Lioudyno Maria I, Sevrioukov Evgueni A, Olivarria Gema M, Hitchcock Lauren, Javonillo Dominic I, Campos Sydney M, Rivera Isabel, Wright Sierra T, Head Elizabeth, Fortea Juan, Wisniewski Thomas, Cuello A Claudio, Do Carmo Sonia, Lane Thomas E, Busciglio Jorge
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.
Acta Neuropathol. 2025 May 30;149(1):54. doi: 10.1007/s00401-025-02895-2.
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.
唐氏综合征（DS）患者是感染重症新冠病毒肺炎（COVID-19）的易感人群之一，也是研究神经易损个体对严重急性呼吸综合征冠状病毒2（SARS-CoV-2）感染易感性分子机制的独特人类遗传疾病模型。DS患者中人类21号染色体（HSA21）三体导致整体转录失调，影响多个可能直接（如跨膜丝氨酸蛋白酶2，TMPRSS2）或间接影响SARS-CoV-2进入中枢神经系统（CNS）细胞的基因。由于编码几种干扰素受体亚基和干扰素刺激基因（ISGs）的基因三体化，21三体（T21）细胞中的抗病毒免疫反应也可能发生改变。在此，我们证明，源自胎儿皮质标本并维持在原代培养中的人类细胞易受工程改造表达SARS-CoV-2刺突蛋白的水疱性口炎病毒分子克隆（VSV-eGFP-SARS-CoV-2）和 authentic SARS-CoV-2感染。源自不同皮质标本的培养物中SARS-CoV-2感染性水平各不相同，这似乎取决于细胞的倍性和染色体性别。我们证实培养物中存在血管紧张素转换酶2（ACE2）和TMPRSS2，并发现XY T21组的TMPRSS2 mRNA水平最高，这与XY T21培养物相比XX T21培养物中感染性增加有关。XX T21培养物表现出几种ISGs（MX1、信号转导和转录激活因子1，STAT1和信号转导和转录激活因子2，STAT2）表达升高，这与较低的感染性有关。对死后老年脑标本的比较显示，与对照组和阿尔茨海默病（AD）组相比，DS和阿尔茨海默病（DS-AD）患者的ACE2、TMPRSS2蛋白水平降低，但STAT2蛋白水平升高。总体而言，这些结果表明，皮质细胞中SARS-CoV-2感染性受多因素调节，其中包括倍性、染色体性别以及与病毒进入调节和抗病毒反应相关的基因表达，这些都是影响因素。
