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Multimodal single-cell omics analysis identifies epithelium-immune cell interactions and immune vulnerability associated with sex differences in COVID-19.
Hou, Yuan; Zhou, Yadi; Gack, Michaela U; Lathia, Justin D; Kallianpur, Asha; Mehra, Reena; Chan, Timothy A; Jung, Jae U; Jehi, Lara; Eng, Charis; Cheng, Feixiong.
  • Hou Y; Genomic Medicine Institute, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA.
  • Zhou Y; Genomic Medicine Institute, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA.
  • Gack MU; Florida Research and Innovation Center, Cleveland Clinic, Port Saint Lucie, FL, USA.
  • Lathia JD; Department of Cardiovascular and Metabolic Science, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA.
  • Kallianpur A; Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine, Case Western Reserve University, Cleveland, OH, USA.
  • Mehra R; Genomic Medicine Institute, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA.
  • Chan TA; Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine, Case Western Reserve University, Cleveland, OH, USA.
  • Jung JU; Department of Population and Quantitative Health Sciences, Case Western Reserve University, Cleveland, OH, USA.
  • Jehi L; Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine, Case Western Reserve University, Cleveland, OH, USA.
  • Eng C; Neurological Institute, Cleveland Clinic, Cleveland, OH, USA.
  • Cheng F; Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine, Case Western Reserve University, Cleveland, OH, USA.
Signal Transduct Target Ther ; 6(1): 292, 2021 07 30.
Article in English | MEDLINE | ID: covidwho-1333904
ABSTRACT
Sex differences in the susceptibility of SARS-CoV-2 infection and severity have been controversial, and the underlying mechanisms of COVID-19 in a sex-specific manner remain understudied. Here we inspected sex differences in SARS-CoV-2 infection, hospitalization, admission to the intensive care unit (ICU), sera inflammatory biomarker profiling, and single-cell RNA-sequencing (scRNA-seq) profiles across nasal, bronchoalveolar lavage fluid (BALF), and peripheral blood mononuclear cells (PBMCs) from COVID-19 patients with varying degrees of disease severities. Our propensity score-matching observations revealed that male individuals have a 29% elevated likelihood of SARS-CoV-2 positivity, with a hazard ratio (HR) 1.32 (95% confidence interval [CI] 1.18-1.48) for hospitalization and HR 1.51 (95% CI 1.24-1.84) for admission to ICU. Sera from male patients at hospital admission had elevated neutrophil-lymphocyte ratio and elevated expression of inflammatory markers (C-reactive protein and procalcitonin). We found that SARS-CoV-2 entry factors, including ACE2, TMPRSS2, FURIN, and NRP1, have elevated expression in nasal squamous cells from male individuals with moderate and severe COVID-19. We observed male-biased transcriptional activation in SARS-CoV-2-infected macrophages from BALF and sputum samples, which offers potential molecular mechanism for sex-biased susceptibility to viral infection. Cell-cell interaction network analysis reveals potential epithelium-immune cell interactions and immune vulnerability underlying male-elevated disease severity and mortality in COVID-19. Mechanistically, monocyte-elevated expression of Toll-like receptor 7 (TLR7) and Bruton tyrosine kinase (BTK) is associated with severe outcomes in males with COVID-19. In summary, these findings provide basis to decipher immune responses underlying sex differences and designing sex-specific targeted interventions and patient care for COVID-19.
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Full text: Available Collection: International databases Database: MEDLINE Main subject: Leukocytes, Mononuclear / Cell Communication / Sex Characteristics / SARS-CoV-2 / COVID-19 / Nasal Mucosa Type of study: Observational study / Prognostic study Limits: Adult / Aged / Female / Humans / Male / Middle aged Language: English Journal: Signal Transduct Target Ther Year: 2021 Document Type: Article Affiliation country: S41392-021-00709-x

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Full text: Available Collection: International databases Database: MEDLINE Main subject: Leukocytes, Mononuclear / Cell Communication / Sex Characteristics / SARS-CoV-2 / COVID-19 / Nasal Mucosa Type of study: Observational study / Prognostic study Limits: Adult / Aged / Female / Humans / Male / Middle aged Language: English Journal: Signal Transduct Target Ther Year: 2021 Document Type: Article Affiliation country: S41392-021-00709-x