COVID-19 treatments and pathogenesis including anosmia in K18-hACE2 mice

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 1 . 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. While COVID-19 severity ranges from asymptomatic to lethal 2 , most experimental infections provide insights into mild disease 3 . Here, using K18-hACE2 mice that we originally developed for SARS studies 4 , 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 protected against lethal disease. Mice developed anosmia at early times after infection. Notably, while pretreatment 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.

Neuroinvasion and encephalitis following intranasal inoculation of SARS-CoV-2 in K18-hACE2 mice

“…However, we could not detect any virus in the serum of the infected mice at any time after infection tested, suggesting a limited role of BBB disruption in SARS-CoV-2 neuroinvasion. This finding is in agreement with previously published studies that detected little or no virus in the blood of K18-hACE2 mice after infection with SARS-CoV-1 or SARS-CoV-2 [22- 25,27,36].…”

“…There was a slight increase in RNA levels on days 3 and 5 in each of these organs, suggesting limited virus replication at these sites ( Figure 2). These data agree with previous reports that also showed the presence of SARS-CoV-2 RNA in these organs [22][23][24][25]27,36].…”

“…An important distinction between our study and others is that we detected high infectious virus titers in the olfactory system and brains of 100% of the infected K18-hACE2 mice. This phenotype was not consistently observed in the aforementioned K18-hACE2 mouse studies [22][23][24][25]. Moreover, none of the published studies evaluated the extent of neuroinflammation and neuropathology at the later stages of infection.…”

“…It was recently reported that SARS-CoV-2 infection of K18-hACE2 mice causes severe pulmonary disease with high virus levels detected in the lungs of these mice and that mortality was due to the lung infection [22][23][24][25]. In these studies, viral RNA was undetectable in the brains of the majority of the infected animals, indicating a limited role of brain infection in disease induction.…”

Convalescent plasma-mediated resolution of COVID-19 in a patient with humoral immunodeficiency

“…In contrast, CP transfusion of our CLL patient resulted in an obvious rise in NAb titers ( Figures 3 A–3D, green samples) to levels that are protective in animal studies. 19 , 20 , 21 , 22 …”