Gebert J Thomas, Scribano Francesca J, Engevik Kristen A, Huleatt Ethan M, Eledge Michael R, Dorn Lauren E, Philip Asha A, Kawagishi Takahiro, Greenberg Harry B, Patton John T, Hyser Joseph M
Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, TX 77030, USA.
Alkek Center for Metagenomics & Microbiome Research, Baylor College of Medicine, Houston, TX 77030, USA.
Sci Adv. 2025 Jan 17;11(3):eadq8115. doi: 10.1126/sciadv.adq8115.
Viruses engage in a variety of processes to subvert host defenses and create an environment amenable to replication. Here, using rotavirus as a prototype, we show that calcium conductance out of the endoplasmic reticulum by the virus encoded ion channel, , induces intercellular calcium waves that extend beyond the infected cell and contribute to pathogenesis. Viruses that lack the ability to induce this signaling show diminished viral shedding and attenuated disease in a mouse model of rotavirus diarrhea. This implicates nonstructural protein 4 (NSP4) as a virulence factor and provides mechanistic insight into its mode of action. Critically, this signaling induces a transcriptional signature characteristic of interferon-independent innate immune activation, which is not observed in response to a mutant NSP4 that does not conduct calcium. This implicates calcium dysregulation as a means of pathogen recognition, a theme broadly applicable to calcium-altering pathogens beyond rotavirus.
病毒会参与多种过程来颠覆宿主防御机制，并创造一个有利于其复制的环境。在此，我们以轮状病毒为原型，证明病毒编码的离子通道从内质网向外的钙传导会诱导细胞间钙波，这种钙波会延伸至受感染细胞之外并促进发病机制。在轮状病毒腹泻小鼠模型中，缺乏诱导这种信号传导能力的病毒显示出病毒脱落减少和疾病减轻。这表明非结构蛋白4（NSP4）是一种毒力因子，并为其作用模式提供了机制性见解。至关重要的是，这种信号传导会诱导出独立于干扰素的先天免疫激活的转录特征，而对不传导钙的突变型NSP4的反应中未观察到这种特征。这表明钙失调是一种病原体识别方式，这一主题广泛适用于轮状病毒以外的改变钙的病原体。
