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.
【저자키워드】 Infectious diseases, Molecular medicine, Systems biology, TMPRSS2, 【초록키워드】 COVID-19, Macrophage, viral infection, ACE2, immune response, Mortality, macrophages, intensive care, severe COVID-19, Hospitalization, furin, SARS-COV-2 infection, susceptibility, severity, disease severity, Sequencing, intensive care unit, TLR7, inflammatory markers, C-reactive protein, procalcitonin, nasal, outcome, Toll-like receptor, immune, ICU, monocyte, Peripheral blood, Viral, Bronchoalveolar lavage fluid, immune responses, sera, male, Patient, Peripheral blood mononuclear cells, network analysis, NRP1, Hospital admission, Inflammatory marker, Sex difference, expression, BALF, Admission, moderate, scRNA-seq, mechanism, targeted intervention, COVID-19 patients, Inflammatory biomarker, BTK, Interaction, PBMCs, COVID-19 patient, mononuclear cells, tyrosine, mononuclear cell, squamous cells, observation, Patient care, cell interaction, 95% CI, 95% confidence interval, profile, hazard ratio, individual, SARS-CoV-2 positivity, disease severities, Single-cell RNA-sequencing, sputum samples, toll-like receptor 7, transcriptional activation, offer, SARS-CoV-2 entry factors, neutrophil–lymphocyte ratio, Cell, likelihood, elevated, reveal, potential molecular, with COVID-19, 【제목키워드】 COVID-19, immune, Sex difference, single-cell, Analysis, cell interaction, identify,