biostudies-literatureCooper LVictorian Cancer AgencyNIAID NIH HHSNational Health and Medical Research CouncilNational Institutes of HealthAustralian Research Council1037-1055.e6https://www.ebi.ac.uk/biostudies/studies/S-EPMC11096045biostudies-literatureUnknown57(5)Memory B cells (MBCs) are key providers of long-lived immunity against infectious disease, yet in chronic viral infection, they do not produce effective protection. How chronic viral infection disrupts MBC development and whether such changes are reversible remain unknown. 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. Blockade of IFNAR-1 early in infection transformed the chromatin landscape of chronic MBCs, decreasing accessibility at ISG-inducing transcription factor binding motifs and inducing phenotypic changes in the dominating MBC subset, with a decrease in the ISG subset and an increase in CD11c⁺CD80⁺ cells. However, timing was critical, with MBCs resistant to intervention at 4 weeks post-infection. Together, our research identifies a key mechanism to instruct MBC identity during viral infection.ImmunityType I interferons induce an epigenetically distinct memory B cell subset in chronic viral infection.PMC11096045R01 AI148471Cooper LUtzschneider DTScharer CDPolmear JKirn ASzeto CTaylor JJXu HBroomfield BJGras SMartelotto LLa Gruta NPang ESGroom JRO'Keeffe MKealy LGago da Graca CParish IAJackson KJLNguyen AGood-Jacobson KLGupta MfalseType I interferons induce an epigenetically distinct memory B cell subset in chronic viral infection.Memory B cells (MBCs) are key providers of long-lived immunity against infectious disease, yet in chronic viral infection, they do not produce effective protection. How chronic viral infection disrupts MBC development and whether such changes are reversible remain unknown. 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. Blockade of IFNAR-1 early in infection transformed the chromatin landscape of chronic MBCs, decreasing accessibility at ISG-inducing transcription factor binding motifs and inducing phenotypic changes in the dominating MBC subset, with a decrease in the ISG subset and an increase in CD11c⁺CD80⁺ cells. However, timing was critical, with MBCs resistant to intervention at 4 weeks post-infection. Together, our research identifies a key mechanism to instruct MBC identity during viral infection.2024-01-01T00:00:00Z2024 May2026-06-01T05:56:47.843Z2026-04-08T09:42:12.509ZS-EPMC110960453859379610.1016/j.immuni.2024.03.016