December 1, 2020
Written by: Nitsan Goldstein
COVID-19 continues to spread around the world at an alarming rate. When we first wrote about neurologic complications from COVID-19 on June 30th, just under 10 million people had been infected globally. As of the writing of this post less than 5 months later, 12 million people have been infected in the United States alone, with over 58 million infections worldwide. Normally, one would not expect any major scientific advancements in 5 months on a single topic. These are not normal times, however, and the massive push to study this disease by scientists around the world has led to an outpouring of research on how SARS-CoV-2 might affect the brain. Here we will provide an update on what has been found, and the big questions that still need to be answered.
As more cases are reported, possible causes of neurological symptoms (see June 30th article for symptoms) have been proposed.
Direct invasion of the central nervous system
Studies on live and deceased human COVID-19 patients suggest that direct SARS-CoV-2 infection of brain tissue is quite rare1,2. However, even rare complications will affect thousands of people when 58 million people are infected, so it is important to understand when and how this virus can enter the brain and cause damage. A likely route of entry to the central nervous system is through the nose. The proteins the virus needs to enter cells are present at high levels in the nasal passage3, and the frequency of anosmia (loss of smell) in COVID-19 patients suggests that the virus is damaging the sensory neurons in the nose that transmit smell information to the brain.
Can the virus replicate in brain cells and damage them once it enters the brain? Previous work with the SARS-CoV virus suggested that it might be able to, but one group of researchers has now confirmed that SARS-CoV-2 can also replicate in brain tissue4. Using organoids to model human brains, scientists found that SARS-CoV-2 infects, replicates in, and damages neurons. The infection could be prevented by treating the organoids with an antibody targeting the ACE2 protein, which is the key protein used by the virus to enter cells. As with the SARS-CoV virus, SARS-CoV-2 was fatal to mice when delivered into the brain. Finally, this study examined brains of people who had died from COVID-19. They found evidence of viral infection in the brain, and showed damage likely caused by small strokes in the areas with more virus4. While it is hard to determine whether the virus actually caused the damage, the authors claim it is possible that the virus damages the brain’s blood vessels, weakening its defense system and making brain tissue more vulnerable to invasion by the virus. It is important to note that this study has not yet been peer reviewed, meaning other expert scientists have not vetted it to ensure it used the proper methodology and controls, and that the conclusions made were appropriate. Another study, however, that was peer reviewed, found similar evidence of brain invasion by SARS-CoV-2 in mice5.
Even without directly infecting brain tissue, COVID-19 can cause neurologic symptoms due to a systemic (whole body) inflammatory response. The immune system is an army meant to identify and kill foreign invaders, like viruses, from attacking our body’s cells. Specialized cells, called T cells, are the soldiers that are released to find and kill cells that have been infected with virus so that it cannot replicate and infect other cells. Like soldiers, T cells have weapons, called cytokines, that are toxic to cells and used by T cells to kill the virus-infected cells. Proper immune function, however, is a delicate balance; too picky and the virus can spread rapidly throughout the body, too aggressive and the immune cells can attack and damage healthy cells. Recent work shows that in COVID-19 patients, especially in severe cases requiring hospitalization, the immune system balance is off. Namely, there are fewer T cells to fight the infection, and the ones that remain are weaker. Additionally, cytokine levels, the toxic weapons used to kill cells, are elevated.6 This condition has been referred to as a “cytokine storm,” and can result in respiratory distress and multi-system organ failure7. Whether and how this systemic inflammatory response can explain some of the neurologic symptoms observed in patients without active infection in the brain is an active area of investigation.
Strokes have been reported in anywhere from 3% to 23% of hospitalized COVID-19 patients7. Strokes are more common in older patients or those that are at increased risk stroke, but have been reported in younger patients as well8. Most of these reported strokes are ischemic, which means that the brain is deprived of blood and, as a result, oxygen. Two main mechanisms have been described that would explain the occurrence of strokes in COVID-19 patients9. Evidence suggests that the blood of COVID-19 patients is hypercoagulable, or clots too easily10. While it is still not clear why this shift occurs during SARS-CoV-2 infection, it is possible that the immune responses described above are at least in part to blame. It has also been suggested that SARS-CoV-2 may infect and damage epithelial cells, which are the cells that line the body’s organs, including blood vessels10. Damage to these cells also causes inflammation, narrowing blood vessels and increasing the likelihood of strokes. It’s likely that both increased clotting and epithelial cell damage contribute to strokes in COVID-19 patients, and more work is needed to understand how to prevent these life-threatening complications from occurring in vulnerable populations. A year ago, this disease didn’t exist. Doctors and scientists had to use every tool at their disposal to understand how this virus gets into the body, which cells and organs it is most likely to attack, and whether certain symptoms are a direct result of the virus or a consequence of the body trying to fight it. Though the disease is still killing people at a devastating rate, research has led to improvements in treatments. For example, doctors are now using steroids to suppress the immune system in cases where heightened immune activity may become dangerous11. Unlike other cells in the body, brain cells cannot regenerate. Therefore, it is important to consider that neurologic complications from COVID-19 may persist long after infection, making it crucial to continue investigating exactly how this virus affects the brain, and what we can do to stop it.
- Solomon, I.H., Normandin, E., Bhattacharyya, S., et al. Neuropathological features of Covid-19. N Engl J Med. (2020).
- Josephson, S.A. & Kamel, H. Neurology and COVID-19. JAMA 324:1139–1140 (2020).
- Sungnak, W., Huang, N., Bécavin, C., et al. SARS-CoV-2 entry factors are highly expressed in nasal epithelial cells together with innate immune genes. Nat Med. 26:681-687 (2020).
- Song E, Zhang C, Israelow B, et al. Neuroinvasion of SARS-CoV-2 in human and mouse brain. Preprint. bioRxiv (2020).
- Zheng, J., Wong, L.R., Li, K., et al. COVID-19 treatments and pathogenesis including anosmia in K18-hACE2 mice. Nature (2020) Epub ahead of print.
- Diao, B., Wang, C., Tan, Y., et al. Reduction and Functional Exhaustion of T Cells in Patients With Coronavirus Disease 2019 (COVID-19). Front Immunol. 11:827 (2020).
- Koralnik, I.J. & Tyler K.L. COVID-19: A Global Threat to the Nervous System. Ann Neurol. 88:1-11 (2020).
- Oxley, T.J., Mocco, J., Majidi, S., et al. Large-Vessel Stroke as a Presenting Feature of Covid-19 in the Young. N Engl J Med. 382:e60 (2020).
- Qi, X., Keith, K.A., Huang, J.H. COVID-19 and stroke: A review. Brain Hemorrhages (2020). Epub ahead of print.
- Ellul, M.A., Benjamin, L., Singh, B., et al. Neurological associations of COVID-19. Lancet Neurol. 19:767-783 (2020).
- Meyerowitz, E.A., Sen, P., Schoenfeld, S.R., Neilan, T.G., Frigault, M.J., Stone, J.H., Kim, A.Y., Mansour, M.K.; CIG (COVID-19 Immunomodulatory Group). Immunomodulation as Treatment for Severe COVID-19: a systematic review of current modalities and future directions. Clin Infect Dis. (2020) Epub ahead of print.
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