Image: Human mini-brain bioengineered from human stem cells. Size is about 1/3 millimeter and mini-brain is composed of approximately 30,000 cells. Cell nuclei are blue, SARS-CoV-2 virus is red. Image courtesy of CAAT.
A Johns Hopkins collaboration has demonstrated that the novel coronavirus, SARS-CoV-2, can infect and replicate within a human mini-brain model
A multidisciplinary team from two Johns Hopkins University institutions, including neurotoxicologists and virologists from the Bloomberg School of Public Health and infectious disease specialists from the School of Medicine, has found that organoids (tiny tissue cultures that simulate whole organs) made from human cells (known as “mini-brains”) can be infected by the SARS-CoV-2 virus that causes COVID-19. The results were published online today, June 26, in the journal ALTEX: Alternatives to Animal Experimentation.
Early reports from Wuhan, China, have suggested that 36% of COVID-19 patients show neurological symptoms, but until now it was not clear whether the virus infects human brain cells. The Johns Hopkins researchers have now demonstrated that certain human neurons express a receptor, ACE2, that the SARS-CoV-2 virus uses for entering the lungs — and possibly the brain.
When the researchers introduced SARS-CoV-2 virus particles into a human “mini-brain” model, the team found — for what is believed to be the first time — evidence of infection by and replication of the pathogen.
The human brain is well-shielded against many viruses, bacteria and chemical agents by the blood-brain barrier, which in turn, often prevents infections of the brain. “Whether or not the SARS-CoV-2 virus passes this barrier has yet to be shown,” notes senior author Thomas Hartung, MD, PhD, chair for evidence-based toxicology at the Bloomberg School of Public Health. “However, it is known that severe inflammations, such as those observed in COVID-19 patients, make the barrier disintegrate.”
The impermeability of the blood-brain barrier, he adds, also can present a problem for drug developers targeting the brain.
The impact of SARS-CoV-2 on the developing brain is another concern raised by the study. Other research from Paris Saclay University has shown that the virus crosses the placenta, and embryos lack the blood-brain barrier during early development. “To be very clear,” Hartung says, “we have no evidence that the virus produces developmental disorders.”
However, the mini-brains — which model the developing human brain — contain from the very earliest stages the same ACE2 receptor that allows the virus to enter lung tissues. Therefore, Hartung says, the findings suggest that extra caution should be taken during pregnancy.
“This study is another important step in our understanding of how infection leads to symptoms, and where we might tackle the COVID-19 disease with drug treatment,” says William Bishai, MD, PhD, professor of medicine at the Johns Hopkins University School of Medicine, and leader of the infectious disease team for the study.
“There is no doubt that the virus infects neurons and multiplies” Hartung adds, “and now we have to find out what this means for patients and public health.”
The human stem cell-derived “mini-brain” models — known as BrainSpheres — were developed at the Bloomberg School of Public Health four years ago. They were the first mass-produced, highly standardized organoids of their kind, and have been used to model a number of diseases, including infections by viruses such as Zika, dengue, and HIV.
“Infectability of human BrainSphere neurons suggests neurotropism of SARS-CoV-2,” as published in ALTEX, was written by C. Korin Bullen, Helena Therese Hogberg, Asli Bahadirli-Talbott, William R. Bishai, Thomas Hartung, Casey Keuthan, Monika M. Looney, Andrew Pekosz, Carolina Romero, Fenna Claudia Margaretha Sillé, Peter Um, and Lena Smirnova.
Co-authors Thomas Hartung and Helena Hogberg are named inventors on a patent by Johns Hopkins University on the production of mini-brains, which is licensed to AxoSim, New Orleans, Louisiana. Thomas Hartung, Helena Hogberg, and Lena Smirnova consult for AxoSim and Thomas Hartung is a shareholder. Thomas Hartung is a member of the North American editorial team of ALTEX: Alternatives to Animal Experimentation.