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Brain ; 144(12): 3727-3741, 2021 12 31.
Article in English | MEDLINE | ID: covidwho-1455243


Recently, we reported oligoadenylate synthetase 1 (OAS1) contributed to the risk of Alzheimer's disease, by its enrichment in transcriptional networks expressed by microglia. However, the function of OAS1 within microglia was not known. Using genotyping from 1313 individuals with sporadic Alzheimer's disease and 1234 control individuals, we confirm the OAS1 variant, rs1131454, is associated with increased risk for Alzheimer's disease. The same OAS1 locus has been recently associated with severe coronavirus disease 2019 (COVID-19) outcomes, linking risk for both diseases. The single nucleotide polymorphisms rs1131454(A) and rs4766676(T) are associated with Alzheimer's disease, and rs10735079(A) and rs6489867(T) are associated with severe COVID-19, where the risk alleles are linked with decreased OAS1 expression. Analysing single-cell RNA-sequencing data of myeloid cells from Alzheimer's disease and COVID-19 patients, we identify co-expression networks containing interferon (IFN)-responsive genes, including OAS1, which are significantly upregulated with age and both diseases. In human induced pluripotent stem cell-derived microglia with lowered OAS1 expression, we show exaggerated production of TNF-α with IFN-γ stimulation, indicating OAS1 is required to limit the pro-inflammatory response of myeloid cells. Collectively, our data support a link between genetic risk for Alzheimer's disease and susceptibility to critical illness with COVID-19 centred on OAS1, a finding with potential implications for future treatments of Alzheimer's disease and COVID-19, and development of biomarkers to track disease progression.

2',5'-Oligoadenylate Synthetase/genetics , Alzheimer Disease/genetics , COVID-19/genetics , Genetic Linkage/genetics , Genetic Predisposition to Disease/genetics , Patient Acuity , Adolescent , Aged , Aged, 80 and over , Alzheimer Disease/diagnosis , Alzheimer Disease/epidemiology , COVID-19/diagnosis , COVID-19/epidemiology , Cells, Cultured , Female , Gene Regulatory Networks/genetics , Genetic Predisposition to Disease/epidemiology , Humans , Induced Pluripotent Stem Cells/physiology , Male , Middle Aged , Polymorphism, Single Nucleotide/genetics , Young Adult
Stem Cells Transl Med ; 10(11): 1491-1499, 2021 11.
Article in English | MEDLINE | ID: covidwho-1321718


Experimental cell models are indispensable for clarifying the pathophysiology of coronavirus disease 2019 (COVID-19), which is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, and for developing therapeutic agents. To recapitulate the symptoms and drug response of COVID-19 patients in vitro, SARS-CoV-2 studies using physiologically relevant human embryonic stem (ES)/induced pluripotent stem (iPS) cell-derived somatic cells and organoids are ongoing. These cells and organoids have been used to show that SARS-CoV-2 can infect and damage various organs including the lung, heart, brain, intestinal tract, kidney, and pancreas. They are also being used to develop COVID-19 therapeutic agents, including evaluation of their antiviral efficacy and safety. The relationship between COVID-19 aggravation and human genetic backgrounds has been investigated using genetically modified ES/iPS cells and patient-derived iPS cells. This review summarizes the latest results and issues of SARS-CoV-2 research using human ES/iPS cell-derived somatic cells and organoids.

COVID-19 , Human Embryonic Stem Cells/physiology , Organoids/physiology , SARS-CoV-2/physiology , Biomedical Research/methods , Biomedical Research/trends , COVID-19/etiology , COVID-19/pathology , COVID-19/therapy , Genetic Therapy/methods , Genetic Therapy/trends , Human Embryonic Stem Cells/transplantation , Humans , Induced Pluripotent Stem Cells/physiology , Induced Pluripotent Stem Cells/transplantation , Organoids/cytology , Organoids/transplantation