Cerebral Organoids Derived from a Parkinson’s Patient Exhibit Unique Pathogenesis from Chikungunya Virus Infection When Compared to a Non-Parkinson’s Patient

Abstract

(1) Background: Arboviruses of medical and veterinary significance have been identified on all seven continents, with every human and animal population at risk for exposure. Like arboviruses, chronic neurodegenerative diseases, like Alzheimer’s and Parkinson’s disease, are found wherever there are humans. Significant differences in baseline gene and protein expression have been determined between human-induced pluripotent stem cell lines derived from non-Parkinson’s disease individuals and from individuals with Parkinson’s disease. It was hypothesized that these inherent differences could impact cerebral organoid responses to viral infection. (2) Methods: In this study, cerebral organoids from a non-Parkinson’s and Parkinson’s patient were infected with Chikungunya virus and observed for two weeks. (3) Results: Parkinson’s organoids lost mass and exhibited a differential antiviral response different from non-Parkinson’s organoids. Neurotransmission data from both infected non-Parkinson’s and Parkinson’s organoids had dysregulation of IL-1, IL-10, and IL-6. These cytokines are associated with mood and could be contributing to persistent depression seen in patients following CHIKV infection. Both organoid types had increased expression of CXCL10, which is linked to demyelination. (4) Conclusions: The differential antiviral response of Parkinson’s organoids compared with non-Parkinson’s organoids highlights the need for more research in neurotropic infections in a neurologically compromised host.

Human Brain Organoids as Models for Central Nervous System Viral Infection

“…Chikungunya virus, an RNA virus from the Togaviridae family, was studied in cerebral organoids derived from Parkinson’s disease (PD) iPSCs and non-PD iPSC derived cerebral organoids. The immune response of PD cerebral organoids was altered compared to the non-PD organoids, highlighting the need for studies on the influence of host genetic variation on host-pathogen interactions [ 95 ]. John Cunningham virus (JCV), a DNA polyomavirus, was studied once in cerebral organoids [ 96 ].…”

Methodologies for Generating Brain Organoids to Model Viral Pathogenesis in the CNS

“…LACV, according to Winkler et al, diminished CO cell viability and that committed neurons were much more susceptible to LACV apoptosis than neural progenitors, which replicate data from humans, primates and rodents [83,121]. Using COs, Schultz et al found that organoids derived from patients with Parkinson's disease had increased pathology from Chikungunya virus (CHIKV) than organoids derived from normal patients [62]. This is intriguing since recent reports indicate a link between SARS CoV-2 and exacerbated Parkinson's disease [122][123][124].…”

“…Virus researchers typically present data from brain organoids derived from a single cell line, although some recent studies have derived brain organoids from two unique cell lines [55,[61][62][63][64][65][66]. While dozens of organoids can be produced through a single generation protocol, the resultant organoids are basically clones of each other and donor-specific characteristics persist in unique cell lines.…”

3D engineered tissue models for studying human-specific infectious viral diseases

“…Scale bar, 500 μm. Reproduced from Schultz et al under the terms of the CC BY license [ 164 ]. Copyright 2021, MDPI.…”