Modeling neuroinvasion of SARS-CoV-2 variants in human iPSC-derived brain organoids

Authors

• SM Patwardhan
• JS Schofield
• WMJ Joiner
• TC Bulea
• S Sikdar

Abstract

While SARS-CoV-2 is predominantly recognized as a respiratory virus, its infection has been linked with neurological manifestations. It remains uncertain whether these symptoms result from the direct viral invasion of the Central Nervous System (CNS) or are secondary to other mechanisms like inflammation or hypoxia. Post-mortem examinations of COVID-19 patients have revealed the presence of viral RNA and protein in brain tissues. Furthermore, there are reports suggesting that the original strain of SARS-CoV-2 can infect and replicate within iPSC-derived neurons, glial cells, and brain organoids. Nevertheless, the capacity of SARS-CoV-2 variants to infect or replicate within the CNS remains largely unexplored. In this study, we leveraged iPSC-derived cortical organoids to investigate the differential neurotropism of the WA1, Alpha, Beta, Gamma, Delta, and Omicron BA.5 variants of SARS-CoV-2. Our preliminary findings reveal that some variants exhibit a heightened infection rate that can't be solely attributed to the differential affinity of each variant's Spike protein for the ACE2 receptor. Moreover, we employed a multi-omic approach to study whether these variants induce distinct immunological and metabolic responses in the brain organoids. Going forward, we aim to use this data to decipher the potential mechanisms underlying the neurological symptoms observed in clinical settings and to develop targeted therapeutic interventions.

Scientific Focus Area: Microbiology and Infectious Diseases

This page was last updated on Monday, September 25, 2023