RESUMEN
The potential protective or pathogenic role of the adaptive immune response to SARS-CoV-2 infection has been vigorously debated. While COVID-19 patients consistently generate a T lymphocyte response to SARS-CoV-2 antigens, evidence of significant immune dysregulation in these patients continues to accumulate. In this study, next generation sequencing of the T cell receptor beta chain (TRB) repertoire was conducted in hospitalized COVID-19 patients to determine if immunogenetic differences of the TRB repertoire contribute to disease course severity. Clustering of highly similar TRB CDR3 amino acid sequences across COVID-19 patients yielded 781 shared TRB sequences. The TRB sequences were then filtered for known associations with common diseases such as EBV and CMV. The remaining sequences were cross-referenced to a publicly accessible dataset that mapped COVID-19 specific TCRs to the SARS-CoV-2 genome. We identified 158 SARS-CoV-2 specific TRB sequences belonging to 134 clusters in our COVID-19 patients. Next, we investigated 113 SARS-CoV-2 specific clusters binding only one peptide target in relation to disease course. Distinct skewing of SARS-CoV-2 specific TRB sequences toward the nonstructural proteins (NSPs) encoded within ORF1a/b of the SARS-CoV-2 genome was observed in clusters associated with critical disease course when compared to COVID-19 clusters associated with a severe disease course. These data imply that T-lymphocyte reactivity towards peptides from NSPs of SARS-CoV-2 may not constitute an effective adaptive immune response and thus may negatively affect disease severity.
Asunto(s)
COVID-19/inmunología , COVID-19/patología , Hospitalización , Receptores de Antígenos de Linfocitos T alfa-beta/inmunología , Índice de Severidad de la Enfermedad , Proteínas Virales/inmunología , Anciano , Secuencia de Aminoácidos , COVID-19/virología , Regiones Determinantes de Complementariedad/inmunología , Genoma Viral , Humanos , Poliproteínas/química , Poliproteínas/inmunología , Poliproteínas/metabolismo , SARS-CoV-2/genética , Factores de Tiempo , Proteínas Virales/química , Proteínas Virales/metabolismoRESUMEN
COVID-19 differs substantially between individuals, ranging from mild to severe or even fatal. Heterogeneity in the immune response against SARS-COV-2 likely contributes to this. Therefore, we explored the temporal dynamics of key cellular and soluble mediators of innate and adaptive immune activation in relation to COVID-19 severity and progression. Forty-four patients with a PCR-proven diagnosis of COVID-19 were included. Extensive cellular (leukocytes and T-lymphocyte subsets) and serological immune profiling (cytokines, soluble cell surface molecules, and SARS-CoV-2 antibodies) was performed at hospital admission and every 3-4 days during hospitalization. Measurements and disease outcome were compared between patients with an unfavorable (IC admission and/or death) and favorable (all others) outcome. Patients with an unfavorable outcome had higher leukocyte numbers at baseline, mostly due to increased neutrophils, whereas lymphocyte and monocyte numbers were reduced. CRP, IL-6, CCL2, CXCL10, and GM-CSF levels were higher at baseline in the unfavorable group, whereas IL-7 levels were lower. SARS-CoV-2 antibodies were more frequently absent in the unfavorable group. Longitudinal analysis revealed delayed kinetics of activated CD4 and CD8 T-lymphocyte subsets in the unfavorable group. Furthermore, whereas CRP, IL-6, CXCL10, and GM-CSF declined in the favorable group, these cytokines declined with delayed kinetics, remained increased, or even increased further in the unfavorable group. Our data indicate a state of increased innate immune activation in COVID19-patients with an unfavorable outcome at hospital admission, which remained over time, as compared with patients with a favorable outcome.