New Study By Cornell University Shows SARS-CoV-2 Causes Epigenetic Changes To Innate Immune Cells and Their Progenitors, Contributing To Long COVID!
A new study lead by researchers from Weill Cornell Medicine-New York that also involved scientists and experts from University of Connecticut Health Center, Broad Institute of MIT and Harvard, Harvard University, Harvey Mudd College, Boston Children's Hospital and the Rockefeller University shows that the that SARS-CoV-2 causes epigenetic changes to innate immune cells and their progenitors! Such changes could also be contributing to the various condition seen in long COVID
The COVID-19 disease is characterized by systemic inflammation and can result in protracted symptoms. Robust systemic inflammation may trigger persistent changes in hematopoietic cells and innate immune memory through epigenetic mechanisms.
The study findings reveal that rare circulating hematopoietic stem and progenitor cells (HSPC), enriched from human blood, match the diversity of HSPC in bone marrow, enabling investigation of hematopoiesis and HSPC epigenomics.
It was found that following COVID-19, HSPC retain epigenomic alterations that are conveyed, through differentiation, to progeny innate immune cells.
The epigenomic changes vary with disease severity, persist for months to a year, and are associated with increased myeloid cell differentiation and inflammatory or antiviral programs. Epigenetic reprogramming of HSPC may underly altered immune function following infection and be broadly relevant, especially for millions of COVID-19 survivors and contribute to long COVID.
The study findings were published on a preprint server and are currently being peer reviewed. https://www.biorxiv.org/content/10.1101/2022.02.09.479588v1
This new fascinating study may provide a partial explanation for the long-term immunologic phenomena associated with COVID-19, caused by infections with the SARS-CoV-2 coronavirus.
It has been noted that during acute COVID-19, there are flu-like symptoms, along with respiratory features which may eventually progress to involve multiple other organs. With severe disease, prolonged fever, high levels of inflammatory signaling molecules, complement activation and tissue damage occur. This is mediated by delayed adaptive responses with high innate immune cell activity.
Interestingly in many COVID-19 survivors, symptoms are often reported to persist after the initial infection, but vary widely from person to person. These include post-acute sequelae of COVID-19 (PASC) as well as COVID-19-associated multisystem inflammatory syndrome in adults (MIS-A) and children (MIS-C).
To date the underlying basis of these post-COVID-19 syndromes is unknown, but it could be due to persistent immune changes, that could also cause alterations in the individual’s response to other pathogens or vaccines.
The study team proposes that one interesting possibility is the induction of long-term epigenetic changes in the innate immune cells and their progenitors, which cause alterations of baseline and responsive innate immunity, both progenitor and mature cells. These changes maintain an immunologic memory of the encounter with an infectious or pro-inflammatory agent and are cumulatively termed trained innate immuni
Typically, epigenetic changes of this sort involve alterations in chromatin that cause adaptive changes in the type of cell response and the breadth of such responses.
The cells that undergo such alterations may be long-lived innate immune cells, epithelial stem cells or hematopoietic progenitors, or the differentiated cells resulting from these precursors.
Animal studies involving murine models have shown that hematopoietic stem and progenitor cells (HSPC) are also involved in such durable epigenetic reprogramming. The result is that their progeny cells carry the memory of the inflammation-inducing agent and therefore show a different phenotype, also called central trained immunity. https://pubmed.ncbi.nlm.nih.gov/32132681/
Hematopoietic stem and progenitor cells or HSPCs are long-lived precursors of many immune cells, with self-renewing properties. This makes them unique in their capacity to harbor the epigenetic memory of inflammation and the reprogrammed DNA that leads to the expression of a different blood cell profile and different cell phenotypes in the mature innate immune cells.
Hence, the study team sought to investigate whether this was happening with respect to HSPCs exposed to COVID-19-associated inflammation.
The study covered the period from 2-12 months after the onset of a COVID-19 infection, either mild or severe.
Single-cell studies of monocytes and their HSPC progenitors were carried out, utilizing a novel process to enrich rare circulating HSPCs. Called Peripheral Blood Mononuclear Cell analysis with Progenitor Input Enrichment (PBMC-PIE), it provides superior access to HSPCs without requiring the painful and potentially complicated procedure of bone marrow aspiration.
Together with PBMC-PIE, the study team used single-nuclei combined RNA-sequencing (RNA-seq) and assay for transposase-accessible chromatin (snRNA/ATAC-seq), to achieve high-resolution maps of the chromatin-accessible cells among many different HSPCs and PBMCs, and their transcriptomic profile.
Utilizing PBMC-PIE, the study team isolated and annotated approximately 30,000 HSPCs, showing that the rare circulating HSPCs do reflect the variety of HSPCs found in bone marrow.
Interestingly, the shift in the frequency and populations was most conspicuous for hematopoietic stem cells and multipotent progenitors (HSC/MPP). This appeared to be a broad activation response to inflammation, in order to renew the supply of white blood cells and respond effectively to the stimulus, and agreed with the active inflammatory response seen in early convalescence following severe COVID-19.
It was found that the neutrophil progenitors were also raised, in response to high plasma cytokines and acute-phase proteins, but this was seen even in late convalescence, perhaps because of the epigenetic reprogramming of the HSPCs.
Importantly, this was supported by the finding of differentially expressed genes (DEGs) in both mild and severe convalescent COVID-19 patients. They also found two major anti-inflammatory genes were downregulated in HSPCs and their progeny, which could potentially trigger hyperinflammatory responses.
DORC or Domains of Regulatory Chromatin were also examined, and almost a thousand were identified.
The most prominent of these included those linked to monocyte differentiation factor CEBPA, found in CD14+ monocytes than in HSC/MPP. The DORC study component revealed its ability to mirror the direction of differentiation of different lineages and the linked marker genes.
The study team further found that the ratio of chromatin binding by the two factors IRF/AP-1 result in either antiviral or pro-inflammatory responses after infection. The negative regulation of AP-1 and the persistence of IRF are apparently the drivers of the epigenetic memory response in this infection.
The study findings showed persistent epigenetic and transcriptional changes in HSPCs and monocytes after severe COVID-19. These changes result in an altered innate immune response, including inflammation and the differentiation of neutrophils and various monocyte phenotypes.
The study team found that after a severe bout of COVID-19, monocytes demonstrated a reprogramming in both the HSPC progenitors and their monocyte progeny, lasting for months, with active antiviral programs driven by interferon regulatory factor/signal transducer and activator of transcription (IRF/STAT) pathways.
Interestingly, the changes in plasma cytokines, complement, and vascular response factors persisted for months, but eventually subsided by 4-12 months.
Significantly, this indicates a complete resolution of the active inflammation, while cellular composition and phenotypic changes continued to persist and also indicates the presence of epigenetic mechanisms.
The usage of PBMC-PIE paired with combined snRNA/ATAC analysis allowed the HSPCs to be studied in detail along with the progeny cells. This covered chromatin alterations, gene expression, and differentiation trajectories. The combined results suggest that COVID-19, especially when severe, causes epigenetic changes in HSPCs that can last up to 12 months.
The unique technique also showed that bone marrow white cell production in severe COVID-19 underwent persistent alterations, favoring monocyte and neutrophil precursor HSPC production even at 4-12 months. While mild COVID-19 activates antiviral programs, severe COVID-19 induces inflammation, both persisting into convalescence but eventually resolving.
Inside progenitor cells, inflammatory signaling leads to epigenetic memory that persists in self-renewing stem cells, and also is transmitted into differentiated progeny cell phenotypes. This could mean that central trained immunity is established after influenza and other viral infections.
Importantly, the associated inflammatory response triggered by the activation of cytokines, chemokines, complement, and other vascular risk factors, along with tissue-migratory and persistently activated monocytes may explain PASC, especially the ongoing inflammatory changes and fibrosis of the lung and upper respiratory mucosa.
Also, altered and increased patterns of neutrophil production induced by epigenetic changes also favor inflammation.
Significantly, one standout finding of the study is the identification of months-long altered monocyte programs following severe, but also mild, SARS-CoV-2 infection, suggesting monocytes may also contribute to chronic inflammation, either in affected tissues, via migratory and chemoattractant programs, or systemically. These epigenetic programs underlie distinct CD14+ monocyte phenotypes with variable persistence depending on disease severity. Unlike mild post-COVID-19 interferon programming, the HSPC and monocyte programs following severe COVID-19 are complex, with individual cells bearing mixed inflammatory and interferon signatures and reduced expression of key negative feedback factors DUSP1 and NFKBIA.
The study findings showed that mild (non-hospitalized) COVID-19 can result in a months-long epigenetic and transcriptional program, characterized by prominent IRF transcription factor activity and interferon-stimulated gene (ISG) expression (e.g., ISG15, MX1, MX2, IFI44L, IFI44, OAS3, AOAH, and PARP14).
However, in contrast, CD14+ monocytes of patients recovering from severe disease (2-4 months post-acute, following discharge from the ICU) feature epigenetic and transcriptional signatures of inflammation likely mediated by NFkB and AP-1 TFs
. This active inflammatory CD14+ monocyte program resolves in late convalescence (4-12 months), though a distinct epigenetic monocyte phenotype persists, including increased chromatin accessibility at certain chemokines (e.g., CCL2, CCL7, CCL24), chemokine receptors (e.g., CCR1, CCR3, CCRL2), ISG (e.g., IFI6, SOC3, OASL), and inflammatory genes (e.g., IL8, caspases, S100A genes).
Many other cell types also undergo epigenetic changes that may persist, manifesting in altered cell frequency, differentiation trajectories and phenotypes, while also retaining epigenetic antiviral inflammatory memory that affects future responses to infection or inflammatory agents.
This highlights the importance of further research to better understand functional changes in the post-COVID-19 immune system and the clinical implications of these prolonged epigenetic signatures of severe COVID-19 in HPSCs and their progeny
The study team concluded, “While our study focuses on blood cells, it is important to point out that diverse other cell types have been demonstrated to harbor epigenetic memory. Particularly when they reside in affected tissues, these cells may change in their frequencies, differentiation programs, and phenotypes, and also retain epigenetic memory of anti-viral inflammation with important and enduring influence on tissue defense or sequelae. Here, we present evidence of central trained immunity, in the form of epigenetic reprogramming in HSPC, in humans following viral infection and severe illness. Importantly, enrichment of rare circulating progenitor cells using PBMC-PIE was a critical advance enabling evaluation of hematopoietic stem and progenitor cells together with their progeny immune cells from peripheral blood samples. Extending this approach to diverse tissues (particularly those with resident stem and progenitor cells, e.g., intestinal epithelium) and disorders (hematologic disease, malignancy, inflammation, and infection) can unveil epigenetic and progenitor-based mechanisms of pathogenesis and inform therapeutic strategies and targets.”
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