SARS-CoV-2 infection of human cortical cells is influenced by the interaction between aneuploidy and biological sex : insights from a Down syndrome in vitro model
Lioudyno, Maria I. (University of California Irvine)
Sevrioukov, Evgueni A. (University of California Irvine)
Olivarria, Gema M. (University of California Irvine)
Hitchcock, Lauren (UC Irvine School of Medicine)
Javonillo, Dominic I. (University of California Irvine)
Campos, Sydney M. (University of California Irvine)
Rivera, Isabel (University of California Irvine)
Wright, Sierra T. (University of California Irvine)
Head, Elizabeth (University of California Irvine)
Fortea, Juan (Institut de Recerca Sant Pau)
Wisniewski, Thomas (New York University Grossman School of Medicine)
Cuello, AC (McGill University)
Do Carmo, Sonia (McGill University)
Lane, Thomas E. (University of California Irvine)
Busciglio, Jorge (University of California Irvine)

Date:	2025
Abstract:	Individuals with Down Syndrome (DS) represent one of the most susceptible populations for developing severe COVID-19, and a unique human genetic condition for investigating molecular mechanisms underlying susceptibility of neurologically vulnerable individuals to SARS-CoV-2 infection. Human Chromosome-21 (HSA21) triplication in DS causes global transcriptional deregulation, affecting multiple genes that may directly (e. g. , TMPRSS2) or indirectly influence the SARS-CoV-2 entry into central nervous system (CNS) cells. The anti-viral immune response may also be altered in cells with trisomy-21 (T21) due to triplication of genes encoding for several interferon receptor subunits and interferon-stimulated genes (ISGs). Here, we demonstrate that human cells derived from fetal cortical specimens and maintained in primary cultures are susceptible to infection with a molecular clone of vesicular stomatitis virus engineered to express the Spike protein of SARS-CoV-2 (VSV-eGFP-SARS-CoV-2) and to authentic SARS-CoV-2. The level of SARS-CoV-2 infectivity in cultures originated from different cortical specimens varied, seemingly depending on ploidy and chromosomal sex of the cells. We confirmed the presence of ACE2 and TMPRSS2 in cultures and found that XY T21 group had the highest TMPRSS2 mRNA levels, which was associated with increased infectivity in XY-compared to XX T21 cultures. The XX T21 cultures exhibited elevated expression of several ISGs (MX1, STAT1, and STAT2) which was associated with lower infectivity. The comparisons of postmortem aged brain specimens revealed reduced ACE2, TMPRSS2, but elevated STAT2 protein levels in individuals with DS and Alzheimer's disease (DS-AD) compared to control and Alzheimer's disease (AD) group. Collectively, these results suggest multifactorial regulation of SARS-CoV-2 infectivity in cortical cells that involves ploidy, chromosomal sex, and the expression of genes implicated in regulation of virus entry and anti-viral response as contributing factors.
Grants:	Instituto de Salud Carlos III INT21/00073 European Commission H2020-SC1-BHC-2018-2020
Note:	Altres ajuts: US National Institutes of Health (5T32 AI007319-33, T32T32NS121727, P30AG066519, RO1AG056850, RO1AG056850, RO1AG056850, RO1AG056850); National Institutes of Health (T32 AG000096)
Rights:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.
Language:	Anglès
Document:	Article ; recerca ; Versió publicada
Subject:	Trisomy-21 ; SARS-CoV-2 ; Interferon system ; Sex differences ; Primary cortical cultures ; Postmortem brain specimens
Published in:	Acta Neuropathologica, Vol. 149 Núm. 1 (May 2025) , ISSN 1432-0533

DOI: 10.1007/s00401-025-02895-2
PMID: 40445428

27 p, 12.2 MB

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