Unravelling Pathophysiology of Neurological and Psychiatric Complications of COVID-19 Using Brain Organoids

Abstract

Neuropsychiatric manifestations of coronavirus disease 2019 (COVID-19) have been increasingly recognized. However, the pathophysiology of COVID-19 in the central nervous system remains unclear. Brain organoid models derived from human pluripotent stem cells are potentially useful for the study of complex physiological and pathological processes associated with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) as they recapitulate cellular heterogeneity and function of individual tissues. We identified brain organoid studies that provided insight into the neurotropic properties of SARS-CoV-2. While SARS-CoV-2 was able to infect neurons, the extent of neurotropism was relatively limited. Conversely, choroidal epithelial cells consistently showed a high susceptibility to SARS-CoV-2 infection. Brain organoid studies also elucidated potential mechanism for cellular entry, demonstrated viral replication, and highlighted downstream cellular effects of SARS-CoV-2 infection. Collectively, they suggest that the neuropsychiatric manifestations of COVID-19 may be contributed by both direct neuronal invasion and indirect consequences of neuroinflammation. The use of high throughput evaluation, patient-derived organoids, and advent of “assembloids” will provide a better understanding and functional characterization of the neuropsychiatric symptoms seen in post-acute COVID-19 syndrome. With advancement of organoid technology, brain organoids offer a promising tool for unravelling pathophysiologic clues and potential therapeutic options for neuropsychiatric complications of COVID-19.

Neurological sequela and disruption of neuron-glia homeostasis in SARS-CoV-2 infection

“…Beyond autopsy studies, brain organoids have also expanded our understanding of viral neurotropism ( Ng et al, 2021 ). The first obstacles to viral penetration into the CNS are the BBB and blood-cerebrospinal fluid (CSF) barriers, which regulate entry of material into the brain.…”

COVID-19 – prime time for microphysiological systems, as illustrated for the brain

“…However, the central role of the ACE2 receptor for SARS-CoV-2 infection was confirmed several times. These studies also triggered several reviews (Sanclemente-Alaman et al, 2020; Ng et al, 2021;Caporale and Testa, 2021;Willner et al, 2021;Bodnar et al, 2021;Harschnitz and Studer, 2021;Ramani et al, 2021;Chen et al, 2021).…”

“…have provided several crucial pieces of evidence on the effects of SARS-CoV-2 on the brain." (Ng et al, 2021). Projects including MPSCoRe and the COVID-19 AOP development in the CIAO project, the upcoming 1 st MPS World Summit 19 in 2022, and the creation of an international MPS society will further data collection and awareness of the part MPS can play in providing understanding of SARS-CoV-2 and its pathways.…”

“…Specifically, the use of MPS may illuminate SARS-CoV-2 entry into the brain and subsequent neurological pathomechanisms that lead to NeuroCOVID. Challenges for MPS for Neuro-COVID ahead include (see also Ng et al, 2021): -identification of the conditions and cell types under which infection, replication and shedding of SARS-CoV-2 occurs (leading to better protocols and hypotheses for the clinic); -improvement of brain organoids for COVID-19 studies (maturity, immune competence, blood-brain-barrier, regional differentiation, long-term culture); -combination of brain organoids with models of, for instance, the olfactory nerve; -comparison of relevant genetic backgrounds through iPSCs to understand interindividual differences; -establishment of models of SARS-CoV-2 blood-brain barrier crossing; -study of brain immune activation as consequence of infection; -study the possible disruption of neurodevelopment; -study the neurodegenerative effect of infection; -study neuropsychiatric effects of infection including cross-talk of brain regions; -probe pathways from infection to disease manifestation; -efficacy evaluation of medical countermeasures; and -study factors improving resolution of infection. The contribution of MPS to the challenge of COVID-19 has just begun.…”

Human Brain Organoids as Models for Central Nervous System Viral Infection

“…Neurological symptoms and sequelae, during or after SARS-CoV-2 infection, have been reported [ 66 , 67 ]. Whether SARS-CoV-2 infection causes these complications through direct infection of the CNS or via a SARS-CoV-2-induced immune response is still unclear [ 65 , 68 ]. To investigate if the CNS is susceptible to direct infection, 8 out of 11 studies on SARS-CoV-2 (73%) reported on SARS-CoV-2 receptor expression in the CNS ( Table 1 ).…”