Explore the immune memory mechanism of people who have recovered from the new crown

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The COVID-19 pandemic, caused by the coronavirus (SARS-CoV-2), is now in its third year, with serious
implications for global health.
To date, effective vaccines are still considered one of the most viable strategies to end the
pandemic.

However, we still know very little
about the long-term effects of COVID infection on the body's immune system.
How long is the vaccine protection period? What kind of immune protection mechanism is behind it? Why do different individuals have different severity of symptoms after being infected with the new crown? Therefore, we need to gain a deeper understanding of the innate and adaptive immune responses of individuals recovering from coronavirus infection, especially whether they have established immune memory
.

The new coronavirus
attacked by antibodies.
CREDIT: CHRISTOPH BURGSTEDT/SCIENCE PHOTO LIBRARY/GETTY

In June 2021, Professor Pengyuan Yang of the Institute of Biophysics, Chinese Academy of Sciences, Professor Mark M.
Davis of Stanford University and Dr.
Liang Chen (now a professor at Shanghai University) published a ^study1 in Nature Cell Biology, in which they used single-cell sequencing technology to delineate the multidimensional map of chromatin accessible to peripheral immune cells of recovered patients, and elucidated the epigenetic mechanism behind the formation of immune memory in recovered immune cells
。

Some pathogenic infections can strengthen our innate immune system
.
Infection stimulates immune system regulators to "train" innate immune cells (such as macrophages or other antigen-presenting cells) to exhibit immune memory characteristics similar to adaptive immune cells; When the immune system is reactivated, they produce an enhanced, nonspecific immune response, often driven
by epigenetic modifications and metabolism.
Part of the vaccine's protective effect stems from this "trained immunity.
"
In response to this, the researchers first explored the immune memory mechanism
of B cells and T cells of new crown survivors.
These lymphocytes and the immune responses they participate in modulating often play an important role in the long-term protection inspired by viral infections and ^vaccination2
.

The research team matched six healthy individuals who were not infected (five of whom were collected from this study and one whose data came from a public database) and ten individuals
who recovered from moderate or severe coronavirus infection 4-12 weeks after recovery.
Through single-cell chromatin open sequencing technology (scATAC-seq), the researchers found that lymphocytes of new crown survivors underwent a large number of chromatin remodeling (chromatin remodelling) compared to healthy individuals, which means that the gene regulation of these "cell legions" has been altered
by new crown virus infection.

The results of the analysis of the development trajectory of B cell lineage showed that transcription factor (TF) modulators, which were originally responsible for maintaining homeostasis of B cells, could promote B cell activation, differentiation and IgG class conversion in new crown survivors, so that immature B cells accelerated the development into antibody-secreting plasma cells
.

The researchers also developed a new single-cell multiomics technique: Ti-ATAC-seq
.
It can simultaneously obtain accessible chromatin information, T cell receptor (TCR) sequence, and protein surface molecule expression levels for each T cell at the single-cell level
.
Using this technique, they found that the number of coronavirus-specific CD8⁺ T cells increased
significantly in recovered people.
The epigenomes of these cells also exhibit characteristics
that promote effector or memory cell differentiation.

At the same time, another group of immune cells, bone marrow biome cells (including monocytes, granulocytes, red blood cells and platelets), also changed
due to the new crown infection.
The authors found that the peripheral blood of the new crown recovered patients contained a large number of CD16+ monocytes and CD14⁺ monocytes, which not only showed a trained and activated apparent state, but also enriched their chromosomal accessibility on transcription factor motifs such as TBET and IRF1, IL1B recombinant protein and chemokine genes.
They are closely related
to the differentiation and maturation of immune cells and the establishment of trained immunity, respectively.

In this study, the authors used cutting-edge single-cell ATAC-seq and single-cell multi-omics Ti-ATAC-seq technologies to depict the transcriptome module, transcription factor level regulatory map of new crown survivors, and the overall reconstruction of chromatin accessibility of B cells, T cells, and monocytes, indicating that immune memory and immune training have been established in new crown patients
.

In a commentary on the study published in Nature Cell Biology at the same ^time,3 it wrote, "This study is the first to describe important regulatory nodes of immune memory in adaptive immunity and opens the door to a whole new field of research on the
long-term immune effects of novel coronavirus infection.
" The commentary also pointed out that this study also provides a reference for in-depth study of the efficacy, effectiveness and protection of new crown vaccines, allowing us to move closer to a long-term effective vaccine
.

References:

1.
You, M.
, Chen, L.
, Zhang, D.
 et al.
 Single-cell epigenomic landscape of peripheral immune cells reveals establishment of trained immunity in individuals convalescing from COVID-19.
 Nat Cell Biol 23, 620–630 (2021).
https://doi.
org/10.
1038/s41556-021-00690-1

2.
Mulligan, M.
J.
, Lyke, K.
E.
, Kitchin, N.
 et al.
 Phase I/II study of COVID-19 RNA vaccine BNT162b1 in adults.
 Nature 586, 589–593 (2020).
https://doi.
org/10.
1038/s41586-020-2639-4

3.
Netea, M.
G.
, Li, Y.
Immune memory in individuals with COVID-19.
Nat Cell Biol 23, 582–584 (2021).
https://doi.
org/10.
1038/s41556-021-00689-8

© nature

Nature Cell Biology|doi:10.
1038/s41556-021-00690-1