Human brain organoids to explore SARS‐CoV‐2‐induced effects on the central nervous system

Abstract

Severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) is the causative agent of coronavirus disease 2019 . In less than three years, an estimated 600 million infections with SARS-CoV-2 occurred worldwide, resulting in a pandemic with tremendous impact especially on economic and health sectors. Initially considered a respiratory disease, COVID-19, along with its longterm sequelae (long-COVID) rather is a systemic disease. Neurological symptoms like dementia or encephalopathy were reported early during the pandemic as concomitants of the acute phase and as characteristics of long-COVID. An excessive inflammatory immune response is hypothesized to play a major role in this context. However, direct infection of neural cells may also contribute to the neurological aspects of (long)-COVID-19. To mainly explore such direct effects of SARS-CoV-2 on the central nervous system, human brain organoids provide a useful platform. Infecting these three-dimensional tissue cultures allows the study of viral neurotropism as well as of virus-induced effects on single cells or even the complex cellular network within the organoid. In this review, we summarize the experimental studies that used SARS-CoV-2-infected human brain organoids to unravel the complex nature of (long)-COVID-19-related neurological manifestations.

Current clinical findings of acute neurological syndromes after SARS‐CoV‐2 infection

“…The detection of intact viral particles in CSF represents the most reliable evidence of SARS‐CoV‐2 infiltrating the CNS 20,27,28 . Hence, we selected 44 CSF samples (the RT‐PCR test results Ct < 25) and 12 matched NPS (nasopharyngeal swab) samples from RNA CSF ‐positive patients with high‐quality RNA for virus whole viral sequencing (whole‐genome sequencing [WGS]) detection.…”

“…The detection of intact viral particles in CSF represents the most reliable evidence of SARS-CoV-2 infiltrating the CNS. 20,27,28 Hence, we selected 44 CSF samples (the RT-PCR test results Ct < 25) and 12 matched NPS (nasopharyngeal swab) samples from RNA CSF -positive patients with high-quality RNA for virus whole viral sequenc-ing (whole-genome sequencing [WGS]) detection. Among them, 17 CSF samples exhibited high coverage of the complete SARS-CoV-2 genome (including Omicron BA.5.2 and BF.7 variants), revealing that they were not the viral genome fragments residuum (Table S1).…”

“…[22][23][24][25][26] Indeed, the direct infection of neuronal cells has been highly recognized as a significant factor contributing to neurological complications associated with COVID-19. 27,28 Over time, an increasing number of novel variants, such as XBB and JN.1, continue to emerge, leading to a growing interconnectedness between the virus and human existence. 29,30 Therefore, it is crucial to be vigilant about the potential neurological syndromes that may arise from the direct invasion of the CNS by SARS-CoV-2.…”

“…Omicron and its successor variants can infiltrate the CNS through the olfactory bulb, they not only induce inflammation in neurons, microglial cells, and astrocytes but can also directly damage neuronal cells 22–26 . Indeed, the direct infection of neuronal cells has been highly recognized as a significant factor contributing to neurological complications associated with COVID‐19 27,28 . Over time, an increasing number of novel variants, such as XBB and JN.1, continue to emerge, leading to a growing interconnectedness between the virus and human existence 29,30 .…”

Development of brain organoid technology derived from iPSC for the neurodegenerative disease modelling: a glance through

“…By delivering an almost infinite amount of pluripotent material from any patient, iPSC technology has offered new opportunities to uncover disease-modulating treatments plus the genomes of iPSCs can be edited to introduce or correct disease-associated variants ( Pantazis et al, 2022 ). In addition, iPSCs have proved to be significant in various areas of studies in virology, including modeling target organ viruses such as Cerebral Malaria (CM), HIV and SARS – CoV-2, toxicology, and doubtless in the modeling of neurological diseases, using which has established innovative opportunities for both mechanistic types of research and recognition of new disease treatments ( di Val Cervo et al, 2021 ; Ostermann and Schaal, 2023 ; Silva-Pedrosa et al, 2023a ).…”