K18-hACE2 Mice for Studies of COVID-19 Treatments and Pathogenesis Including Anosmia

Abstract

The ongoing COVID-19 pandemic is associated with substantial morbidity and mortality. While much has been learned in the first months of the pandemic, many features of COVID-19 pathogenesis remain to be determined. For example, anosmia is a common presentation and many patients with this finding show no or only minor respiratory signs. Studies in animals experimentally infected with SARS-CoV-2, the cause of COVID-19, provide opportunities to study aspects of the disease not easily investigated in human patients. COVID-19 severity ranges from asymptomatic to lethal. Most experimental infections provide insights into mild disease. Here, using K18-hACE2 mice that we originally developed for SARS studies, we show that infection with SARS-CoV-2 causes severe disease in the lung, and in some mice, the brain. Evidence of thrombosis and vasculitis was detected in mice with severe pneumonia. Further, we show that infusion of convalescent plasma (CP) from a recovered COVID-19 patient provided protection against lethal disease. Mice developed anosmia at early times after infection. Notably, while treatment with CP prevented significant clinical disease, it did not prevent anosmia. Thus K18-hACE2 mice provide a useful model for studying the pathological underpinnings of both mild and lethal COVID-19 and for assessing therapeutic interventions.

Lethality of SARS-CoV-2 infection in K18 human angiotensin-converting enzyme 2 transgenic mice

“…Of interest, other studies infected the K18 hACE2 transgenic mice with a lower MOI (10 4 PFUs) than used in this present study, wherein the majority of mice showed morbidity by 7 DPI but not mortality 12,13 . However, when K18 hACE2 transgenic mice were infected with 10 5 PFU in those studies, they developed progressive weight loss and lung pathologies at 2 DPI and central nervous system (CNS) involvement by 6 DPI, 2-days later than our observations 28,32,34 . Thus, in addition to the presence of hACE2 on the upper and lower respiratory tract epithelium for establishing SARS-CoV-2 infection in K18 hACE2 transgenic mice, it appears that the number of viral particles during the initial exposure is also a critical determinant of developing severe COVID-19 morbidity and mortality in this model, similar to the situation with other respiratory viral infections (e.g., influenza) 35 .…”

“…Although most chemokines and cytokines expression levels were An important distinction between our study and others is that K18 hACE2 transgenic mice succumbed to SARS-CoV-2 infection by 6 DPI when infected at 1 × 10 5 PFUs. This lethal phenotype is not observed in other hACE2 mouse studies of SARS-CoV-2 infection, where ACE2 is expressed under a different promoter [12][13][14][15][16][17][18][19]28 , including a study using ∼10 5 PFU (i.n.) of the Hong Kong/VM20001061/2020 SARS-CoV-2 strain 12 .…”

Evidence of central nervous system infection and neuroinvasive routes, as well as neurological involvement, in the lethality of SARS‐CoV‐2 infection

“…Using K18‐hACE2 mice, Zheng et al 62 found that the predominant target organs were the lung at early time points, and variably, the brain at later time points 62 . In some, but not all animals, the brain tissue titers gradually increased from Day 2 to 6 postinfection.…”

Post-exposure protection of SARS-CoV-2 lethal infected K18-hACE2 transgenic mice by neutralizing human monoclonal antibody

“…A reliable animal model for COVID-19, is essential for the development of anti-SARS-CoV-2 countermeasures and for deciphering the pathogenicity of the disease 15 . Accordingly, mouse models that exploit the recombinant hACE2 expression, either by transgenic or viral-transduction approaches were developed 16-27 . A transgenic mouse strain expressing hACE2 under the K18 promoter (K18-hACE2) was shown to be highly susceptible to SARS-CoV-2 infection, resulting in significant viral load in the lungs, heart, brain and spleen as well as mortality 26,27 .…”