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US study looks at how Covid alters the immune system

Scientists have reported that innate immune cells – a critical part of the immune system activated to battle Covid-19 – remain unchanged for at least a year after infection, suggesting that these may play a role in some of the symptoms linked to long Covid.

One thing the Covid pandemic has done is make us all more familiar with some of the important players in the immune system, reports TIME.

Antibodies, B cells and T cells are among the best known parts of the body’s response to a virus like SARS-CoV-2, but they don’t act alone. The innate immune system is the body’s first line of defence, made up of general pathogen-fighting cells that recognise and fight off all various pathogens, including bacteria, viruses, fungi and parasites in a non-specific way. (B cells and T cells, in contrast, are more customised to remember and recognise specific pathogens, and only those pathogens.)

Steven Josefowicz, an associate professor of pathology and laboratory medicine at Weill Cornell Medical College, and his colleagues, found, however, that even innate immune cells retain some memory of fighting SARS-CoV-2 after a severe infection.

This recall, and the response it generates, can last for at least a year after infection.

Their paper, published in Cell, has important implications for understanding how the immune system – even the less bespoke parts that aren’t targeting specific bacteria or viruses – is changed by infections. Understanding these alterations could also shed light on why some people continue to experience long-term symptoms after encountering SARS-CoV-2, says Josefowicz.

He and his team focused on the parent cells of innate immune cells–stem cells in the bone marrow that continuously replenish the supply of these immune cells. Since most of these stem cells live in the bone marrow, the easiest way to access them is through a bone marrow aspiration, a painful and invasive procedure in which doctors puncture a portion of the hip bone to reach the marrow.

A small number of these stem cells, however, circulate in the blood, and Josefowicz conducted studies to not only extract and enrich their numbers from blood samples, but to confirm they represent the same stem cells found in the marrow.

That allowed him to study these cells from patients who were admitted to the ICU with severe Covid-19 infections by collecting their blood, rather than obtaining bone marrow biopsies.

By analysing those stem cells, what was clear is that the immune system is fundamentally changed after a severe infection like Covid-19, he says.

These cells contain genetic changes that alter which genes they express, skewing them toward generating more inflammatory factors. The change lasts for at least a year after a severe Covod-19 infection, which is how long Josefowicz studied cells from a few dozen patients.

Since these stem cells are responsible for producing more copies of innate immune cells, the changes in the genes they express are carried over to the new generations of cells they make.

When he studied the cells in a dish, Josefowicz found they were capable of producing higher levels of inflammatory factors and are more likely to migrate – which, in a human body, means they can spread their inflammatory effects to other tissues.

In animal models, these hyper responsive cells preferentially gravitate toward the lungs, brain, and heart, some of the organs most heavily affected by long Covid.

The higher levels of inflammatory factors may be a response to the intense effect of a severe SARS-CoV-2 infection.

“Severe Covid-19 could look to the immune system like the beginning of a chronic infection,” says Josefowicz, “and since the immune system is having trouble clearing this particular pathogen, it’s pulling out all the stops to give itself a better chance of dealing with the virus.”

Whether this memory of Covid-19 is contributing to long Covid isn’t clear yet, but the research could inspire additional studies to better understand how viruses like SARS-CoV-2 affect the immune system, both in the short and long term.

“This is the beginning of a very long story that will hopefully open up our understanding of how viral infections, and in particular Covid-19, are different from a cold,” says Dr Lindsay Lief, director of the medical ICU and post ICU recovery clinic at Weill Cornell New York Presbyterian Hospital and one of the co-authors of the paper.

“We need to understand how infections change the immune system to impact not just what symptoms you experience, but how you respond to your next infection or your next vaccination.”

The pandemic provided the scientists with a unique opportunity to study how the immune system changes in response to a virus, since so many people were infected at the same time, and there were no vaccines to confound the immune response.

All of the blood samples came from participants who were admitted to the ICU in 2020 with severe Covid-19 infections, before vaccines were available.

Because their health records during their ICU stay were available, the researchers could look at any treatments they were given, and found a potentially useful clue about one intervention that could mitigate how much the immune system was altered.

People who received drugs to block IL6, which causes inflammation and increases in response to an infection, seemed to show lower levels of innate immune cells that were prone to producing inflammatory factors.

While the drug did not have much effect in improving severe Covid-19 symptoms while in the ICU, the study suggests it might have suppressed some of the gene expression changes in the innate immune stem cells.

That in turn could reduce the chances of long Covid-like symptoms from developing, although more studies are needed to confirm that theory.

“What we hope is that others will use our approaches to link these types of changes to different clinical outcomes and disease states,” says Josefowicz.

“Since these blood cells are more plastic than most people presumed they would be, it offers the therapeutic possibility of returning them toward a healthier state (after an infection).”

Study details

Epigenetic memory of coronavirus infection in innate immune cells and their progenitors

Jin-Gyu Cheong, Arjun Ravishankar, Siddhartha Sharma, Joseph Sun, Duygu Ucar, Steven Josefowicz.

Published in Cell on 18 August 2023

• Severe Covid-19 programmes durable epigenetic changes and hyper-activation in monocytes
• Circulating HSPC capture post-COVID-19 changes in haematopoiesis and stem cell programs
• Post-Covid-19 HSPC convey epigenetic and transcriptional memory to mature progeny cells
• IL-6 contributes to epigenetic reprogramming of mouse and human HSPC and myeloid cells


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.


Cell article – Epigenetic memory of coronavirus infection in innate immune cells and their progenitors (Open access)


TIME article – How Covid-19 Changes the Immune System (Open access)


See more from MedicalBrief archives:


Why some people don’t get sick from Covid-19 – US study


Surge of 300 COVID variants with increased immune escape properties


One in every eight adults likely infected with long Covid, large study finds


T-cells from common colds cross-protect against COVID – Imperial College London



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