TRB sequences targeting ORF1a/b are associated with disease severity in hospitalized COVID-19 patients

Abstract

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.

SARS-CoV-2 Spatiotemporal Genomic and Molecular Analysis of the First Wave of the COVID-19 Pandemic in Macaé, the Brazilian Capital of Oil

“…Tracking SARS-CoV-2 mutations is recognized worldwide as an important strategy for predicting infective patterns by viral-host canonical disturbances [ 34 , 35 , 36 ]. To correlate the physiological dynamics of the COVID-19 disease and its viral genetic mutations, SARS-CoV-2 genomes derived from Macaé patients were classified by severity.…”

“…Until May 2022, we did not find any reports in the literature regarding the identification or functional aspects of mutation orf1a:A1352V, which occurs in a region of the genome that is responsible for the production of non-structural proteins (NSPs). These proteins are reported as important players in SARS-CoV-2’s biology, with roles in viral transcription, replication, proteolytic processing, inhibition of host immune responses, and suppression of host gene expression [ 34 ]. The association observed for samples that carry this mutation with a higher mortality frequency suggests a possible link between these two variables and a potential increase in severity.…”

Whole Sequencing and Detailed Analysis of SARS-CoV-2 Genomes in Southeast Spain: Identification of Recurrent Mutations in the 20E (EU1) Variant with Some Clinical Implications

“…Regarding local surveillance programs, another important aspect should also be the confrontation between the genomic data and the clinical features of COVID-19. The information provided by full-length genome sequences of SARS-CoV-2 from COVID-19 patients not only helps to detect any new genetic variants but also might have important epidemiological and clinical implications, as it allows aspects about the evolution of the virus and the effect of identified mutations in the disease severity to be elucidated [ 11 , 12 ].…”