Rotavirus Calcium Dysregulation Manifests as Dynamic Calcium Signaling in the Cytoplasm and Endoplasmic Reticulum
Year: 2019
Type: article
Abstract: Like many viruses, rotavirus (RV) dysregulates calcium homeostasis by elevating cytosolic calcium ([Ca 2+ ]cyt) and decreasing endoplasmic reticulum (ER) stores. While an overall, monophasic increase in [Ca 2+ ]cyt during RV infection has been shown, the nature of the RV-induced aberrant calcium signals and how they manifest over time at the single-cell level have not been characterized. Thus, we generated cell lines and human intestinal enteroids (HIEs) stably expressing cytosolic and/or ER-targeted genetically-encoded calcium indicators to characterize calcium signaling throughout RV infection by time-lapse imaging. We found that RV induces highly dynamic [Ca 2+ ]cyt signaling that manifest as hundreds of discrete [Ca 2+ ]cyt spikes, which increase during peak infection. Knockdown of nonstructural protein 4 (NSP4) attenuates the [Ca 2+ ]cyt spikes, consistent with its role in dysregulating calcium homeostasis. RV-induced [Ca 2+ ]cyt spikes were primarily from ER calcium release and were attenuated by inhibiting the store-operated calcium entry (SOCE) channel Orai1. RV-infected HIEs also exhibited prominent [Ca 2+ ]cyt spikes that were attenuated by inhibiting SOCE, underlining the relevance of these [Ca 2+ ]cyt spikes to gastrointestinal physiology and role of SOCE in RV pathophysiology. Thus, our discovery that RV increases [Ca 2+ ]cyt by dynamic calcium signaling, establishes a new, paradigm-shifting understanding of the spatial and temporal complexity of virus-induced calcium signaling.
Source: Scientific Reports
Language: English
Subfield: Infectious Diseases
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $1,790
Funders: U.S. Department of Health and Human Services, Cancer Prevention and Research Institute of Texas, John S. Dunn Gulf Coast Consortium for Chemical Genomics, National Institutes of Health, National Cancer Institute, National Institute of General Medical Sciences, National Institute of Allergy and Infectious Diseases, National Institute of Diabetes and Digestive and Kidney Diseases, National Center for Research Resources
Awards: G1523030235, G1927715600, Regulation of secretory diarrhea by ER-PM junction signaling, BD Biosciences Special Order LSRII, Regulation of Enteric Virus Secretory Diarrhea, G274084553, G2859315832, G3102002109, Enteric Virus Calcium Channel Inhibitors, G4446559736, The Combinatorial Drug Discovery Program (CDDP), G4819929959, G5139064906, G5313339769, Training Program in Cell and Molecular Biology, G5715578560, G5843987319, Genetic Engineering of the rotavirus genome through a fully recombinant reverse gene, G5979933414, Rotavirus Vaccines Engineered as Vectors Against Other Enteric Diseases, GCC Center for Advanced Microscopy and Image Informatics, G7514240623, Advanced Multiparameter Cytometry and Cell Sorting Core, G7837447426, G8153776008, G8413015676, G9000013585, G9000032296, G9000240210, Enteric virus exploitation of calcium signaling, Regulation of Rotavirus Replication, Texas Medical Center Digestive Diseases Center, Baylor College of Medicine Cancer Center - Cancer Center Support Grant, Human Biomimetics for Mucosal Infections
OpenAlex ID: W2963608494