform experimental interrogation of putative causal mechanisms for CAD.

Rapid progress of the discovery of genetic loci associated with common, complex diseases has outpaced the elucidation of mechanisms pertinent to disease pathogenesis. To address relevant barriers for coronary artery disease (CAD), we combined genetic discovery analyses with downstream characterization of likely causal variants, genes, and biological pathways. Specifically, we conducted a genome-wide association study (GWAS) comprising 181,522 cases of CAD among 1,165,690 participants. We detected 241 associations, including 54 associations and 30 loci not previously linked to CAD. Next, we prioritized likely causal variants using functionally-informed fine-mapping, yielding 42 associations with fewer than five variants in the 95% credible set. Combining eight complementary predictors, we prioritized 185 candidate causal genes, including 94 genes supported by three or more predictors. Similarity-based clustering underscored a role for early developmental processes, cell cycle signaling, and vascular proliferation in the pathogenesis of CAD. Our analysis identifies and systematically characterizes risk loci for CAD to inform experimental interrogation of putative causal mechanisms for CAD.

Key Points RAF1 Ser259 phosphorylation is a critical regulator step controlling arterial morphogenesis and arterial-venous patterning. ERK activation controls DLL4/Notch signaling and semaphorin 6A–mediated endothelial cell repulsion.

Pathologic immune hyperactivation is emerging as a key feature of critical illness in COVID-19, but the mechanisms involved remain poorly understood. We carried out proteomic profiling of plasma from cross-sectional and longitudinal cohorts of hospitalized patients with COVID-19 and analyzed clinical data from our health system database of over 3,300 patients. Using a machine learning algorithm, we identified a prominent signature of neutrophil activation, including resistin, lipocalin-2, HGF, IL-8, and G-CSF, as the strongest predictors of critical illness. Neutrophil activation was present on the first day of hospitalization in patients who would only later require transfer to the intensive care unit, thus preceding the onset of critical illness and predicting increased mortality. In the health system database, early elevations in developing and mature neutrophil counts also predicted higher mortality rates. Altogether, we define an essential role for neutrophil activation in the pathogenesis of severe COVID-19 and identify molecular neutrophil markers that distinguish patients at risk of future clinical decompensation.