Journal Article Research Support, Non-U.S. Gov't Research Support, N.I.H., Extramural Epublish
PubMed: 40445428 DOI: 10.1007/s00401-025-02895-2
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.
Acta Neuropathol 149(1):54
Authors: Maria I Lioudyno, Evgueni A Sevrioukov, Gema M Olivarria, Lauren Hitchcock, Dominic I Javonillo, Sydney M Campos, Isabel Rivera, Sierra T Wright, Elizabeth Head, Juan Fortea, Thomas Wisniewski, A Claudio Cuello, Sonia Do Carmo, Thomas E Lane, Jorge Busciglio
Affiliations
- Department of Neurobiology and Behavior, Institute for Memory Impairments and Neurological Disorders, University of California Irvine, Irvine, CA, USA.
- Department of Neurobiology and Behavior, Institute for Memory Impairments and Neurological Disorders, University of California Irvine, Irvine, CA, USA.
- Department of Medicine, Division of Infectious Diseases, UC Irvine School of Medicine, Irvine, CA, USA.
- Samueli School of Engineering, University of California Irvine, Irvine, CA, USA.
- Department of Pathology and Laboratory Medicine, Institute for Memory Impairments and Neurological Disorders, University of California Irvine, Irvine, CA, USA.
- Sant Pau Memory Unit, Department of Neurology, Hospital de La Santa Creu I Sant Pau, Institut d'Investigació Biomèdica Sant Pau (IIB SANT PAU), Facultad de Medicina - Universitat Autònoma de Barcelona, Barcelona, Spain.
- Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain.
- Barcelona Down Medical Center, Fundació Catalana de SÃndrome de Down, Barcelona, Spain.
- Departments of Neurology, Pathology and Psychiatry and Center for Cognitive Neurology, New York University Grossman School of Medicine, New York, NY, USA.
- Department of Pharmacology and Therapeutics, McGill University, Montreal, QC, Canada.
- Department of Molecular Biology and Biochemistry, University of California Irvine, Irvine, CA, USA.
- Department of Neurobiology and Behavior, Institute for Memory Impairments and Neurological Disorders, University of California Irvine, Irvine, CA, USA.
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.
MeSH
Cells, Genes, Sars-Cov-2, Down Syndrome, Pathology, Aneuploidy, Covid-19, Viruses, Sex, Severe Acute Respiratory Syndrome-Related Coronavirus, Ploidies, Neurology, Infections