ABSTRACT
Due to the highly variable clinical phenotype of Coronavirus disease 2019 (COVID-19), deepening the host genetic contribution to severe COVID-19 may further improve our understanding about underlying disease mechanisms. Here, we describe an extended GWAS meta-analysis of 3,260 COVID-19 patients with respiratory failure and 12,483 population controls from Italy, Spain, Norway and Germany, as well as hypothesis-driven targeted analysis of the human leukocyte antigen (HLA) region and chromosome Y haplotypes. We include detailed stratified analyses based on age, sex and disease severity. In addition to already established risk loci, our data identify and replicate two genome-wide significant loci at 17q21.31 and 19q13.33 associated with severe COVID-19 with respiratory failure. These associations implicate a highly pleiotropic ~0.9-Mb 17q21.31 inversion polymorphism, which affects lung function and immune and blood cell counts, and the NAPSA gene, involved in lung surfactant protein production, in COVID-19 pathogenesis.
Subject(s)
COVID-19 , Respiratory InsufficiencyABSTRACT
The systemic processes involved in the manifestation of life-threatening COVID-19 and in disease recovery are still incompletely understood, despite investigations focusing on the dysregulation of immune responses after SARS-CoV-2 infection. To define hallmarks of severe COVID-19 and disease recovery in convalescent patients, we combined analyses of immune cells and cytokine/chemokine networks with endothelial activation and injury. ICU patients displayed an altered immune signature with prolonged lymphopenia but expansion of granulocytes and plasmablasts along with activated and terminally differentiated T and NK cells and high levels of SARS-CoV-2-specific antibodies. Core signature of seven plasma proteins revealed a highly inflammatory microenvironment in addition to endothelial injury in severe COVID-19. Changes within this signature were associated with either disease progression or recovery. In summary, our data suggest that besides a strong inflammatory response, severe COVID-19 is driven by endothelial activation and barrier disruption, whereby recovery depends on the regeneration of the endothelial integrity.
Subject(s)
COVID-19 , Lymphopenia , Wounds and InjuriesABSTRACT
To investigate the role of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-specific T-cell immunity and its relationship with antibody levels and pre-existing immunity against endemic human coronaviruses (huCoV) during disease and beyond, we analyzed patients with recovered (RC, n=178) and active Coronavirus Disease-2019 (COVID-19; AC, n=10) and healthy donors (HD, n=58). Overall, ACs had highest SARS-CoV-2 antibody levels against nucleocapsid (N) and spike (S) proteins but reduced antiviral T-cell immunity, whereas in RCs, antibody levels partially correlated with SARS-CoV-2-specific T-cell frequencies. Interestingly, humoral responses declined throughout convalescence, whereas T-cell immunity remained stable. RCs exhibited polyfunctional, mainly IFN-γ-secreting CD4 + effector memory T-cell responses. Humoral and cellular response towards huCoV strains in RCs with strong SARS-CoV-2 T-cell immunity implies a protective role of pre-existing immunity against huCoV. This study provides essential evidence-based data about stable protective T-cell immunity during disease and recovery which is essential to guide diagnosis and treatment of COVID-19.
Subject(s)
Coronavirus Infections , COVID-19ABSTRACT
Given the importance of the humoral immune response to SARS-CoV-2 as a global benchmark for immunity, a detailed analysis is needed to (i) monitor seroconversion in the general population, (ii) understand manifestation and progression of the disease, and (iii) predict the outcome of vaccine development. Currently available serological assays utilize single analyte technologies such as ELISA to measure antibodies against SARS-CoV-2 antigens including spike (S) or nucleocapsid (N) protein. To measure individual antibody (IgG and IgA) responses against SARS-CoV-2 and the endemic human coronaviruses (hCoVs) NL63, 229E, OC43, and HKU1, we developed a multiplexed immunoassay (CoVi-plex), for which we included S and N proteins of these coronaviruses in an expanded antigen panel. Compared to commercial in vitro diagnostic (IVD) tests our CoVi-plex achieved the highest sensitivity and specificity when analyzing 310 SARS-CoV-2 infected and 866 uninfected individuals. Simultaneously we see high IgG responses against hCoVs throughout all samples, whereas no consistent cross reactive IgG response patterns can be defined. In summary, our CoVi-plex is highly suited to monitor vaccination studies and will facilitate epidemiologic screenings for the humoral immunity toward pandemic as well as endemic coronaviruses.
Subject(s)
Severe Acute Respiratory SyndromeABSTRACT
Background: Elucidating the role of T cell responses in COVID-19 is of utmost importance to understand the clearance of SARS-CoV-2 infection. Methods: 90 individuals were enrolled in this study, 30 hospitalized COVID-19 patients and 60 age- and gender-matched healthy controls (HC). Using two comprehensive 11-color flow cytometric panels conforming to Good Laboratory Practice (GLP) and approved for clinical diagnostics, we longitudinally examined cell count differences in lymphocyte populations and T cell activation in COVID-19 patients. Findings: Absolute numbers of lymphocyte subsets were differentially decreased in COVID-19 patients according to clinical severity. In severe disease (SD) patients, all lymphocyte subsets were reduced, whilst in mild disease (MD) NK, NKT and {gamma}{delta} T cells were at the level of HC. Additionally, we provide evidence of T cell activation in MD but not SD, when compared to HC. Interestingly, follow up samples revealed a marked increase in effector T cells and memory subsets in convalescing but not in non-convalescing patients. Interpretation: Our data suggest that activation and expansion of innate and adaptive lymphocytes play a major role in COVID-19. Additionally, recovery is associated with formation of T cell memory as suggested by the missing formation of effector and central memory T cells in SD but not in MD. Our data imply that the presence of SARS-CoV-2 responsive T cells contributes to convalescence in MD. Thus, understanding the T cell-response in the context of clinical severity might serve as foundation to overcome the lack of effective anti-viral immune response in severely affected COVID-19 patients and can offer prognostic value as biomarker for disease outcome and control.