Study shows an inflammatory response in the mice brain is responsible for severe COVID-19

In a bioRxiv* preprint paper, a research group from Georgia State University in Atlanta demonstrated that neuroinvasion and encephalitis caused by the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is associated with significant mortality in a special mouse model, and suggested a direct infectious route for cells in the central nervous system.

Analysis of survival, body weight and virus titers in K18-hACE2 mice following SARSCoV-2 infection

Analysis of survival, body weight and virus titers in K18-hACE2 mice following SARSCoV-2 infection. Image Credit: https://www.biorxiv.org/content/10.1101/2020.12.14.422714v1.full.pdf

A causative agent of the ongoing coronavirus disease (COVID-19) pandemic, SARS-CoV-2, has been implicated in various neurological diseases and dysfunctions in humans; however, not much is known about the exact pathogenesis of such manifestations.

It is now well known that certain cells in the central nervous system express angiotensin-converting enzyme 2 (ACE2), which is a proven SARS-CoV-2 cell receptor. These are primarily neurons, astrocytes, and glial cells, and ACE2 is pervasive in many human brain areas (such as the cerebral cortex, brainstem, and amygdala).

Furthermore, a large number of autopsy reports have shown the presence of meningitis, lymphocytic panencephalitis, and brainstem interstitial inflammatory changes with the loss of neurons in COVID-19 patients. This means that SARS-CoV-2 can indeed infect the cells of the central nervous system, albeit the exact mechanism is unknown.

Luckily, small animal models can be used to study neurological complications linked to SARS-CoV-2 infection. Some recent studies show that intranasal inoculation with this virus can prompt a rapid and fatal disease in K18-hACE2 transgenic mice.

In this study, researchers from the Department of Biology at the College of Arts and Sciences of the Georgia State University in Atlanta decided to appraise the effects of intranasal infection of K18-hACE2 mice by using SARS-CoV-2.

From molecular methods to histopathology

All the animal experiments on six-week-old hemizygous K-18 hACE2 mice were conducted in a certified animal biosafety level-3 laboratory at the Georgia State University in Atlanta. In short, animals were infected with 105 plaque-forming units of SARS-CoV-2 strain initially isolated from an oropharyngeal swab from a patient in the US.

The virus titers were analyzed in the tissues by plaque assay and quantitative real-time PCR. Moreover, the levels of messenger RNA (mRNA) for specific cytokines and chemokines were appraised in total RNA from the lungs and brain with the use of using quantitative reverse transcription PCR.

Finally, sagittal sections were conducted on hemi-brain tissues frozen in optimum cutting temperature. Such tissue sections were subsequently stained with hematoxylin and eosin to enable their histopathological evaluation.

High viral titers in the brain

K18-hACE2 mice that were intranasally infected with 105 plaque-forming units of SARS-CoV-2 had striking 100% mortality by day 6 after infection. Viral titers were the highest in the lungs on day 3, and they declined at days 5 and 6 after infection.

Conversely, high amounts of infectious virus were consistently detected in the brains of the test animals at days 5 and 6. What was also a significant finding is that the onset of severe disease in mice actually correlated with peak levels of SARS-CoV-2 in the brain.

Such infection of the central nervous system was accompanied by an inflammatory response with copious production of cytokines and chemokines, leukocyte infiltration into the perivascular space, hemorrhage, as well as neuronal death.

The virus was also implicated in a productive infection of cells within the nasal turbinate, eye, and olfactory bulb – implying the utilization of this route (primarily by traversing the cribriform plate) for its entry into the brain upon intranasal infection.

Specific tissue tropism

This study demonstrates a critical role of direct infection of CNS cells and of the inflammatory response in mediating SARS-CoV-2-induced lethal disease in K18-hACE2 mice"

"Peak virus titers in the brains were approximately 1,000 times higher than the peak titers in the lungs, suggesting a high replicative potential of SARS-CoV-2 in the brain", they add.

The important finding is that the virus can enter the brain via the olfactory bulb and spread among neurons, akin to other coronaviruses. Hence, this is an important distinction from other studies in the field that aimed to explore the same issue.

Nonetheless, more studies are necessary to pinpoint the exact parameters responsible for such protean tissue tropism, bit also viral dissemination routes and mechanisms of lung/brain injuries in K18-hACE2 mice after SARS-CoV-2 infection.

*Important Notice

bioRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.

Journal reference:
Dr. Tomislav Meštrović

Written by

Dr. Tomislav Meštrović

Dr. Tomislav Meštrović is a medical doctor (MD) with a Ph.D. in biomedical and health sciences, specialist in the field of clinical microbiology, and an Assistant Professor at Croatia's youngest university - University North. In addition to his interest in clinical, research and lecturing activities, his immense passion for medical writing and scientific communication goes back to his student days. He enjoys contributing back to the community. In his spare time, Tomislav is a movie buff and an avid traveler.

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