Journal Article

Mechanism of Multi-Organ Injury in Experimental COVID-19 and Its Inhibition by a Small Molecule Peptide

Ndubizu, Chima Obianuju, Paidas, Michael J., Kwal, Jaclyn, Rodriguez, Suset, Schindler, Emma A., Shamaladevi, Nagarajarao, Ahmad, Anis, Kenyon, Norma Sue, Cosio, Daniela S., Jayakumar, Arumugam R., Sampath, Natarajan

2022

Overview

Severe disease from SARS-CoV-2 infection often progresses to multi-organ failure and results in an increased mortality rate amongst these patients. However, underlying mechanisms of SARS- CoV-2-induced multi-organ failure and subsequent death are still largely unknown. Cytokine storm, increased levels of inflammatory mediators, endothelial dysfunction, coagulation abnormalities, and infiltration of inflammatory cells into the organs contribute to the pathogenesis of COVID-19. One potential consequence of immune/inflammatory events is the acute progression of generalized edema, which may lead to death. We, therefore, examined the involvement of water channels in the development of edema in multiple organs and their contribution to organ dysfunction in a Murine Hepatitis Virus-1 (MHV-1) mouse model of COVID-19. Using this model, we recently reported multi-organ pathological abnormalities and animal death similar to that reported in humans with SARS-CoV-2 infection. We now identified an alteration in protein levels of AQPs 1, 4, 5, and 8 and associated oxidative stress, along with various degrees of tissue edema in multiple organs, which correlate well with animal survival post-MHV-1 infection. Furthermore, our newly created drug (a 15 amino acid synthetic peptide, known as SPIKENET) that was designed to prevent the binding of spike glycoproteins with their receptor(s), angiotensin- converting enzyme 2 (ACE2), and carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) (SARS-CoV-2 and MHV-1, respectively), ameliorated animal death and reversed altered levels of AQPs and oxidative stress post-MHV-1 infection. Collectively, our findings suggest the possible involvement of altered aquaporins and the subsequent edema, likely mediated by the virus-induced inflammatory and oxidative stress response, in the pathogenesis of COVID- 19 and the potential of SPIKENET as a therapeutic option.

• Publisher: Frontiers Media SA,Frontiers Media S.A
• Subject: ACE2 / Amino acids / Angiotensin / Angiotensin-converting enzyme 2 / animal death / Aquaporins / Carcinoembryonic antigen / CD66 antigen / CEACAM1 protein / Cell adhesion & migration / Cell adhesion molecules / COVID-19 / COVID-19 vaccines / Cytokine storm / Death / Disease transmission / Edema / Glycoproteins / Hepatitis / Immunization / Infections / Inflammation / Mortality / multiorgan failure / Oxidative stress / Pathogenesis / Peptides / Pharmacology / Proteins / Severe acute respiratory syndrome coronavirus 2 / Stress response / Thrombosis / tissue edema