Biomarkers prediction and immune landscape in COVID-19 and "brain fog"
Ben Wang, Cuiying Xie #, Qiong Wu #, Qiong Xu, Liyan Zhang, Yunfeng Zhao, Xueling Wu, Cuiying Xie, Qiong Wu
Background Recent studies have shown that there is a decline in cognitive and memory abilities following SARS-CoV-2 infection, but it is unclear how SARS-CoV-2 causes neurological dysfunction and which molecular processes in the brain(which is called brain fog)are affected. The study aimed to identify key "brain fog"-related genes in COVID-19 patients.
Methods To investigate weather COVID-19 affects cognitive decline, differential expression analysis was employed to identify differentially "brain fog"-related expressed genes (DEGs) of frontal cortex from the GEO database (GSE188847). Functional enrichment analysis was conducted to identify relevant signaling pathways. LASSO regression was utilized to screen pivotal genes. Weighted gene co-expression network anlaysis (WGCNA) was applied to identify different modules. Additionally, we use the Comparative Toxicogenomics Database (CTD) database to search key genes related to drugs or molecular compounds.
Results 81 up-regulated and 441 down-regulated DEGs, obtained from the frontal cortex samples between COVID-19 and normal samples, were identified. Furthermore, we identified upregulated DEGs is almost in lung fibrosis and immune-related pathways, yet down-regulated DEGs is in neuron and synapse pathways. We then identified five key genes associated with aging in COVID-19, including SST, S100A9, SOSC3, FKBP5 and HBB. Compared to normal tissue, the expression levels off SST significantly decreased, the other four genes were significantly increased. Finally, we identified seven drugs associated with key genes: Fulvestrant, Bucladesine, S-Adenosylmethionine, Valproic Acid, Folic Acid, kaempferol and Quercetin.
Conclusions Our findings revealed several key "brain fog"-related genes related to COVID-19 and several relevant drugs, providing a novel insight into the mechanism of SARS-CoV-2 infection in brain and potential implications for future cognitive decline treatment. This study contributes to a better understanding of critical genes in COVID-19 and its implications for future therapeutic interventions.
Consent for publication All authors have read and agreed to the published version of the manuscript.
Availability of data and material The original contributions presented in the study are included in the article/supplementary material. Further inquiries can be directed to the corresponding authors.
Competing interests The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. Authors' contributions BW, YZ, and XW conceived the study. BW,CX and QW collected data. BW, LZ and QX analyzed and interpreted data. BW and QW drafted the manuscript. YZ, and XW revised the manuscript. All authors contributed to the article and approved the submitted version. Authors' information (optional) P r e p r i n t n o t p e e r r e v i e w e d
References
Augustin, Schommers, Stecher, Dewald, Gieselmann et al., Post-COVID syndrome in non-hospitalised patients with COVID-19: a longitudinal prospective cohort study, Lancet Reg. Health Eur
Douaud, Lee, Alfaro-Almagro, Arthofer, Wang et al., SARS-CoV-2 is associated with changes in brain structure in UK Biobank, Nature
Duan, Ma, Tan, Miao, Zhang, Identification of genetic molecular markers and immune infiltration characteristics of Alzheimer's disease through weighted gene co-expression network analysis, Front Neurol
Díez-Cirarda, Yus, Gómez-Ruiz, Polidura, Gil-Martínez et al., Multimodal neuroimaging in post-COVID syndrome and correlation with cognition, Brain
Ellingjord-Dale, Brunvoll, Søraas, Prospective Memory Assessment before and after Covid-19, N Engl J Med
Greene, Connolly, Brennan, Laffan, 'keeffe et al., Blood-brain barrier disruption and sustained systemic inflammation in individuals with long COVIDassociated cognitive impairment, Nat Neurosci
Hampshire, Azor, Atchison, Trender, Hellyer et al., Cognition and Memory after Covid-19 in a Large Community Sample, N Engl J Med
Henri-Bhargava, Stuss, Ritchie, Phipson, Wu et al., limma powers differential expression analyses for RNA-sequencing and microarray studies, Nucleic Acids Res
Hingorani, Bhadola, Cervantes-Arslanian, COVID-19 and the brain, Trends Cardiovasc Med
Hosp, Reisert, Dressing, Götz, Kellner et al., Cerebral microstructural alterations in Post-COVID-condition are related to cognitive impairment, olfactory dysfunction and fatigue, Nat Commun
Hu, Kaluzova, Dawson, Sotelo, Papas et al., Clinical and CSF single-cell profiling of post-COVID-19 cognitive impairment, Cell Rep Med
Hänzelmann, Castelo, Guinney, GSVA: gene set variation analysis for microarray and RNA-seq data, BMC Bioinformatics
Langfelder, Horvath, WGCNA: an R package for weighted correlation network analysis, BMC Bioinformatics
Li, Li, Zhang, Wang, Qian et al., Inflammation and aging: signaling pathways and intervention therapies, Signal Transduct Target Ther
Mavrikakim, Solomonih, Slack, Fj, Severe COVID-19 isassociated with molecular signatures of aging in the human brain, Nat Aging
Mocci, Littera, Chessa, Campagna, Melis et al., A review of the main genetic factors influencing the course of COVID-19 in Sardinia: the role of human leukocyte antigen-G, Front Immunol
Peter, Nieters, Kräusslich, Brockmann, Göpel et al., Postacute sequelae of covid-19 six to 12 months after infection: population-based study, BMJ
Petersen, Gossling, Adam, Aepfelbacher, Behrendt et al., Multiorgan assessment in mainly non-hospitalized individuals after SARS-CoV-2 infection: The Hamburg city health study COVID programme, Eur Heart J
Soriano, Murthy, Marshall, Relan, Diaz, WHO Clinical Case Definition Working Group on Post-COVID-19 Condition.A clinical case definition of post-COVID-19 condition by a Delphi consensus, Lancet Infect Dis
Stein, Ramelli, Grazioli, Chung, Singh et al., SARS-CoV-2 infection and persistence in the human body and brain at autopsy, Nature
Theoharides, Cholevas, Polyzoidis, Politis, Long-COVID syndrome-associated brain fog and chemofog: Luteolin to the rescue, Biofactors
Venkataramani, Winkler, Cognitive deficits in long COVID-19, N Engl J Med
Venkataramani, Winkler, Cognitive deficits in long COVID-19, N Engl J Med
Zhang, Horvath, A General Framework for Weighted Gene Co-Expression Network Analysis, Stat. Appl. Genet. Mol. Biol
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'autopsy',
'author': 'S R Stein',
'year': '2022',
'journal-title': 'Nature'},
{ 'key': 'ref4',
'article-title': 'Post-COVID syndrome in non-hospitalised patients with COVID-19: a '
'longitudinal prospective cohort study',
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'author': 'M Augustin',
'year': '2021',
'journal-title': 'Lancet Reg. Health Eur'},
{ 'key': 'ref5',
'article-title': 'Postacute sequelae of covid-19 six to 12 months after infection: '
'population-based study',
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'author': 'R S Peter',
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'clinical case definition of post-COVID-19 condition by a Delphi '
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'article-title': 'Long-COVID syndrome-associated brain fog and chemofog: Luteolin to the '
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'key': 'ref9',
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'first-page': '1813',
'DOI': '10.1056/NEJMcibr2210069',
'article-title': 'Cognitive deficits in long COVID-19',
'volume': '387',
'author': 'V Venkataramani',
'year': '2022',
'journal-title': 'N Engl J Med'},
{ 'issue': '1',
'key': 'ref10',
'article-title': 'Inflammation and aging: signaling pathways and intervention therapies',
'volume': '8',
'author': 'X Li',
'year': '2023',
'journal-title': 'Signal Transduct Target Ther'},
{ 'issue': '5',
'key': 'ref11',
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'first-page': '2142',
'DOI': '10.1093/brain/awac384',
'article-title': 'Multimodal neuroimaging in post-COVID syndrome and correlation with '
'cognition',
'volume': '146',
'author': 'M D�ez-Cirarda',
'year': '2023',
'journal-title': 'Brain'},
{ 'issue': '1',
'key': 'ref12',
'article-title': 'Cerebral microstructural alterations in Post-COVID-condition are '
'related to cognitive impairment, olfactory dysfunction and fatigue',
'volume': '15',
'author': 'J A Hosp',
'year': '2024',
'journal-title': 'Nat Commun'},
{ 'issue': '7',
'key': 'ref13',
'article-title': 'limma powers differential expression analyses for RNA-sequencing and '
'microarray studies',
'volume': '43',
'author': 'Alexandre Henri-Bhargava',
'year': '2015',
'journal-title': 'Nucleic Acids Res'},
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'DOI': '10.2202/1544-6115.1128',
'article-title': 'A General Framework for Weighted Gene Co-Expression Network Analysis',
'volume': '4',
'author': 'B Zhang',
'year': '2005',
'journal-title': 'Stat. Appl. Genet. Mol. Biol'},
{ 'key': 'ref15',
'doi-asserted-by': 'crossref',
'DOI': '10.1186/1471-2105-9-559',
'article-title': 'WGCNA: an R package for weighted correlation network analysis',
'volume': '9',
'author': 'P Langfelder',
'year': '2008',
'journal-title': 'BMC Bioinformatics'},
{ 'key': 'ref16',
'article-title': 'GSVA: gene set variation analysis for microarray and RNA-seq data',
'volume': '14',
'author': 'S H�nzelmann',
'year': '2013',
'journal-title': 'BMC Bioinformatics'},
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'key': 'ref17',
'doi-asserted-by': 'crossref',
'first-page': '697',
'DOI': '10.1038/s41586-022-04569-5',
'article-title': 'SARS-CoV-2 is associated with changes in brain structure in UK Biobank',
'volume': '604',
'author': 'G Douaud',
'year': '2022',
'journal-title': 'Nature'},
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'key': 'ref18',
'doi-asserted-by': 'crossref',
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'DOI': '10.1056/NEJMoa2311330',
'article-title': 'Cognition and Memory after Covid-19 in a Large Community Sample',
'volume': '390',
'author': 'A Hampshire',
'year': '2024',
'journal-title': 'N Engl J Med'},
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'key': 'ref19',
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'first-page': '1813',
'DOI': '10.1056/NEJMcibr2210069',
'article-title': 'Cognitive deficits in long COVID-19',
'volume': '387',
'author': 'V Venkataramani',
'year': '2022',
'journal-title': 'N Engl J Med'},
{ 'issue': '3',
'key': 'ref20',
'doi-asserted-by': 'crossref',
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'DOI': '10.1038/s41593-024-01576-9',
'article-title': 'Blood-brain barrier disruption and sustained systemic inflammation in '
'individuals with long COVIDassociated cognitive impairment',
'volume': '27',
'author': 'C Greene',
'year': '2024',
'journal-title': 'Nat Neurosci'},
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'key': 'ref21',
'doi-asserted-by': 'crossref',
'first-page': '863',
'DOI': '10.1056/NEJMc2311200',
'article-title': 'Prospective Memory Assessment before and after Covid-19',
'volume': '390',
'author': 'M Ellingjord-Dale',
'year': '2024',
'journal-title': 'N Engl J Med'},
{ 'key': 'ref22',
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'article-title': 'Identification of genetic molecular markers and immune infiltration '
"characteristics of Alzheimer's disease through weighted gene "
'co-expression network analysis',
'volume': '13',
'author': 'K Duan',
'year': '2022',
'journal-title': 'Front Neurol'},
{ 'issue': '5',
'key': 'ref23',
'article-title': 'Clinical and CSF single-cell profiling of post-COVID-19 cognitive '
'impairment',
'volume': '5',
'author': 'W T Hu',
'year': '2024',
'journal-title': 'Cell Rep Med'},
{ 'key': 'ref24',
'volume': '14',
'author': 'S Mocci',
'year': '2023',
'journal-title': 'A review of the main genetic factors influencing the course of COVID-19 '
'in Sardinia: the role of human leukocyte antigen-G.Front Immunol'}],
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