We try to keep exciting research findings in our epigenetic “family,” and a recent article now reports that our stem and immune cells are not so different when it comes to their epigenetic memory of SARS-CoV-2 infection! A new study now describes how SARS-CoV-2-mediated epigenetic reprogramming in hematopoietic stem and progenitor cells (HSPCs) severely impacts the function of their immune cell “progeny” in severe cases of COVID-19.
COVID-19 can involve long-term complications that influence subsequent immune responses, but by what mechanism? We knew that inflammation epigenetically reprograms HSPCs to negatively impact their differentiated progeny and that COVID-19 induces long-lasting chromatin accessibility alterations in immune cells. Now, a study led by Duygu Ucar (Jackson Laboratory for Genomic Medicine) and Steven Z. Josefowicz (Weill Cornell Medicine) uses single-cell transcriptomics and chromatin accessibility assays to show that HSPCs keep the epigenetic memory of SARS-CoV-2 infection “in the family,” which passes on altered immune functions to their progeny.
Let’s hear more from Cheong and colleagues on how HPSCs keep SARS-CoV-2 in the family thanks to epigenetic memory:
- Persistent epigenetic /transcriptional reprogramming occurs in HSPCs/immune cell progeny in COVID-19 patients
- SARs-CoV-2 infection induces hematopoietic reprogramming, including increases in the frequency of immune cell progenitors/immune cell progenitor signatures present in other stem/progenitor cell populations
- Epigenetic poising of inflammatory genes in HSPCs/immune cell progeny after SARs-CoV-2 infection correlates with altered immune responses, such as immune cell hyper-responsiveness to stimulation
- Epigenetic alterations in HSPCs become passed on to their innate immune cell progeny through differentiation
- SARs-CoV-2-induced transcriptional and epigenetic alterations in HPSCs prompt inflammatory, migratory, and differentiating immune cell phenotypes, which may contribute to ongoing pathology in inflamed tissues
- Virally-infected mice display prolonged immune cell infiltration in the brain and lung, suggesting that the epigenetic changes observed in COVID-19 patients augment inflammatory responses post-infection
- Activation of the IL-6R signaling pathway represents a potential mediator of SARs-CoV-2-induced effects
- Sustained increases in chromatin accessibility at STAT3 motifs in HSPCs/immune cell progeny represent a durable molecular signature of IL-6R signaling during acute infection
- STAT3 can establish and maintain epigenetic memory of inflammation in epidermal stem cells via increased chromatin accessibility at binding motifs for myelopoietic transcription factors
- However, IL-6R blockade during acute SARS-CoV-2 infection strongly reduces the level of post-infection HSPCs and immune cell progeny with inflammatory programs in human patients and mice
- Sustained increases in chromatin accessibility at STAT3 motifs in HSPCs/immune cell progeny represent a durable molecular signature of IL-6R signaling during acute infection
These findings suggest that the altered immune functions observed in severe COVID-19 cases can come from stem cells that keep SARS-CoV-2 infection “in the family” and pass down the epigenetic memory underlying the loss of immune function to their differentiated progeny. Furthermore, identifying IL-6 as a family-busting “interloper” supports the development of therapeutics that may inhibit these enduring epigenetic memories.
“It is fascinating that COVID-19 can induce such robust epigenetic changes in stem and progenitor cells as well as in their progeny mature innate immune cells, which can last for months and can reshape the innate immune responses to future immune threats,” Duygu Ucar said. “Understanding epigenetic memory associated with infections can be a way for us to understand how certain diseases like COVID-19 have such long-lasting health consequences. Furthermore, it provides us an opportunity to assess immune status at the epigenetic level upon infections and even upon vaccination.”
For more on how HSPCs keep it in the family after SARS-CoV-2 infections via epigenetic memory, see Cell, August 2023.