Researchers at the Monash University Biomedicine Discovery Institute have identified a previously unknown type of immune system memory B cell (MBC) that can cause poor antibody responses in chronic viral infections. The team used techniques including single-cell ATAC sequencing (scATAC-seq) and single-cell RNA sequencing (scRNA-seq) to defined discrete subsets of B cells that arose during chronic or acute lymphocytic choriomeningitis virus (LCMV) infection in mice. Their research identified a memory B cell subset generated during chronic infection that does not produce high levels of antibody.

The findings, the researchers suggest, may lead to new approaches to earlier intervention and possibly even the prevention of some types of viral infections such as HIV or hepatitis.

“Revealing this new immune memory cell type, and what genes it expresses, allows us to determine how we can target it therapeutically and whether that will lead to better antibody responses,” said research co-lead Lucy Cooper, PhD, who is first author of the team’s published paper in Immunity. Added co-lead Kim Good-Jacobson, PhD “What we discovered was a previously unknown cell that is produced by chronic viral infection. We also determined that early intervention with therapeutics was the most effective to stop this type of memory cell being formed, whereas late intervention could not.”

Cooper, Good-Jacobson and colleagues reported on their findings in a paper in Immunity, titled “Type I interferons induce an epigenetically distinct memory B cell subset in chronic viral infection.”

Memory B cells are key providers of long-lived immunity against infectious diseases, and drive antibody-mediated responses when the body is reinfected with a familiar virus, enabling rapid clearance of the infection, the authors explained. A “fundamental pillar of immunity is immune memory, consisting of antigen-experienced cells with increased capabilities to persist and rapidly reactivate upon reinfection,” they wrote.

However, MBCs do not produce effective protection in cases of chronic viral infection. “… chronic viral infections such as HIV, hepatitis C, and cytomegalovirus can disrupt MBC development and antibody production, leading to incomplete and ineffective immune protection,” the team stated. Yet the reasons for this weaker capacity of MBCs to protect against persistent infections is one of the remaining mysteries of the human immune system. “How chronic viral infection disrupts MBC development and whether such changes are reversible remain unknown.”

Studies in mice by the Monash University Biomedicine Discovery Institute team provided answers to this mystery, with the discovery of how chronic viral infection induces a previously unknown type of B cell. “Through single-cell (sc)ATAC-seq and scRNA-seq during acute versus chronic lymphocytic choriomeningitis viral infection, we identified a memory subset enriched for interferon (IFN)-stimulated genes (ISGs) during chronic infection that was distinct from the T-bet+ subset normally associated with chronic infection,” they wrote. “Collectively, these experiments provide critical insights into how changes in IFN dynamics during early viral infection can redirect MBC development in addition to IFN-mediated effects on viral persistence and severity of disease.”

Importantly, the research team also determined the most effective time during the immune response for therapeutics such as anti-viral and anti-cancer drugs to better boost immune memory cell development. “Our research demonstrates that antigen-specific B cell subset distribution during infection is underpinned by distinct epigenetic states and that it is possible to remodel MBCs to promote or repress certain subsets,” they stated. “Given that epigenetic factors can be targeted in vivo, such as with small-molecule inhibitors, these findings portend the development of ways to therapeutically target MBCs.”

Cooper commented, “In the future, this research may result in new therapeutic targets, with the aim to reduce the devastating effect of chronic infectious diseases on global health, specifically those that are not currently preventable by vaccines.”

The research team is also looking to see whether this population of B cells might also be a feature of long COVID, which results in some people having a reduced capacity to fight off the symptoms of COVID infection long after the virus has dissipated.

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