{"title":"The crucial role of intercellular calcium wave propagation triggered by influenza A virus in promoting infection.","authors":"Fumiya Kozawa, Tomokazu Tamura, Naoki Takahashi, Taishi Kakizuka, Taro Ichimura, Rumi Shimada, Yasuyuki Hashimoto, Hironoshin Onizuska, Sayaka Kashiwagi, Tomoko Kamasaki, Maho Amano, Takeharu Nagai, Takasuke Fukuhara, Yoichiro Fujioka, Yusuke Ohba","doi":"10.1186/s12964-025-02357-y","DOIUrl":null,"url":null,"abstract":"<p><strong>Background: </strong>Influenza A viruses (IAVs) initially infect a few host cells before spreading to neighboring cells. However, the molecular mechanisms underlying this dissemination remain unclear. We have previously demonstrated that intracellular Ca<sup>2+</sup> plays a crucial role in facilitating IAV infection. This study aims to clarify the connections between intracellular Ca<sup>2+</sup> dynamics and spread of IAV infection.</p><p><strong>Methods: </strong>Madin-Darby canine kidney (MDCK) cells stably expressing a Ca<sup>2+</sup> indicator for optical imaging were established. Cells were cultured in Matrigel to form monolayers, and cell-to-cell Ca<sup>2+</sup> dynamics within IAV-infected cells were analyzed using fluorescence microscopy.</p><p><strong>Results: </strong>IAV infection upregulated the frequency of intercellular calcium wave propagations (iCWPs), facilitating viral spread. ADP released from initially infected cells mediated iCWPs via the P2Y<sub>1</sub> receptor. P2Y<sub>1</sub> antagonist suppressed both the generation of iCWPs and spread of viral infection. Enhanced endocytosis by the surrounding cells that received ADP signaling upregulated viral entry. Expression of IAV matrix protein 2 (M2) in initially infected cells triggered iCWPs through ADP diffusion, thereby increasing infection. Conversely, an ion permeability-deficient mutation of M2 or inhibition of its ion channel activity suppressed iCWPs.</p><p><strong>Conclusions: </strong>Intercellular calcium signaling plays a crucial role in the early expansion and establishment of IAV infection, presenting a potential target for IAV prophylaxis.</p>","PeriodicalId":55268,"journal":{"name":"Cell Communication and Signaling","volume":"23 1","pages":"361"},"PeriodicalIF":8.2000,"publicationDate":"2025-08-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12317542/pdf/","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Cell Communication and Signaling","FirstCategoryId":"99","ListUrlMain":"https://doi.org/10.1186/s12964-025-02357-y","RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"CELL BIOLOGY","Score":null,"Total":0}
引用次数: 0
Abstract
Background: Influenza A viruses (IAVs) initially infect a few host cells before spreading to neighboring cells. However, the molecular mechanisms underlying this dissemination remain unclear. We have previously demonstrated that intracellular Ca2+ plays a crucial role in facilitating IAV infection. This study aims to clarify the connections between intracellular Ca2+ dynamics and spread of IAV infection.
Methods: Madin-Darby canine kidney (MDCK) cells stably expressing a Ca2+ indicator for optical imaging were established. Cells were cultured in Matrigel to form monolayers, and cell-to-cell Ca2+ dynamics within IAV-infected cells were analyzed using fluorescence microscopy.
Results: IAV infection upregulated the frequency of intercellular calcium wave propagations (iCWPs), facilitating viral spread. ADP released from initially infected cells mediated iCWPs via the P2Y1 receptor. P2Y1 antagonist suppressed both the generation of iCWPs and spread of viral infection. Enhanced endocytosis by the surrounding cells that received ADP signaling upregulated viral entry. Expression of IAV matrix protein 2 (M2) in initially infected cells triggered iCWPs through ADP diffusion, thereby increasing infection. Conversely, an ion permeability-deficient mutation of M2 or inhibition of its ion channel activity suppressed iCWPs.
Conclusions: Intercellular calcium signaling plays a crucial role in the early expansion and establishment of IAV infection, presenting a potential target for IAV prophylaxis.
期刊介绍:
Cell Communication and Signaling (CCS) is a peer-reviewed, open-access scientific journal that focuses on cellular signaling pathways in both normal and pathological conditions. It publishes original research, reviews, and commentaries, welcoming studies that utilize molecular, morphological, biochemical, structural, and cell biology approaches. CCS also encourages interdisciplinary work and innovative models, including in silico, in vitro, and in vivo approaches, to facilitate investigations of cell signaling pathways, networks, and behavior.
Starting from January 2019, CCS is proud to announce its affiliation with the International Cell Death Society. The journal now encourages submissions covering all aspects of cell death, including apoptotic and non-apoptotic mechanisms, cell death in model systems, autophagy, clearance of dying cells, and the immunological and pathological consequences of dying cells in the tissue microenvironment.