3 September 2020 – The potential for SARS-CoV-2 infection to damage nerve cells was demonstrated in human brain-like organoids derived from pluripotent stem cells. This could help explain the accumulating clinical reports of neurological symptoms in people who had earlier tested positive for SARS-CoV-2 infection, suggesting possible long-term damage to elements of the CNS. The research carried out by a primarily German team across several university hospitals also advances further our understanding of developing and exploiting effective organoid platforms for modelling human infectious disease. Such models did not exist at the time of the SARS-CoV-1 outbreak in 2003, which threatened to become the first significant coronavirus pandemic of recent times.
Organoids are tiny 3D tissues typically around 2 mm in diameter across derived from stem cells to mirror the complex structures of an organ, or at least to express selected aspects of it to meet a given biomedical research objective. Techniques for creating suitably complex and diverse organoids accurately reflecting structures of counterpart in vivo tissues have advanced rapidly over recent years. Insights into infection mechanisms have already been gained from kidney and gut organoids, and the current work is establishing brain organoids as a promising test system for study of neurotoxic effects resulting from infection by SARS-CoV-2, as well as other viruses.
The same German group and others had already obtained unprecedented insights into infection mechanisms, target cell types and toxicity effects of the Zika virus (ZIKV) during the ZIKV epidemic that affected mainly the Americas during 2016. That was a very different virus transmitted by the Aedes mosquito. The primary concerns were neurological effects and particularly microcephaly in infants after vertical transmission of the virus from pregnant women to their fetus.
The latest research has revealed that SARS-CoV-2 targets different cell types of the CNS compared to the recent ZIKV that infected mostly Neural Progenitor Cells (NPCs). NPCs are responsible for generating most, if not all cells of the CNS. By contrast, the current research found that SARS-CoV-2 readily targets neurons but not the NPCs responsible for their generation. Although SARS-CoV-2 can induce cell death in brain organoids, it does not appear to replicate effectively in the CNS, which may limit its potential for neurological damage.
However, the application of high-resolution imaging has indicated that SARS-CoV-2 exposure in vitro can cause neurodegeneration-like effects associated with Alzheimer’s, exhibiting an aberrant localization of the Tau protein in neurons. There was no direct evidence yet of potential to cause degenerative disease, but the studies have yielded insights into the impact of SARS-CoV-2 as a neurotropic virus capable of infecting nerve cells and confirmed that brain organoids could model CNS pathologies of COVID-19.
These initial insights will be followed by further experiments combining mature brain organoids with other techniques including animal investigation in vivo to unravel more critical details of neuropathology associated with SARS-CoV-2. This should help develop therapies to combat such pathologies at early stages while they are still reversible.
SARS-CoV-2 targets neurons of 3D human brain organoids
The EMBO Journal
Anand Ramani, Lisa Müller, Philipp Niklas Ostermann, Elke Gabriel, Pranty Abida-Islam, Andreas Müller-Schiffmann, Aruljothi Mariappan, Olivier Goureau, Henning Gruell, Andreas Walker, Marcel Andrée, Sandra Hauka, Torsten Houwaart, Alexander Dilthey, Kai Wohlgemuth, Heymut Omran, Florian Klein, Dagmar Wieczorek, Ortwin Adams, Jörg Timm, Carsten Korth, Heiner Schaal, Jay Gopalakrishnan
Read the paper: www.embopress.org/doi/10.15252/embj.2020106230