Impairing RAGE signaling promotes survival and limits disease pathogenesis following SARS-CoV-2 infection in mice.

Forrest Jessop,Eric Bohrnsen,Benjamin Schwarz,Catharine M Bosio,John R Hoidal,Lydia M Roberts,Dana Scott

doi:10.1172/jci.insight.155896

Abstract

Cellular and molecular mechanisms driving morbidity following SARS-CoV-2 infection have not been well defined. The receptor for advanced glycation end products (RAGE) is a central mediator of tissue injury and contributes to SARS-CoV-2 disease pathogenesis. In this study, we temporally delineated key cell and molecular events leading to lung injury in mice following SARS-CoV-2 infection and assessed efficacy of therapeutically targeting RAGE to improve survival. Early following infection, SARS-CoV-2 replicated to high titers within the lungs and evaded triggering inflammation and cell death. However, a significant necrotic cell death event in CD45– populations, corresponding with peak viral loads, was observed on day 2 after infection. Metabolic reprogramming and inflammation were initiated following this cell death event and corresponded with increased lung interstitial pneumonia, perivascular inflammation, and endothelial hyperplasia together with decreased oxygen saturation. Therapeutic treatment with the RAGE antagonist FPS-ZM1 improved survival in infected mice and limited inflammation and associated perivascular pathology. Together, these results provide critical characterization of disease pathogenesis in the mouse model and implicate a role for RAGE signaling as a therapeutic target to improve outcomes following SARS-CoV-2 infection.

Highlights

SARS-CoV-2 infection can lead to serious pulmonary and vascular tissue damage
One of the challenges of therapeutic intervention among individuals infected with SARS-CoV-2 is the limited understanding of the temporal nature of the molecular and cellular events driving disease progression
Using the K18-hACE2/SARS-CoV-2 mouse model of infection, we demonstrate that there are at least 2 distinct phases of disease pathogenesis based on molecular events

Summary

Introduction

SARS-CoV-2 infection can lead to serious pulmonary and vascular tissue damage. Pathological reports indicate that diffuse alveolar damage, the presence of hyaline membranes, alveolar edema, and microthrombosis are hallmark features of advanced SARS-CoV-2 infection [1, 2]. Among patients admitted to intensive care units, mortality rates are reported to range between 26% and 61.5%. There are limited therapeutic interventions available to treat SARS-CoV-2– associated lung injury beyond supportive care. Current treatment strategies for SARS-CoV-2 infection focused on targeting antiviral or antiinflammatory responses have shown conflicting or limited efficacy depending on when they are administered, in part because of our limited understanding of disease pathogenesis [5,6,7]. An improved understanding of the pathogenesis of severe SARS-CoV-2 illness will inform optimal therapeutic intervention and reveal new molecular targets to treat disease

Methods

Results

Conclusion