Characterizing and targeting inflammation in COVID-19 using a rhesus macaque model of SARS-CoV-2 infection Restricted; Files Only
Viox, Elise (Fall 2023)
Published
Abstract
The Coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has resulted in over 6.9 million deaths and continues to pose a significant threat to global health. Although several therapeutics have been approved or granted emergency use authorization for COVID-19, these drugs have limited therapeutic indications. Therefore, it is essential that SARS-CoV-2 viral pathogenesis and COVID-19 immune responses are fully characterized to inform the design of additional, effective therapeutics that can be used across the full spectrum of disease.
Inflammation following SARS-CoV-2 infection is a hallmark of COVID-19 severity, but the inflammatory pathways contributing to host defense vs. immune-mediated pathology have not been fully elucidated. To investigate the early inflammatory events in COVID-19, we utilized a rhesus macaque model of SARS-CoV-2 which recapitulates key features of mild-to-moderate disease. In this model, we found that SARS-CoV-2 infection resulted in a robust, but transient, upregulation of the type I interferon (IFN-I) response and a significant enrichment of several inflammatory cytokine signaling pathways in the lower airways. To characterize the cell subsets that were contributing towards the production of these inflammatory cytokines in the lower airways, we performed longitudinal single cell RNA sequencing (scRNAseq) of Bronchoalveolar Lavage (BAL) fluid in infected RMs. We found that SARS-CoV-2 infection induced an influx of two subsets of infiltrating myeloid cells, CD163+MRC1- and TREM2+ macrophages, into the alveolar space and that these infiltrating macrophages produced the majority of inflammatory cytokines in the lower airway during acute SARS-CoV-2 infection.
Type I interferons (IFN-I) are essential for defense against viral infections but also drive recruitment of inflammatory cells to sites of infection, a key feature of severe COVID-19. To dissect the roles of antiviral and pro-inflammatory IFN-I responses in early SARS-CoV-2 infection, we modulated IFN-I signaling in rhesus macaques (RMs) prior to and during the first few days of SARS-CoV-2 infection using a mutated IFNα2 called IFN modulator (IFNmod). IFNmod binds with high affinity to IFNAR2, but markedly lower affinity to IFNAR1, blocking the binding and signaling of all forms of endogenous IFN-I. Administration of IFNmod in SARS-CoV-2-infected RMs not only resulted in an attenuation of antiviral interferon-stimulated genes (ISGs) and inflammatory genes, but also led to a profound decrease in SARS-CoV-2 viral loads, with 1-3-log reductions in both the upper and lower airways of treated animals. Additionally, a reduction in the influx of CD163+MRC1- and TREM2+ macrophages to the lung as well as lower levels of inflammatory chemokines and cytokines and lung pathology was observed with IFNmod treatment.
Collectively, the results of these studies are consistent with a model where an early and controlled IFN-I response is beneficial following SARS-CoV-2 infection, whereas excess IFN-I signaling leads to an influx of inflammatory macrophages in the lower airways and immunopathology.
Table of Contents
Chapter One: Introduction – SARS-CoV-2
Chapter Two: TREM2+ and interstitial-like macrophages orchestrate airway inflammation in SARS-CoV-2 infection in rhesus macaques
Chapter Three: Modulation of type I interferon responses potently inhibits SARS-CoV-2 replication and inflammation in rhesus macaques
Chapter Four: Discussion
References
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File download under embargo until 10 July 2024 | 2023-10-25 19:20:52 -0400 | File download under embargo until 10 July 2024 |
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