Calmodulin controls the tempo of HSV-1 gene-expression cascade to reshape infection heterogeneity

Maruzuru, Y.; Kuze, Y.; Seki, M.; Kanai, A.; Liu, S.; Kato, A.; Suzuki, Y.; Kawaguchi, Y.

doi:10.64898/2026.06.02.729706

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bioRxiv · 10.64898/2026.06.02.729706

Calmodulin controls the tempo of HSV-1 gene-expression cascade to reshape infection heterogeneity

Maruzuru, Y.·Kuze, Y.·Seki, M.·Kanai, A.·Liu, S.·Kato, A.·Suzuki, Y.·Kawaguchi, Y.

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Abstract

Viral replication exhibits substantial heterogeneity among individual cells. Although temporally ordered gene-expression cascades are thought to contribute to such heterogeneity in DNA viruses, whether and how their tempo is regulated, and how cell-to-cell variability shapes population-level infection outcomes, remain unknown. Here, we developed a high-throughput live-cell imaging platform to track HSV-1 gene-expression dynamics in individual cells and, in combination with single-cell RNA sequencing, identified calmodulin (CaM) as a host regulator of HSV-1 gene-expression tempo. CaM accelerates progression from immediate-early to early and late phases at the single-cell level by advancing their onset. By increasing the fraction of virus-producing cells without altering burst size, CaM reshapes the distribution of infection outcomes, thereby promoting population-level viral replication. Pharmacological inhibition of CaM protects mice from lethal infection, exceeding acyclovir. These findings establish CaM-mediated temporal control as a key determinant of population-level viral output and a regulator of infection heterogeneity.

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Maruzuru, Y., Kuze, Y., Seki, M., Kanai, A., Liu, S., Kato, A., Suzuki, Y., Kawaguchi, Y.. 2026-06-03. Calmodulin controls the tempo of HSV-1 gene-expression cascade to reshape infection heterogeneity. https://doi.org/10.64898/2026.06.02.729706

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