Severe COVID-19 infection triggers changes that affect gene expression in immune system stem cells, causing long-lasting alterations in the body’s immune response, according to a new study by Weill Cornell Medicine and Jackson Laboratory investigators. The finding could help explain symptoms of prolonged inflammation and “long COVID” in people who have had the disease.

The research team, led by Dr. Steven Josefowicz, an associate professor of pathology and laboratory medicine at Weill Cornell Medicine, and Dr. Duygu Ucar, an associate professor at Jackson Laboratory for Genomic Medicine, published the work Aug. 18 in Cell. For the study, the team developed a new technique to isolate and analyze rare stem cells found in human blood called CD34+ hematopoietic stem and progenitor cells.

Using such cells from patients who had recovered from severe COVID-19, they examined changes to the way the DNA was packaged and condensed, collectively known as the epigenetic landscape. These epigenetic alterations determine the probability or level that a gene will be turned on in both the stem cells and their offspring, which are mature immune cells. The investigators found that the patients’ stem cells acquired more accessible DNA, thereby permitting gene activation, especially at genes that drive inflammation and genes that determine whether the cells develop into inflammatory cell types. The mature immune cells that derived from these stem cells were also sensitized to future encounters with pathogens.

“All immune cells and all blood cells come from hematopoietic stem cells,” Dr. Josefowicz said. “We found that these stem cells can pass their epigenetic ‘memories’ on to their progeny immune cells, changing those cells’ inflammatory programs. So, when they see another pathogen, they respond in a different way than they would if they came from progenitor cells that hadn’t seen inflammation to the same extent.”

It is well known that exposure to a virus, such as SARS-CoV-2, causes adaptive immune cells to respond to fight the diseases (for example, by producing antibodies), and eventually form a "memory" of past infections, enabling them to recognize and fight future infections by the same virus faster and more effectively. But scientists are just beginning to understand immune memory in innate immune cells, a different group of cells that first respond to an infection, before antibody-producing cells are activated. The process is thought to occur through epigenetic changes to hematopoietic stem cells.

Research on hematopoietic stem cells, which are most abundant in bone marrow, has been limited by the costly and invasive techniques required to profile these cells. However, using their novel approach for isolating, enriching and studying hematopoietic stem cells circulating in the blood, the team demonstrated that these hematopoietic stem and progenitor cells—0.05 percent of all circulating peripheral blood mononuclear cells—capture the full cellular diversity of their bone marrow counterparts. This revelation opened the doors to study, at single cell resolution, how stem cells are affected upon infection and vaccination with a simple blood draw.

The team, including first author Dr. Jin-Gyu Cheong, a postdoctoral associate in the Josefowicz lab and recent graduate from the Weill Cornell Graduate School of Medical Sciences Immunology and Microbial Pathogenesis doctoral program, applied this technique to thoroughly characterize how severe COVID-19 infections affect the epigenetic state of human hematopoietic stem cells and implications of these changes for the future immune responses. They observed that the epigenetic changes persisted over time; although the patients had recovered months ago, their stem cells still carried the epigenetic “signatures” of the disease. 

In addition to looking at stem cells, the team also looked at monocytes, a type of white blood cell involved in the innate immune response that are newly minted every few days from stem cells. They found that these cells had different epigenetic programming up to one year after a severe COVID-19 infection. Alterations included changes that made these immune cells hyper-responsive to stimulation.

Next, the researchers took a closer look at the stem cells themselves. They found that after COVID-19 infection, these cells had changes to their programming that made them more likely to create myeloid-type blood cells, the first responders to infection.

“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,” Dr. 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.”

The researchers also looked at variables that could explain why some patients had more epigenetic changes than others. They found that COVID-19 patients who received a treatment to block IL6, a well-known inflammatory molecule, during acute disease, were less likely to have significant immune memory changes a year later. How IL6 and other factors present during an infection can program lasting changes in stem cells is an ongoing focus for the researchers.

Next, the researchers are interested in using this new platform to expand the study of hematopoietic stem cell changes, as they are much easier to access in the blood than from bone marrow. The work will help reveal how these important cells are impacted by a variety of diseases, as well as how they might be affected by therapies.

“Studying how hematopoietic stem cells respond in the context of human disease has been a bit of a black box because it’s so hard to access these cells in bone marrow,” said Dr. Josefowicz, who is also a member of the Drukier Institute for Children’s Health and the Sandra and Edward Meyer Cancer Center at Weill Cornell Medicine. “With this workflow to study plasticity of blood stem cells from a simple blood draw, it’s now game on.”

The research described in this story was supported by the National Institutes of Health through the National Institute of Allergy and Infectious Diseases under award numbers R01AI148416, U19AI144301, R01AI148416-S1, R01AI148416-S2, U01AI165452, R01AI142086, R01AI132447, and R01AI161444; the National Institute of General Medical Sciences under award number RM1GM139738; and the National Cancer Institute under award number R25CA233208. Additional support was provided by WCM WCG-COVID-19 and the Burroughs Wellcome Fund's Investigator in the Pathogenesis of Infectious Disease award.

The content of this story is solely the responsibility of the author and does not necessarily represent the official views of the National Institutes of Health.