Given the evidence for a hyperactive platelet phenotype in COVID-19, we investigated effector cell properties of COVID-19 platelets on endothelial cells (ECs). Integration of EC and platelet RNA sequencing revealed that plateletreleased factors in COVID-19 promote an inflammatory hypercoagulable endotheliopathy. We identified S100A8 and S100A9 as transcripts enriched in COVID-19 platelets and were induced by megakaryocyte infection with SARS-CoV-2. Consistent with increased gene expression, the heterodimer protein product of S100A8/A9, myeloidrelated protein (MRP) 8/14, was released to a greater extent by platelets from COVID-19 patients relative to controls. We demonstrate that platelet-derived MRP8/14 activates ECs, promotes an inflammatory hypercoagulable phenotype, and is a significant contributor to poor clinical outcomes in COVID-19 patients. Last, we present evidence that targeting platelet P2Y 12 represents a promising candidate to reduce proinflammatory platelet-endothelial interactions. Together, these findings demonstrate a previously unappreciated role for platelets and their activationinduced endotheliopathy in COVID-19.
Summary Although diminutive in size, bacteria possess highly diverse and spatially confined cellular structures. Two related alpha-proteobacteria, Sinorhizobium meliloti and Caulobacter crescentus, serve as models for investigating the genetic basis of morphologic variations. S. meliloti, a symbiont of leguminous plants, synthesizes multiple flagella and no prosthecae, whereas C. crescentus, a freshwater bacterium, has a single polar flagellum and stalk. The podJ gene, originally identified in C. crescentus for its role in polar organelle development, is split into two adjacent open reading frames, podJ1 and podJ2, in S. meliloti. Deletion of podJ1 interferes with flagellar motility, exopolysaccharide production, cell envelope integrity, cell division, and normal morphology, but not symbiosis. As in C. crescentus, the S. meliloti PodJ1 protein appears to act as a polarity beacon and localizes to the newer cell pole. Microarray analysis indicates that podJ1 affects the expression of at least 129 genes, the majority of which correspond to observed mutant phenotypes. Together, phenotypic characterization, microarray analysis, and suppressor identification suggest that PodJ1 controls a core set of conserved elements, including flagellar and pili genes, the signaling proteins PleC and DivK, and the transcriptional activator TacA, while alternate downstream targets have evolved to suit the distinct lifestyles of individual species.
AUTHORSHIP B.M. performed the planning and execution of all assays as well as writing and editing of the article. A.T. performed the planning, execution, and analysis of in vitro and in vivo experiments and article development. P.P.T. performed the flow cytometry. D.P. performed the data analysis and planning of experiments. G.B. performed the development of in vivo assays. L.V. and M.L. performed the in vitro assays and article development. A.K.S. and E.L. performed the Plt-EV characterization. R.C., L.Z.K., and A.T.F. performed the Plt aggregometry studies and article development. M.A.S., J.B.H., C.E.W.,and S.P. performed the development and planning ofstudies, data analysis, and article development.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
customersupport@researchsolutions.com
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
This site is protected by reCAPTCHA and the Google Privacy Policy and Terms of Service apply.
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.