SARS-CoV-2 infection and Spike protein exposure alter iPSC-derived human brain organoid homeostasis.

Abstract COVID-19 typically causes respiratory disorders, but several patients (30–60%) manifest also a wide range of neurological conditions, advocating for detrimental effects SARS-CoV-2 or Spike (S) protein on the central nervous system. However, molecular mechanisms responsible these disfunctions as well potential neurotropism SARS-CoV-2, are still under investigation. To assess this issue, by using iPSC-derived-human brain organoids (HBO) we evaluated: expression main receptors: ACE2, CD147, NRP1, Furin, TMPRSS2 (qPCR, IF); their infectability over-time (QPCR, TCID50, and effect SARS-CoV-2-infection S exposure HBO transcriptome (qPCR) secretome (Multiplex ELISA). All receptors expressed with lower NRP1 levels compared to CD147 ACE2. By analyzing viral N1and N2gene sequence over time, VeroE6 cells infected supernatants, nucleocapsid IF confirmed that may be productively virus. Furthermore, infection was accompanied activation apoptotic stress pathways (caspase3, caspase8, Bcl2, S100B), inflammatory process (CCL2, NLRP3) Interferon Stimulated Genes (IFITM1, IFITM3, STAT1, NFkB) antigen presentation pathway (ERAP1, ERAP2, HLA-A, TAP). Notably, trend different targets comparable following S-stimulation. These results confirm infect probably binding ACE2 indicate can affect homeostasis exert neurotoxic presumably driving so called long-COVID symptoms. Partially supported grants from Fondazione Alessandro Vincenzo Negroni Prati Morosini Romeo Erica Invernizzi.