Epigenetic memory of coronavirus infection in innate immune cells and their progenitors, 2023, Cheong et al.

[SNT Gatchaman]

Epigenetic memory of coronavirus infection in innate immune cells and their progenitors
Jin-Gyu Cheong; Arjun Ravishankar; Siddhartha Sharma; Christopher N. Parkhurst; Simon A. Grassmann; Claire K. Wingert; Paoline Laurent; Sai Ma; Lucinda Paddock; Isabella C. Miranda; Emin Onur Karakaslar; Djamel Nehar-Belaid; Asa Thibodeau; Michael J. Bale; Vinay K. Kartha; Jim K. Yee; Minh Y. Mays; Chenyang Jiang; Andrew W. Daman; Alexia Martinez de Paz; Dughan Ahimovic; Victor Ramos; Alexander Lercher; Erik Nielsen; Sergio Alvarez-Mulett; Ling Zheng; Andrew Earl; Alisha Yallowitz; Lexi Robbins; Elyse LaFond; Karissa L. Weidman; Sabrina Racine-Brzostek; He S. Yang; David R. Price; Louise Leyre; André F. Rendeiro; Hiranmayi Ravichandran; Junbum Kim; Alain C. Borczuk; Charles M. Rice; R. Brad Jones; Edward J. Schenck; Robert J. Kaner; Amy Chadburn; Zhen Zhao; Virginia Pascual; Olivier Elemento; Robert E. Schwartz; Jason D. Buenrostro; Rachel E. Niec; Franck J. Barrat; Lindsay Lief; Joseph C. Sun; Duygu Ucar; Steven Z. Josefowicz

Inflammation can trigger lasting phenotypes in immune and non-immune cells. Whether and how human infections and associated inflammation can form innate immune memory in hematopoietic stem and progenitor cells (HSPC) has remained unclear.

We found that circulating HSPC, enriched from peripheral blood, captured the diversity of bone marrow HSPC, enabling investigation of their epigenomic reprogramming following coronavirus disease 2019 (COVID-19). Alterations in innate immune phenotypes and epigenetic programs of HSPC persisted for months to 1 year following severe COVID-19 and were associated with distinct transcription factor (TF) activities, altered regulation of inflammatory programs, and durable increases in myelopoiesis. HSPC epigenomic alterations were conveyed, through differentiation, to progeny innate immune cells. Early activity of IL-6 contributed to these persistent phenotypes in human COVID-19 and a mouse coronavirus infection model.

Epigenetic reprogramming of HSPC may underlie altered immune function following infection and be broadly relevant, especially for millions of COVID-19 survivors.

Link | PDF (Cell) paywall

 

[SNT Gatchaman]

See earlier threads —

Monocyte migration profiles define disease severity in acute COVID-19 and unique features of long COVID (2023)
Transcriptional reprogramming from innate immune functions to a pro-thrombotic signature by monocytes in COVID-19 (2022)

For some related open access articles, see also —

Epigenetic and transcriptomic reprogramming in monocytes of severe COVID-19 patients reflects alterations in myeloid differentiation and the influence of inflammatory cytokines (2022, Genome Medicine)
Monocyte and haematopoietic progenitor reprogramming as common mechanism underlying chronic inflammatory and cardiovascular diseases (2018, European Heart Journal)

 

[Andy]

NIH news release about this study, https://www.nih.gov/news-events/new...y-lead-long-term-innate-immune-system-changes

 

[SNT Gatchaman]

• BMMC = bone marrow mononuclear cells
• GMP = granulocyte-monocyte progenitors
• HSPC = hematopoietic stem and progenitor cells
• PBMC = peripheral blood mononuclear cells

Recent studies have established that innate immune cells and their progenitors can maintain durable epigenetic memory of prior infection or inflammation, altering innate immune equilibrium and responses to subsequent challenges.

Selected abbreviated quotes from the discussion (re-ordered) —

Circulating HSPC analysis: An approach to studying HSPC in a post-COVID-19 cohort

We performed deep characterization of HSPC in a human cohort by enriching rare circulating CD34 + HSPC from PBMC and pairing this with snRNA/ATAC-seq analysis. Paired blood and BMMC samples from the same donors confirmed that rare circulating CD34 + HSPC accurately capture the diversity and major transcriptomic and epigenomic signatures of BM HSPC subsets.

Our approach provides a valuable resource for characterizing the effects of diverse challenges and diseases on human HSPC without invasive BM biopsy collection.

This has implications for understanding dynamic blood cell development and innate immune memory in inflammatory disease, vaccine responses, vaccine design, and non-genetic variance in immune responses to infection.

Persistence of HSPC alterations and molecular phenotypes post-COVID-19

HSPC are long-lived self-renewing precursors to diverse immune cells and have unique potential to store inflammationinduced epigenetic memory, impacting hematopoiesis and progeny innate immune cell phenotypes

We considered that acute viral infections, particularly SARS-CoV-2 causing severe COVID-19 and systemic inflammation, could trigger such a response.

We uncovered linked and persistent epigenetic and transcriptional reprogramming of HSPC and monocytes in convalescent COVID-19 patients up to 1-year post-infection.

Epigenetic poising of inflammatory genes, shared between HSPC and short-lived monocyte progeny correlated with monocyte hyper-responsiveness to stimulation. IL-6R signaling during acute infection contributed to durable epigenetic phenotypes in HSPC and monocytes.

Our study demonstrates lasting HSPC alterations and epigenetic phenotypes following COVID-19.

Implications for post-infection pathology and recovery

Our study indicates persisting post-infection transcriptional and epigenetic programs in monocytes (and their progenitors) associated with activation, differentiation, migration, and antigen presentation. These programs may contribute to ongoing pathology in tissues with inflammation and activated vasculature.

Incomplete recovery after infections or critical illness, including post-ICU syndrome (PICS), lacks clear etiology. These data suggest that hematopoietic reprogramming, including skewed myelopoiesis and epigenetic poising of inflammatory genes, may contribute to persistent myeloid-driven tissue pathology post-infection.

IL-6 regulates post-infection phenotypes

Our data uncovered activation of the IL-6R signaling pathway as a potential mediator of durably altered hematopoiesis and innate immune memory. IL-6, a pleiotropic cytokine, activates immune cells, promotes cytokine secretion and cell recruitment, and the maintenance and differentiation of HSPC.

Additionally, IL-6 plays beneficial functions in epithelial repair, as a myokine and metabolic regulator, and affects appetite and visceral adipose regulation

In severe cases of COVID-19, elevated IL-6 levels correlate with tissue damage, immune cell recruitment/activation, and acute respiratory distress syndrome (ARDS). 85 IL-6R blocking antibodies in critically ill patients with COVID-19 modestly improve outcomes.

Surprisingly, IL-6R blockade during acute infection strongly influenced GMP levels up to 1-year post-infection

One durable molecular signature of IL-6R signaling during acute infection was sustained chromatin accessibility at STAT3 motifs in both HSPC and monocytes/macrophages.

Commenting

Although our study focused on blood cells, other cell types also harbor inflammatory epigenetic memory. It is likely that the HSPC and blood cell phenotypes described here interact extensively with tissue-resident cells, which may also change in frequency, differentiation programs, and activity within tissue communication circuits. These interactions may have an enduring influence on tissue defense or pathology.

 

[SNT Gatchaman]

Comment in Long-COVID-19: the persisting imprint of SARS-CoV-2 infections on the innate immune system (2023, Nature Signal Transduction and Targeted Therapy) —

Given that monocytes have a lifespan of a single day, the discovery of persistent epigenetic changes is notable and may reflect altered hematopoiesis and inheritance of epigenetic states from hematopoietic stem and progenitor cells (HSPC).

A clear correlation of GMP variability was found to treatment with Tocilizumab, an antibody that blocks the interleukin 6 receptor (anti-IL6R). To demonstrate causal involvement of IL6 in the epigenetic reprogramming of HSPCs the authors turned to a mouse infection model, which reproduced the specific and persisting upregulation of GMP and the monocyte lineage after viral clearance.

The revelation that IL-6 induces epigenetic reprogramming of human immune stem cells, which changes the composition and response characteristics of circulating monocytes, is an important step towards understanding the etiology of PASC.

 

[SNT Gatchaman]

Comment in Hematopoietic memory of severe COVID-19 infection (2023, Nature Cell Research) —

Certain infections and vaccines induce long-term epigenetic and metabolic rewiring in innate immune cells and their progenitors, resulting in increased responsiveness to heterologous stimuli, a process termed innate immune memory or trained immunity. While innate immune memory is beneficial to improve host defense against infections, inappropriate induction of trained immunity has also been associated with inflammatory diseases and complications. The elegant study of Cheong and colleagues now provides evidence that similar epigenetic changes in HSPCs underpin innate immune memory in individuals recovering from COVID-19.

The authors applied cutting-edge single-cell technology to HSPCs and monocytes isolated from severe COVID-19 patients that have recovered for up to 1 year. First, the authors reported that severe COVID-19 triggered persistent changes in the epigenetic landscape of circulating monocytes.

the authors argue that IL-6R signaling during the acute phase of the disease contributes to the epigenetic reprogramming of HSPCs. Patients treated with IL-6R blocker during acute infection exhibited dampened HSPC skewing towards myelopoiesis after recovery when compared to untreated recovered patients.

it describes for the first time persistent epigenetic and transcriptional reprogramming of HSPCs after a human infection, which has the potential to open a new field of research in the long-term complications of infections.

 

[SNT Gatchaman]

I've posted a review article for trained innate immunity in Defining trained immunity and its role in health and disease (2020, Nature Reviews Immunology)