Disruption of Adaptive Immunity Enhances Disease in SARS-CoV-2-Infected Syrian Hamsters.

Zhongde Wang,Sawsan Youssef,Tom Gallagher,Jeffrey M. Smith,Dave Gangemi,Xiankun Zeng,Yanan Liu,Robert K. Kim,Lucia M. Principe,Jacob Glanville,Rebecca L. Brocato,Janice A. Williams,Joseph W. Golden,Rong Li,Jay W. Hooper

doi:10.1128/jvi.01683-20

Abstract

Animal models recapitulating human COVID-19 disease, especially severe disease, are urgently needed to understand pathogenesis and to evaluate candidate vaccines and therapeutics. Here, we develop novel severe-disease animal models for COVID-19 involving disruption of adaptive immunity in Syrian hamsters. Cyclophosphamide (CyP) immunosuppressed or RAG2 knockout (KO) hamsters were exposed to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) by the respiratory route. Both the CyP-treated and RAG2 KO hamsters developed clinical signs of disease that were more severe than those in immunocompetent hamsters, notably weight loss, viral loads, and fatality (RAG2 KO only). Disease was prolonged in transiently immunosuppressed hamsters and was uniformly lethal in RAG2 KO hamsters. We evaluated the protective efficacy of a neutralizing monoclonal antibody and found that pretreatment, even in immunosuppressed animals, limited infection. Our results suggest that functional B and/or T cells are not only important for the clearance of SARS-CoV-2 but also play an early role in protection from acute disease.IMPORTANCE Syrian hamsters are in use as a model of disease caused by SARS-CoV-2. Pathology is pronounced in the upper and lower respiratory tract, and disease signs and endpoints include weight loss and viral RNA and/or infectious virus in swabs and organs (e.g., lungs). However, a high dose of virus is needed to produce disease, and the disease resolves rapidly. Here, we demonstrate that immunosuppressed hamsters are susceptible to low doses of virus and develop more severe and prolonged disease. We demonstrate the efficacy of a novel neutralizing monoclonal antibody using the cyclophosphamide transient suppression model. Furthermore, we demonstrate that RAG2 knockout hamsters develop severe/fatal disease when exposed to SARS-CoV-2. These immunosuppressed hamster models provide researchers with new tools for evaluating therapies and vaccines and understanding COVID-19 pathogenesis.

Highlights

The ongoing pandemic has led to the search for animal models faithfully recapitulating salient features of human coronavirus disease (COVID-19) for pathogenesis studies and evaluation of vaccines and therapeutics [1]
In order to develop a small animal model of severe disease, evaluate the role of adaptive immunity, and replicate the COVID-19 lymphopenia observed in human disease, we treated hamsters with CyP
II pneumocytes that were not observed in the sampled RAG2 KO hamsters

Summary

Introduction

The ongoing pandemic has led to the search for animal models faithfully recapitulating salient features of human coronavirus disease (COVID-19) for pathogenesis studies and evaluation of vaccines and therapeutics [1]. Reports indicated that Syrian hamsters, whose ACE2 is highly homologous to its human ortholog, were highly susceptible to SARS-CoV-2 infection but did not develop severe disease [2, 3]. In 2008, administration of cyclophosphamide (CyP), an alkylating agent that suppresses B and T cell function, was used to develop a severe disease model for SARS-CoV in Syrian hamsters [4]. We reasoned that a similar approach might allow the development of a severe disease model for SARS-CoV-2. We used the immunocompetent and immunosuppressed hamster models to evaluate whether pre-exposure to virus through previous infection, or neutralizing antibodies, were sufficient to limit or prevent disease

Objectives

Findings

Conclusion