STAT2 signaling as double-edged sword restricting viral dissemination but driving severe pneumonia in SARS-CoV-2 infected hamsters

Abstract

<jats:title>Introductory paragraph</jats:title><jats:p>Since the emergence of SARS-CoV-2 causing COVID-19, the world is being shaken to its core with numerous hospitalizations and hundreds of thousands of deaths. In search for key targets of effective therapeutics, robust animal models mimicking COVID-19 in humans are urgently needed. Here, we show that productive SARS-CoV-2 infection in the lungs of mice is limited and restricted by early type I interferon responses. In contrast, we show that Syrian hamsters are highly permissive to SARS- CoV-2 and develop bronchopneumonia and a strong inflammatory response in the lungs with neutrophil infiltration and edema. Moreover, we identify an exuberant innate immune response as a key player in pathogenesis, in which STAT2 signaling plays a dual role, driving severe lung injury on the one hand, yet restricting systemic virus dissemination on the other. Finally, we assess SARS-CoV- 2-induced lung pathology in hamsters by micro-CT alike used in clinical practice. Our results reveal the importance of STAT2-dependent interferon responses in the pathogenesis and virus control during SARS-CoV-2 infection and may help rationalizing new strategies for the treatment of COVID-19 patients.</jats:p>

Antiviral treatment of SARS-CoV-2-infected hamsters reveals a weak effect of favipiravir and a complete lack of effect for hydroxychloroquine

“…Although rhesus and cynomolgus macaques seem to be relevant models for studying the early stages of COVID-19 infection in humans 14 , preclinical models using smaller animals are essential to ensure efficient and ethical allocation of resources towards designing (relevant) preclinical and clinical efficacy studies. Syrian hamsters are permissive to SARS-CoV-2 and develop mild lung disease similar to the disease observed in early-stage COVID-19 patients 15,16 . Nevertheless, evidence of antiviral efficacy of repurposed drugs in small animal models is lacking to date.…”

“…A close relation with the prototypic Wuhan-Hu-1 2019-nCoV (GenBank accession number MN908947.3) strain was confirmed by phylogenetic analysis. Infectious virus was isolated by serial passaging on HuH7 and Vero E6 cells 16 ; passage 6 virus was used for the studies described here. The titer of the virus stock was determined by end-point dilution on Vero E6 cells by the Reed and Muench method.…”

“…The hamster infection model of SARS-CoV-2 has been described before 16 . In brief, wild-type Syrian hamsters ( Mesocricetus auratus ) were purchased from Janvier Laboratories and were housed per two in ventilated isolator cages (IsoCage N Biocontainment System, Tecniplast) with ad libitum access to food and water and cage enrichment (wood block).…”

“…Of 50 μL eluate, 4 μL was used as a template in RT-qPCR reactions. RT-qPCR was performed on a LightCycler96 platform (Roche) using the iTaq Universal Probes One-Step RT-qPCR kit (BioRad) with N2 primers and probes targeting the nucleocapsid 16 . Standards of SARS-CoV-2 cDNA (IDT) were used to express viral genome copies per mg tissue or per mL serum.…”

“…Scores for the 5 sections were summed up to obtain a score from 0 to 10 reflecting severity of lung and airway abnormalities compared to scans of healthy, WT control hamsters. As secondary measures, imaging-derived biomarkers (non-aerated lung volume, aerated lung volume, total lung volume and respective densities within these volumes) were quantified as previously 16,26,27 or a manually delineated volume of interest covering the lung, avoiding the heart and main blood vessels. The threshold used to distinguish aerated from non-aerated lung volume was manually defined and kept constant for all data sets 26,27 .…”