Severe Acute Respiratory Syndrome Coronavirus Infection Causes Neuronal Death in the Absence of Encephalitis in Mice Transgenic for Human ACE2

TLDR

SARS‑CoV infection causes severe respiratory failure in humans, can also infect the brain, and its long‑term neurological impact remains poorly understood. The study aims to demonstrate that SARS‑CoV enters the brain through the olfactory bulb and spreads transneuronally to connected regions. Using human ACE2 transgenic mice, the authors traced viral entry via the olfactory bulb and rapid transneuronal dissemination. The findings reveal that SARS‑CoV infects neurons, especially in cardiorespiratory centers, leading to lethal neuronal death without significant inflammation, and that neuronal infection is the primary cause of mortality in these mice.

Abstract

Infection of humans with the severe acute respiratory syndrome coronavirus (SARS-CoV) results in substantial morbidity and mortality, with death resulting primarily from respiratory failure. While the lungs are the major site of infection, the brain is also infected in some patients. Brain infection may result in long-term neurological sequelae, but little is known about the pathogenesis of SARS-CoV in this organ. We previously showed that the brain was a major target organ for infection in mice that are transgenic for the SARS-CoV receptor (human angiotensin-converting enzyme 2). Herein, we use these mice to show that virus enters the brain primarily via the olfactory bulb, and infection results in rapid, transneuronal spread to connected areas of the brain. This extensive neuronal infection is the main cause of death because intracranial inoculation with low doses of virus results in a uniformly lethal disease even though little infection is detected in the lungs. Death of the animal likely results from dysfunction and/or death of infected neurons, especially those located in cardiorespiratory centers in the medulla. Remarkably, the virus induces minimal cellular infiltration in the brain. Our results show that neurons are a highly susceptible target for SARS-CoV and that only the absence of the host cell receptor prevents severe murine brain disease.