A team of scientists from the United States has recently conducted a study using pericyte-like cell-containing brain cortical organoids as an experimental model to investigate the impact of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection on the central nervous system.
The study reveals that SARS-CoV-2 can invade cortical organoids and establish infection when they are integrated with pericyte-like cells. The study is currently available on the bioRxiv* preprint server.
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of coronavirus disease 2019 (COVID-19), is an enveloped RNA virus that primarily affects both upper and lower respiratory tracts. However, in many COVID-19 cases, SARS-CoV-2 has been found to significantly impact other vital organs, including the heart, kidney, gastrointestinal tract, and brain.
A significant proportion of critically ill COVID-19 patients have been found to present with severe neurological complications, including ischemic stroke, seizures, encephalopathy, encephalitis-meningitis, neuro-vasculopathy, and hemorrhages.
Because SARS-CoV-2 enters host cells through angiotensin-converting enzyme 2 (ACE2), neural crest stem cell-derived pericytes that express considerably high levels of ACE2 are believed to be the primary brain entry point of SARS-CoV-2. Brain pericytes are perivascular cells that connect endothelial cells with astrocytic cells and regulate important functions of the central nervous system, such as neurogenesis and neuronal degeneration, neuroinflammation, and blood-brain barrier permeability.
In the current study, the scientists aim to explore whether brain pericytes are susceptible to SARS-CoV-2 infection.
SARS-CoV-2 productively infects pericyte-like-cells.
Using in vitro setups, the scientists generated pericyte-like cells from pluripotent stem cell-derived neural crest stem cells. They observed that the pericyte-like cells expressed a relatively high amount of ACE2 receptor. The next exposed pericyte-like cells with SARS-CoV-2 observed a gradual increase in viral RNA and viral nucleocapsid-positive cells up to 72 hours post-infection to explore the transmission dynamics. Moreover, they estimated that the production of infectious SARS-CoV-2 increased by almost 100-fold after 24 hours of infection.
Given these findings, the scientists investigated whether brain pericytes serve as an entry point for SARS-CoV-2 to the central nervous system. They integrated pericyte-like cells into mature cortical brain organoids, which are three-dimensional cultures of different brain cells that are used as an experimental model of developing the human cerebral cortex. By conducting a series of experiments, they confirmed that pericyte-like cells within cortical organoids were localized together with astrocytes and embedded within the basement membrane.
Upon exposing pericyte-like cell-containing cortical organoids to SARS-CoV-2, they observed significantly higher levels of nucleocapsid-positive cells and viral RNA. In contrast, no such robust infection was observed upon exposing only cortical organoids to SARS-CoV-2. Importantly, they observed that in pericyte-like cell-containing cortical organoids, nucleocapsid-positive cells were co-localized with pericyte-like cells and astrocytes, but not to neurons. Using confocal imaging, they observed that astrocytes were themselves infected by the virus and were localized adjacent to infected pericyte-like cells. These observations indicate that SARS-CoV-2 infects astrocytes via pericyte-like cells.
Regarding the pathogenesis of SARS-CoV-2, they observed a significant induction of neuronal cell death in infected pericyte-like cell-containing cortical organoids. Moreover, transcriptional upregulation of several type I interferon-stimulated genes was observed, indicating a heightened type I interferon inflammatory response in SARS-CoV-2-infected pericyte-like cell-containing cortical organoids. \
PCCOs incorporate pericyte-like cells into cortical organoids.
The study reveals that SARS-CoV-2 can potentially infect pericyte-like cells and that susceptibility of cortical organoids to viral infection can be significantly increased by integrating them with pericyte-like cells. The virus-infected pericyte-like cells can spread the infection to other types of brain cells, including astrocytes. Activation of type I interferon responses and the induction of neuronal cell death are vital pathogenic responses observed in SARS-CoV-2 infected pericyte-like cell-containing cortical organoids.
The scientists believe that the cortical organoid model they developed can be instrumental in studying the pathogenesis of SARS-CoV-2 in the central nervous system.
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.