Kuze, Y. | Search bioRxiv

bioRxiv2026

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

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.

microbiology↗

bioRxiv2024

Giant extrachromosomal element "Inocle" potentially expands the adaptive capacity of the human oral microbiome

Survival strategy of bacteria is expanded by extrachromosomal elements (ECEs). However, their genetic diversity and functional roles for adaptability are largely unknown. Here, we discovered a novel family of intracellular ECEs using 56 saliva samples by developing an efficient microbial DNA extraction method coupled with long-read metagenomics assembly. Even though this ECE family was not hitherto unidentified, our global prevalence analysis using 476 salivary metagenomic datasets elucidated that these ECEs reside in 74% of the population. These ECEs, which we named, "Inocles", are giant plasmid-like circular genomic elements of 395 kb in length, having Streptococcus as a host bacterium. Inocles encode a series of genes that contribute to intracellular stress tolerance, such as oxidative stress and DNA damage, and cell wall biosynthesis and modification involved in the interactions with oral epithelial cells. Moreover, Inocles exhibited significant positive correlations with immune cells and proteins responding to microbial infection in peripheral blood. Intriguingly, we examined and found their marked reductions among 68 patients of head and neck cancers and colorectal cancers, suggesting its potential usage for a novel biomarker of gastrointestinal cancers. Our results suggest that Inocles potentially boost the adaptive capacity of host bacteria against various stressors in the oral environment.

genomics↗