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Long COVID manifests with T cell dysregulation, inflammation, and an uncoordinated adaptive immune response to SARS-CoV-2
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bioRxiv posts many COVID19-related papers. A reminder: they have not been formally peer-reviewed and should not guide health-related behavior or be reported in the press as conclusive.
Feb 2023
our datasets taken together point to not only a dysregulated but also a highly pro-inflammatory signature in LC, consistent with prior data suggesting elevated and persistent inflammation in LC 22,29,48-50
Long COVID (LC), a type of post-acute sequelae of SARS-CoV-2 infection (PASC), occurs after at least 10% of SARS-CoV-2 infections, yet its etiology remains poorly understood. Here, we used multiple omics assays (CyTOF, RNAseq, Olink) and serology to deeply characterize both global and SARS-CoV-2-specific immunity from blood of individuals with clear LC and non-LC clinical trajectories, 8 months following infection and prior to receipt of any SARS-CoV-2 vaccine. Our analysis focused on deep phenotyping of T cells, which play important roles in immunity against SARS-CoV-2 yet may also contribute to COVID-19 pathogenesis.
Our findings demonstrate that individuals with LC exhibit systemic inflammation and immune dysregulation.
This is evidenced by global differences in T cell subset distribution in ways that imply ongoing immune responses, as well as by sex-specific perturbations in cytolytic subsets. Individuals with LC harbored increased frequencies of CD4+ T cells poised to migrate to inflamed tissues, and exhausted SARS-CoV-2-specific CD8+ T cells.
They also harbored significantly higher levels of SARS-CoV-2 antibodies, and in contrast to non-LC individuals, exhibited a mis-coordination between their SARS-CoV-2-specific T and B cell responses.
Collectively, our data suggest that proper crosstalk between the humoral and cellular arms of adaptive immunity has broken down in LC, and that this, perhaps in the context of persistent virus, leads to the immune dysregulation, inflammation, and clinical symptoms associated with this debilitating condition.
One aspect highly consistent between all studies to date is the ability to detect SARS- CoV-2-specific T cells in both LC and non-LC individuals, months after infection. This could simply be attributed to the long-term persistence of memory T cells elicited by SARS-CoV-2, but may also indicate the persistence of a long-lived tissue viral reservoir.
nirmatrelvir-ritonavir treatment as an antiviral strategy to clear this putative LC-associated SARS-CoV-2 reservoir is underway (NCT05576662, NCT05595369, NCT05668091). Future studies could evaluate other antivirals or monoclonal antibodies, and might consider incorporating checkpoint inhibition in conjunction with antivirals to reinvigorate T cells' ability to help eliminate residual viremia.
Our data revealed that, among females, a subset of activated and cytotoxic T cells was more elevated in LC than in non-LC individuals; intriguingly, the opposite pattern was observed in males.
Another intriguing observation we made about the SARS-CoV-2-specific CD4+ T cells from individuals with LC is their production of IL6 in response to spike peptide stimulation.
Most striking from our study was the finding that while fully recovered individuals exhibited coordinated humoral and cellular immune responses to SARS-CoV-2, this coordination was lost in the LC group.

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