Elevated Cytokine Levels in Plasma of Patients with SARS-CoV-2 Do Not Contribute to Pulmonary Microvascular Endothelial Permeability

Anita Kovacs-Kasa, Abdelrahman A. Zaied, Silvia Leanhart, Murat Koseoglu, Supriya Sridhar, Rudolf Lucas, David J. Fulton, Jose A. Vazquez, Brian H. Annex

Research output: Contribution to journalArticlepeer-review

Abstract

The vascular endothelial injury occurs in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections, but the mechanisms are poorly understood. We sought to determine the frequency and type of cytokine elevations and their relationship to endothelial injury induced by plasma from patients with SARSCoV- 2 versus controls. Plasma from eight consecutively enrolled patients hospitalized with acute SARS-CoV-2 infection was compared to controls. Endothelial cell (EC) barrier integrity was evaluated using ECIS (electric cell-substrate impedance sensing) on human lung microvascular EC. Plasma from all SARS-CoV-2 but none from controls decreased transendothelial resistance to a greater degree than that produced by tumor necrosis factor-alpha (TNF-a), the positive control for the assay. Thrombin, angiopoietin 2 (Ang2), and vascular endothelial growth factor (VEGF), complement factor C3a and C5a, and spike protein increased endothelial permeability, but to a lesser extent and a shorter duration when compared to SARS-CoV-2 plasma. Analysis of Ang2, VEGF, and 15 cytokines measured in plasma revealed striking patient-topatient variability within the SARS-CoV-2 patients. Pretreatment with thrombin inhibitors, single, or combinations of neutralizing antibodies against cytokines, Ca3 and C5a receptor antagonists, or with ACE2 antibody failed to lessen the SARS-CoV-2 plasma-induced EC permeability. The EC barrier destructive effects of plasma from patients with SARS-CoV-2 were susceptible to heat inactivation. Plasma from patients hospitalized with acute SARS-CoV-2 infection uniformly disrupts lung microvascular integrity. No predicted single, or set of, cytokine(s) accounted for the enhanced vascular permeability, although the factor(s) were heat-labile. A still unidentified but potent circulating factor(s) appears to cause the EC disruption in SARS-CoV-2 infected patients.

Original languageEnglish (US)
Article numbere01671-21
JournalMicrobiology spectrum
Volume10
Issue number1
DOIs
StatePublished - Feb 2022

Keywords

  • ACE-2 receptor
  • Antiinflammatory cytokines
  • Barrier dysfunction
  • Complements factors
  • Cytokine
  • Endothelial injury
  • Endothelial permeability
  • Heat inactivation
  • Neutralizing antibodies
  • Plasma
  • Proinflammatory cytokines
  • SARS-CoV-2
  • SARS-CoV-2 plasma
  • Spike protein

ASJC Scopus subject areas

  • Physiology
  • Ecology
  • Immunology and Microbiology(all)
  • Genetics
  • Microbiology (medical)
  • Cell Biology
  • Infectious Diseases

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