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Multiplatform Analyses Reveal Distinct Drivers of Systemic Pathogenesis in Adult Versus Pediatric COVID-19

2022; RELX Group (Netherlands); Linguagem: Inglês

10.2139/ssrn.4007576

1556-5068

Samuel Druzak, Elizabeth Iffrig, Blaine R. Roberts, Tiantian Zhang, Anne M. Roberts, Yumiko Sakurai, Kirby S. Fibben, Joshua D. Chandler, Hanna Kim, Frank Schneider, Mario Mosunjac, Marina Mošunjac, Rachel Geller, Andrew Kam Ho Wong, Mirko Paiardini, Steve Bosinger, John D. Roback, Sean R. Stowell, Connie M. Arthur, Evan J. Anderson, Christina A. Rostad, Ann Chahroudi, Anna Ivanova, Jun Young Ahn, Snow Liu, Kristal Maner-Smith, Thomas J. Bowen, Deanna A. Kulpa, Guido Silvestri, Wilbur A. Lam, Eric A. Ortlund, Cheryl L. Maier,

SARS-CoV-2 and COVID-19 Research

The pathogenesis of the multi-organ dysfunction associated with severe COVID-19 remains poorly understood. Endothelial dysfunction has been identified as a driver of severity in SARS-CoV-2-infections, yet the mechanisms underlying this endotheliopathy remain elusive. We performed proteomics, lipidomics and metabolomics using plasma from severely ill COVID adults, controls and children with acute COVID-19 or multisystem inflammatory syndrome in children (MIS-C). Multiomic studies identified fluid shear stress and proteoglycan homeostasis pathways in adults with severe COVID-19. Microfluidic-based demonstrated that severe COVID-19 is associated with increased red blood cell aggregation and decreased membrane deformability resulting in glycocalyx degradation. Plasma cytokine and metabolite profiling reveals little overlap between adults with COVID-19 and children with COVID-19 or MIS-C. This multiplatform approach provides a novel framework linking altered blood biomechanics, endotheliopathy and coagulopathy in adult patients with severe COVID-19 and highlights key differences in the mediators of severe disease in adults versus children.Funding: Financial support from the FastGrant Program from Emergent Ventures at the Mercatus Center at George Mason University and Genentech, Inc. (to A.C.).Declaration of Interests: E.J.A has consulted for Pfizer, Sanofi Pasteur, Janssen, and Medscape, and his institution receives funds to conduct clinical research unrelated to this manuscript from MedImmune, Regeneron, PaxVax, Pfizer, GSK, Merck, Sanofi-Pasteur, Janssen, and Micron. He also serves on a safety monitoring board for Kentucky BioProcessing, Inc. and Sanofi Pasteur. His institution has also received funding from NIH to conduct clinical trials of Moderna and Janssen COVID-19 vaccines. C.A.R.’s institution has received funds to conduct clinical research unrelated to this manuscript from BioFire Inc, GSK, MedImmune, Micron, Janssen, Merck, Novavax, PaxVax, Regeneron, Sanofi-Pasteur. She is co-inventor of patented RSV vaccine technology unrelated to this manuscript, which has been licensed to Meissa Vaccines, Inc. Her institution has received funds from NIH, Moderna, Pfizer, and Janssen to conduct clinical trials of COVID-19 vaccines.Ethics Approval Statement: All studies were conducted according to the guidelines of the Declaration of Helsinki, and approved by the Institutional Review Board (or Ethics Committee) of Emory University (IRB00000723,IRB00087446, STUDY00000401, and STUDY00000510).