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Machine learning assisted analysis on TCR profiling data from COVID-19-convalescent and healthy individuals unveils cross-reactivity between SARS-CoV-2 and a wide spectrum of pathogens and other diseases

During the last two years, the emergence of SARS-CoV-2 has led to millions of deaths worldwide, with a devastating socio-economic impact on a global scale. The scientific community's focus has recently shifted towards the association of the T cell immunological repertoire with COVID-19 progression and severity, by utilising T cell receptor sequencing (TCR-Seq) assays. The Multiplexed Identification of T cell Receptor Antigen (MIRA) dataset, which is a subset of the immunoACCESS study, provides thousands of TCRs that can specifically recognize SARS-CoV-2 epitopes. Our study proposes a novel Machine Learning (ML) assisted approach for analysing TCR-Seq data from the antigens' point of view, with the ability to accurately distinguish between COVID-19-convalescent and healthy individuals in the case of MIRA dataset. Most SARS-CoV-2 antigens were found to exhibit equal levels of recognition by MIRA TCRs in both convalescent and healthy cohorts, leading to the assumption of putative cross-reactivity between SARS-CoV-2 and other infectious agents. This hypothesis was validated by combining MIRA with other public TCR profiling repositories that host assays and sequencing data concerning a plethora of pathogens. Our study provides evidence regarding the cross-reactivity between SARS-CoV-2 and a wide spectrum of pathogens and diseases, with M. tuberculosis and Influenza virus exhibiting the highest levels of cross-reactivity. These results can potentially shift the emphasis of immunological studies towards an increased application of TCR profiling assays that have the potential to uncover key mechanisms of cell-mediated immune response against pathogens and diseases.