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

The study titled “Long COVID manifests with T cell dysregulation, inflammation, and an uncoordinated adaptive immune response to SARS-CoV-2” by Kailin Yin and colleagues, aimed to understand the underlying mechanisms of Long COVID (LC)​​.

Here’s a detailed summary:

Study Overview

  • Objective: The research focused on deciphering the pathophysiology of post-acute sequelae of SARS-CoV-2 infection (PASC), particularly Long COVID (LC). LC affects at least 10% of COVID-19 recoverees and is characterized by unexplained, debilitating symptoms​​.
  • Methodology: The team employed multiple “omics” approaches, including CyTOF for deep T cell phenotyping, RNAseq/scRNAseq, and high-dimensional plasma proteomics. They analyzed blood samples from 27 LC and 16 non-LC individuals from the Long-term Impact of Infection with Novel Coronavirus (LIINC) cohort, 8 months post-infection​​.

Key Findings

  1. T Cell Dysregulation: Among total CD4+ T cells in LC patients, central memory T cells (Tcm), T follicular helper cells (Tfh), and regulatory T cells (Treg) were significantly elevated. No significant differences were found in the SARS-CoV-2-specific CD4+ T cells and in CD8+ T cell subsets between LC and non-LC groups​​.
  2. Checkpoint Molecules in CD8+ T Cells: SARS-CoV-2-specific CD8+ T cells in LC individuals showed elevated levels of checkpoint/exhaustion markers PD1 and CTLA4, suggesting a possible persistent SARS-CoV-2 reservoir​​.
  3. Higher SARS-CoV-2 Antibody Levels in LC: LC patients had significantly higher SARS-CoV-2 RBD antibody levels. Interestingly, the highest antibody levels didn’t correspond to the highest frequencies of exhausted SARS-CoV-2-specific CD8+ T cells​​.
  4. Global Immune and Non-Immune Dysregulation: Two genes, OR7D2 and ALAS2, were found to be over-expressed in LC individuals, indicating broader immune and non-immune system alterations​​.
  5. Sex-Dimorphism in T Cell Phenotypes: The study observed sex-dimorphic differences in T cell phenotypes, with a subset of activated and cytotoxic T cells being more elevated in females with LC than in males​​.
  6. Pro-Inflammatory Signature in LC: LC patients exhibited a highly pro-inflammatory signature, with the elevation of genes like LGALS9 (Galectin 9), which is linked to cytokine release and disease severity during acute COVID-19​​.

Study Limitations

  • Sample Size and Cohort Representation: The study involved only 43 participants and focused on blood specimens. It’s acknowledged that the source of immune dysregulation might originate from tissues, and future studies might explore tissue-based mechanisms​​.

Conclusion The study underscores that LC is associated with an uncoordinated response between the humoral and cellular arms of adaptive immunity, as well as global immune dysregulation. This comprehensive analysis provides critical insights into the complex nature of LC and its underlying mechanisms.

Read More: https://www.biorxiv.org/content/10.1101/2023.02.09.527892v2.full

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