Impairing RAGE signaling promotes survival and limits disease pathogenesis following SARS-CoV-2 infection in mice
Forrest Jessop, Benjamin Schwarz, Dana Scott, Lydia M. Roberts, Eric Bohrnsen, John R. Hoidal, Catharine M. Bosio
Forrest Jessop, Benjamin Schwarz, Dana Scott, Lydia M. Roberts, Eric Bohrnsen, John R. Hoidal, Catharine M. Bosio
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Research Article Immunology Infectious disease

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

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.

Authors

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

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Figure 6

FPS-ZM1 treatment reduces lung perivascular inflammation.

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FPS-ZM1 treatment reduces lung perivascular inflammation. K18-hACE2 mice...
K18-hACE2 mice were infected with 1 × 103 TCID50 SARS-CoV-2 by intranasal instillation, therapeutically treated with vehicle or FPS-ZM1, and evaluated for changes in histopathology. Lesions were scored between 0 (no lesion) and 5 (severe). (A) Representative figures of lungs from mock- or SARS-CoV-2–infected mice and vehicle or FPS-ZM1 treatment on days 2 and 4 after infection along with corresponding pathological scores. (B) Representative images of perivascular cuffing along with pathological scores (×400). The white asterisk indicates regions of perivascular inflammation and interstitial thickening that are reduced in mice with FPS-ZM1 treatment compared with vehicle-treated controls. Black arrowheads show select regions in which hypertrophy of the endothelial cells in the vessel wall is reduced in FPS-ZM1–treated mice. (×40 and ×400 magnification; scale bars: 20 μm at ×400, 200 μm at ×40.) Data are shown as mean score ± SEM (n = 20 per group, pooled from 2 separate experiments). *P < 0.05, **P < 0.01 indicate significance between vehicle and FPS-ZM1 treatment using an unpaired, nonparametric Mann-Whitney test.