Researchers at the School of Biomedical Sciences, the Department of Microbiology and the Department of Medicine, LKS Faculty of Medicine of The University of Hong Kong (HKUMed) collaborated with researchers at the Institute of Synthetic Biology of Chinese Academy of Sciences-Shenzhen Institutes of Advanced Technology to conduct a study on SARS-CoV-2 infection of human neural progenitor cells and brain organoids. The results are now published in life sciences journal Cell Research.

Background
Coronavirus disease 2019 (COVID-19) caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)1 as resulted in over 17 million confirmed cases and more than 686,703 deaths across 218 countries and geographical regions as of 3 August 2020. This novel coronavirus primarily causes respiratory illness with clinical manifestations largely resembling those of SARS. However, neurological symptoms including headache, anosmia, ageusia, confusion, seizure and encephalopathy have also been frequently reported in COVID-19 patients. In a study of 214 hospitalized COVID-19 patients in Wuhan, Mainland China, neurologic findings were reported in 36.4% of patients, and were more commonly observed in patients with severe infections (45.5%)2. Similarly, a study from France reported neurologic findings in 84.5% (49/58) of COVID-19 patients admitted to hospital3. Most Importantly, a recent study in Germany demonstrated that SARS-CoV-2 RNA could be detected in brain biopsies in 36.4% (8/22) of fatal COVID-19 cases4, which highlights the potential for viral infections in the human brain. To date, there has been no direct experimental evidence of SARS-CoV-2 infection in the human central nervous system (CNS).

Research Findings
To explore the direct involvement of SARS-CoV-2 in the CNS in physiologically relevant models, the research team assessed SARS-CoV-2 infection in induced pluripotent stem cells (iPSCs)-derived human neural progenitor cells (hNPCs), neurospheres and brain organoids.

The results demonstrated that iPSC-derived hNPCs were permissive to SARS-CoV-2 infection, but not SARS-CoV infection. Extensive protein expression and infectious viral particles were detected in neurospheres and brain organoids infected with SARS-CoV-2, which suggest SARS-CoV-2 can productively infect the human brain. Importantly, SARS-CoV-2 infection in 3D human brain organoids was localized to TUJ1 (neuronal marker)- and NESTIN (NPC marker)-positive cells, suggesting SARS-CoV-2 could directly target cortical neurons and NPCs.

“Overall, our study provides the first evidence of direct SARS-CoV-2 infection in human brain organoids, which contributes to our understanding on the pathogenesis of neurological complications in COVID-19,” said Professor Huang Jian-dong, L & T Charitable Foundation Professor in Biomedical Sciences, School of Biomedical Sciences, HKUMed, who led the research.

He also pointed out that the Zika virus that re-emerged in 2015 is also well recognized to target neural progenitor cells in the human brain, leading to microcephaly and severe developmental defects in the fetus and other neurological anomalies in adults. The research team suggests that the chronic or long-term consequence of SARS-CoV-2 infection on the CNS should be closely monitored.

1 N. Zhu et al., A Novel Coronavirus from Patients with Pneumonia in China, 2019. N Engl J Med 382, 727-733 (2020).

2 L. Mao et al., Neurologic Manifestations of Hospitalized Patients With Coronavirus Disease 2019 in Wuhan, China. JAMA Neurol 10.1001/jamaneurol.2020.1127 (2020).

3J. Helms et al., Neurologic Features in Severe SARS-CoV-2 Infection. N Engl J Med 382, 2268-2270 (2020).

4 V. G. Puelles et al., Multiorgan and Renal Tropism of SARS-CoV-2. N Engl J Med 10.1056/NEJMc2011400 (2020).

Photo credits to: LKS Faculty of Medicine, The University of Hong Kong

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