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Theranostics 2021; 11(16):8076-8091. doi:10.7150/thno.61810 This issue Cite

Research Paper

Endothelial cell infection and dysfunction, immune activation in severe COVID-19

Zhongnan Qin^1,*, Fengming Liu^1,7,*,✉, Robert Blair^1,*, Chenxiao Wang¹, Haoran Yang², Joseph Mudd¹, Joshua M Currey¹, Naoki Iwanaga², Jibao He³, Ren Mi¹, Kun Han¹, Cecily C. Midkiff¹, Mohammad Afaque Alam¹, Bertal H Aktas⁴, Richard S Vander Heide⁵, Ronald Veazey¹, Giovanni Piedimonte⁶, Nicholas J Maness^1,7, Süleyman Ergün⁸, Franck Mauvais-Jarvis^9,10,11, Jay Rappaport^1,7,✉, Jay K. Kolls^2,✉, Xuebin Qin^1,7,✉

1. Tulane National Primate Research Center, Covington, LA 70433, USA
2. Departments of Medicine and Pediatrics, Center for Translational Research in Infection and Inflammation, Tulane University School of Medicine, New Orleans, LA 70112, USA
3. Coordinated Instrumentation Facility, Tulane University, New Orleans LA 70118, USA
4. Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA
5. Department of Pathology, LSU Health Sciences Center, New Orleans, LA 70112, USA
6. Departments of Pediatrics, Biochemistry & Molecular Biology, Tulane University School of Medicine, New Orleans, LA 70112, USA
7. Department of Immunology and Microbiology, Tulane University School of Medicine, New Orleans, LA 70112, USA
8. Institute of Anatomy and Cell Biology, Julius-Maximilians-Universität Würzburg, Koellikerstrasse 6, 97070 Würzburg, Germany
9. Department of Medicine, Section of Endocrinology and Metabolism, Tulane University Health Sciences Center, School of Medicine, New Orleans, LA 70112, USA
10. Southeast Louisiana Veterans Health Care System, New Orleans, LA 70119, USA
11. Tulane Center of Excellence in Sex-Based Biology & Medicine, LA 70112, USA
*These authors contributed equally: Zhongnan Qin, Fengming Liu, and Robert V. Blair.

✉ Corresponding author: Xuebin Qin, MD, PhD, Division of Comparative Pathology, Tulane National Primate Research Center, Health Sciences Campus, 18703 Three Rivers Road, Covington, LA 70433, USA. Tel: 985 871 6296, e-mail: xqin2edu; Fengming Liu, PhD, Division of Comparative Pathology, Tulane National Primate Research Center, Health Sciences Campus, 18703 Three Rivers Road, Covington, LA 70433, USA. Tel: 985 871 6560, E-Mail: fliu6edu; Jay Kolls, PhD, Center for Translational Research in Infection and Inflammation Tulane School of Medicine, JBJ 375, 333 S. Liberty St, New Orleans, LA 70112, USA, Tel: 504-988-0456E-mail: jkolls1edu; and Jay Rappaport, Ph.D. Division of Comparative Pathology, Tulane National Primate Research Center, Health Sciences Center, 18703 Three Rivers Road, Covington, LA 70433, USA. Tel. 985-871-6201, email: jrappaportedu. More

Abstract

Rationale: Pulmonary vascular endotheliitis, perivascular inflammation, and immune activation are observed in COVID-19 patients. While the initial SARS-CoV-2 infection mainly infects lung epithelial cells, whether it also infects endothelial cells (ECs) and to what extent SARS-CoV-2-mediated pulmonary vascular endotheliitis is associated with immune activation remain to be determined.

Methods: To address these questions, we studied SARS-CoV-2-infected K18-hACE2 (K18) mice, a severe COVID-19 mouse model, as well as lung samples from SARS-CoV-2-infected nonhuman primates (NHP) and patient deceased from COVID-19. We used immunostaining, RNAscope, and electron microscopy to analyze the organs collected from animals and patient. We conducted bulk and single cell (sc) RNA-seq analyses, and cytokine profiling of lungs or serum of the severe COVID-19 mice.

Results: We show that SARS-CoV-2-infected K18 mice develop severe COVID-19, including progressive body weight loss and fatality at 7 days, severe lung interstitial inflammation, edema, hemorrhage, perivascular inflammation, systemic lymphocytopenia, and eosinopenia. Body weight loss in K18 mice correlated with the severity of pneumonia, but not with brain infection. We also observed endothelial activation and dysfunction in pulmonary vessels evidenced by the up-regulation of VCAM1 and ICAM1 and the downregulation of VE-cadherin. We detected SARS-CoV-2 in capillary ECs, activation and adhesion of platelets and immune cells to the vascular wall of the alveolar septa, and increased complement deposition in the lungs, in both COVID-19-murine and NHP models. We also revealed that pathways of coagulation, complement, K-ras signaling, and genes of ICAM1 and VCAM1 related to EC dysfunction and injury were upregulated, and were associated with massive immune activation in the lung and circulation.

Conclusion: Together, our results indicate that SARS-CoV-2 causes endotheliitis via both infection and infection-mediated immune activation, which may contribute to the pathogenesis of severe COVID-19 disease.

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