Immunologic determinants of SARS-CoV-2 susceptibility and disease severity in mice

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Talk abstract:

Infection with SARS-CoV-2 can cause a broad range of outcomes, ranging from asymptomatic to severe disease and the development of fatal SARS-CoV-2 pneumonia. While known risk factors for severe disease are advanced age or obesity, little is known about the immunologic determinants of COVID19 outcomes.

We generated a mouse adapted SARS-CoV-2 virus, named maVie16, which enabled us to study the development of SARS-CoV-2 induced pneumonia in vivo. In an ACE2- and dose dependent manner, maVie16 infection causes either transient or fatal disease in different laboratory mouse strains and reflects many aspects of human disease such as pneumonia, lymphopenia and cytokine storm. As reported earlier, significant differences were observed in the susceptibility of BALB/c mice and C57Bl/6 mice upon infection. While BALB/c mice quickly succumbed to low dose maVie16 SARS-CoV-2, C57Bl/6 animals rather developed transient pneumonia and survived infections with high viral doses. Resistance in C57Bl/6 mice was associated with a high abundance of plasmacytoid dendritic cells (pDCs), which are considered essential antiviral effector cells and potent producers of type I IFN. In contrast, pDCs were basically absent in lungs of BALB/c animals, which instead exhibited a more pronounced early NK cell response and higher lung IFNg levels. In support of a detrimental role for IFNg, therapeutic application of IFNg and TNF blocking antibodies substantially reduced maVie16 induced immunopathology. Our data suggest IFNg as driver of detrimental hyperinflammation upon SARS-CoV-2 infection and a fine balance between pDCs and NK cells as potential determinant of disease severity.

Gawish, R. (1), Starkl, P. (1), Pimenov, L. (1), Hladik, A. (1), Lakovits, K. (1), Ohradanova-Repic, A. (2), Knapp, S. (1)

(1) Research Laboratory of Infection Biology, Department of Medicine 1, Medical University of Vienna, Vienna, Austria, (2) Molecular Immunology Unit, Institute for Hygiene and Applied Immunology, Centre for Pathophysiology, Infectiology and Immunology, Medical University of Vienna, Vienna, Austria.