Multi-Organ Histopathological Changes in a Mouse Hepatitis Virus Model of COVID-19

Abstract

Infection with SARS-CoV-2, the virus responsible for the global COVID-19 pandemic, causes a respiratory illness that can severely impact other organ systems and is possibly precipitated by cytokine storm, septic shock, thrombosis, and oxidative stress. SARS-CoV-2 infected individuals may be asymptomatic or may experience mild, moderate, or severe symptoms with or without pneumonia. The mechanisms by which SARS-CoV-2 infects humans are largely unknown. Mouse hepatitis virus 1 (MHV-1)-induced infection was used as a highly relevant surrogate animal model for this study. We further characterized this animal model and compared it with SARS-CoV-2 infection in humans. MHV-1 inoculated mice displayed death as well as weight loss, as reported earlier. We showed that MHV-1-infected mice at days 7–8 exhibit severe lung inflammation, peribronchiolar interstitial infiltration, bronchiolar epithelial cell necrosis and intra-alveolar necrotic debris, alveolar exudation (surrounding alveolar walls have capillaries that are dilated and filled with red blood cells), mononuclear cell infiltration, hyaline membrane formation, the presence of hemosiderin-laden macrophages, and interstitial edema. When compared to uninfected mice, the infected mice showed severe liver vascular congestion, luminal thrombosis of portal and sinusoidal vessels, hepatocyte degeneration, cell necrosis, and hemorrhagic changes. Proximal and distal tubular necrosis, hemorrhage in interstitial tissue, and the vacuolation of renal tubules were observed. The heart showed severe interstitial edema, vascular congestion, and dilation, as well as red blood cell extravasation into the interstitium. Upon examination of the MHV-1 infected mice brain, we observed congested blood vessels, perivascular cavitation, cortical pericellular halos, vacuolation of neuropils, darkly stained nuclei, pyknotic nuclei, and associated vacuolation of the neuropil in the cortex, as well as acute eosinophilic necrosis and necrotic neurons with fragmented nuclei and vacuolation in the hippocampus. Our findings suggest that the widespread thrombotic events observed in the surrogate animal model for SARS-CoV-2 mimic the reported findings in SARS-CoV-2 infected humans, representing a highly relevant and safe animal model for the study of the pathophysiologic mechanisms of SARS-CoV-2 for potential therapeutic interventions.

Mechanism of Multi-Organ Injury in Experimental COVID-19 and Its Inhibition by a Small Molecule Peptide

“…At death, the lungs showed severe interstitial pneumonitis with the presence of consolidation, hyaline membranes, fibrin deposition, and dense lymphocyte and macrophage infiltrate. Liver histology was normal up to day 6, but on day 7, just prior to death, there was severe hepatic congestion and lung and heart failure, as described in humans ( Agostini et al, 2018 ; Caldera-Crespo et al, 2021 ; De Albuquerque et al, 2006 ; Paidas et al, 2021 ; Tian et al, 2021 ). These findings show that A/J mice develop both a SARS-like pulmonary disease and subsequent multi-organ failure when inoculated with MHV-1 intranasally, despite these two coronaviruses using different receptors, angiotensin-converting enzyme 2 (ACE2) and carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) (SARS-CoV-2 and MHV-1, respectively).…”

“…These findings show that A/J mice develop both a SARS-like pulmonary disease and subsequent multi-organ failure when inoculated with MHV-1 intranasally, despite these two coronaviruses using different receptors, angiotensin-converting enzyme 2 (ACE2) and carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) (SARS-CoV-2 and MHV-1, respectively). It should be highlighted that the activation of CEACAM1 was shown to stimulate clinical aspects similar to those of SARS-CoV-2 ( Khanolkar et al, 2009 ; Leibowitz et al, 2010 ; Agostini et al, 2018 ; Caldera-Crespo et al, 2021 ; De Albuquerque et al, 2006 ; Paidas et al, 2021 ; Tian et al, 2021 ).…”

“…We recently established a Murine Hepatitis Virus-1 (MHV-1) mice model of COVID-19 ( Paidas et al, 2021 ). In this model, infection of A/J mice with MHV-1 produces symptoms similar to those seen clinically in patients with SARS-CoV-2 infection and leads to high mortality ( Khanolkar et al, 2009 ; Leibowitz et al, 2010 ; Agostini et al, 2018 ; Caldera-Crespo et al, 2021 ; De Albuquerque., 2006 ; Paidas et al, 2021 ; Tian et al, 2021 ).…”

“…We recently established a Murine Hepatitis Virus-1 (MHV-1) mice model of COVID-19 ( Paidas et al, 2021 ). In this model, infection of A/J mice with MHV-1 produces symptoms similar to those seen clinically in patients with SARS-CoV-2 infection and leads to high mortality ( Khanolkar et al, 2009 ; Leibowitz et al, 2010 ; Agostini et al, 2018 ; Caldera-Crespo et al, 2021 ; De Albuquerque., 2006 ; Paidas et al, 2021 ; Tian et al, 2021 ). Two days post-MHV-1 inoculation the mice present with severe pulmonary disease and 7 days post-infection the mortality reaches 60% ( Khanolkar et al, 2009 ; Leibowitz et al, 2010 ; Agostini et al, 2018 ; Caldera-Crespo et al, 2021 ; De Albuquerque., 2006 ; Paidas et al, 2021 ; Tian et al, 2021 ).…”

Priming With Rhinovirus Protects Mice Against a Lethal Pulmonary Coronavirus Infection

“…Mouse strain- and dose-dependent severity of MHV-1 infection allows researchers to study a broad range of pulmonary coronavirus disease severities under biosafety level 2 conditions. MHV-1 is particularly virulent in A/J and C3H/HeJ mice, causing severe lung pathology that resembles lethal infections by SARS-CoV or SARS-CoV-2 in addition to pathology in the liver, brain, heart, and kidneys ( 9 , 12 , 13 ). MHV-1 infection of BALB/c mice results in milder pulmonary disease with dose-dependent severity ( 9 , 11 , 14 ).…”