Long COVID manifests with T cell dysregulation, inflammation, and an uncoordinated adaptive immune response to SARS-CoV-2 2023 Yin et al

[Andy]

Abstract

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.

https://www.biorxiv.org/content/10.1101/2023.02.09.527892v1

 

[SNT Gatchaman]

Same authors as Long-term SARS-CoV-2-specific immune & inflammatory responses in individuals recovering from COVID-19 with & without post-acute symptoms (2021, Cell Reports)

 

[SNT Gatchaman]

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. This finding is consistent with observations that about half of individuals with LC with no detectable SARS-CoV-2 antibodies have detectable SARS-CoV- 2-specific T cell responses. That improper crosstalk between T and B cells may be involved in the etiology of LC is also supported by our RNAseq data, which showed that a cluster of genes including both immunoglobulin synthesis and T cell function were co-upregulated in those without LC, but not in individuals with LC.

 

[SNT Gatchaman]

See also Divergent adaptive immune responses define two types of Long COVID (2023) —

However, detailed examination of immune responses within groups showed instances of poorly correlated cellular and humoral responses among seronegative long COVID patients.

 

[SNT Gatchaman]

Preprint recently updated to v2, so possibly this is the version to be published.

Haven't re-read, but the abstract adds the following sentence: "RNAseq/scRNAseq and Olink analyses similarly revealed immune dysregulatory mechanisms, along with non-immune associated perturbations, in individuals with LC."

 

[Hutan]

I'm finding it hard to make much sense out of findings around levels of SARS-CoV 2 antibodies. I think we've seen papers claiming, higher, lower and no different in people with Long Covid.

Within this paper we have higher levels

They also harbored significantly higher levels of SARS-CoV-2 antibodies,

But, at the same time, there were enough people with Long Covid and no SARS-Cov-2 antibodies that 'about half' of them consituted a big enough sample to draw some conclusions from.

This finding is consistent with observations that about half of individuals with LC with no detectable SARS-CoV-2 antibodies have detectable SARS-CoV- 2-specific T cell responses.

I don't think the level of SARS-CoV-2 antibodies is the answer to the LC question.

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.

Some of that may be a clue though. I think we've seen these so-called 'exhausted CD8+ T cells' reported in other papers.

 

[EndME]

Now published as the Letter Long COVID manifests with T cell dysregulation, inflammation and an uncoordinated adaptive immune response to SARS-CoV-2 in Nature Immonology.

Haven't seen if there's new data compared to the preprints, but the reviewers wanted quite a few changes so perhaps there's something interesting that previously wasn't part of the data (according to the reviewers the following data was added:"confirmatory FACS experiments, scRNAseq evaluation of a subset of study participants as well as adjusted and expanded data analyses resulting in a substantial increase of supplementary figures") https://static-content.springer.com/esm/art:10.1038/s41590-023-01724-6/MediaObjects/41590_2023_1724_MOESM3_ESM.pdf.