Single-cell multiomics reveals epigenetic rewiring of splenic memory B cells during murine malaria reinfection

Coronado, M.; Vincelle-Nieto, A.; Azcarate, I. G.; Perez-Benavente, S.; Puyet, A.; Diez, A.; Bautista, J. M.; Reyes-Palomares, A.

doi:10.64898/2025.12.10.693423

bioRxiv · 10.64898/2025.12.10.693423

Single-cell multiomics reveals epigenetic rewiring of splenic memory B cells during murine malaria reinfection

Coronado, M.·Vincelle-Nieto, A.·Azcarate, I. G.·Perez-Benavente, S.·Puyet, A.·Diez, A.·Bautista, J. M.·Reyes-Palomares, A.

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Abstract

Malaria induces slow, gradually acquired, non-sterilizing immunity whose cellular and regulatory underpinnings remain incompletely understood. Here, we combine a sequential Plasmodium yoelii 17XNL infection model in BALB/c mice, in which primary parasitemia resolves spontaneously and confers robust protection upon homologous reinfection, with single-cell RNA and chromatin accessibility profiling to dissect how primary infection and recall reshape splenic immunity, with a focus on B cells. We generate a multiomic atlas of >50,000 splenic mononuclear cells, resolving thirteen major immune lineages and 48 subpopulations, and show that B cells dominate the response and diversify into naive/mature, germinal center, memory, and plasmablast compartments. Trajectory analysis reveals distinct differentiation paths towards germinal center, memory, and mature B cells, and uncovers infection-dependent shifts in transcription factor activity, cis-regulatory element usage, and gene regulatory networks. Reinfection is associated with a shift in memory B-cell composition and transcriptional programs towards extrafollicular-like, IgM- conventional memory B cells together with epigenetic modules linked to rapid antibody production. Together, these data provide a systems-level view of B cell plasticity in experimental malaria and provides a mechanistic framework from a highly protective P. yoelii reinfection model with implications for understanding non-sterilizing immunity in endemic settings.

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Coronado, M., Vincelle-Nieto, A., Azcarate, I. G., Perez-Benavente, S., Puyet, A., Diez, A., Bautista, J. M., Reyes-Palomares, A.. 2025-12-12. Single-cell multiomics reveals epigenetic rewiring of splenic memory B cells during murine malaria reinfection. https://doi.org/10.64898/2025.12.10.693423

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