tetano
Editor, Senior Moderator
Cell Commun Signal
. 2025 Aug 2;23(1):361.
doi: 10.1186/s12964-025-02357-y. The crucial role of intercellular calcium wave propagation triggered by influenza A virus in promoting infection
Fumiya Kozawa[SUP] 1 [/SUP], Tomokazu Tamura[SUP] 2 3 4 5 [/SUP], Naoki Takahashi[SUP] 1 [/SUP], Taishi Kakizuka[SUP] 6 7 [/SUP], Taro Ichimura[SUP] 7 [/SUP], Rumi Shimada[SUP] 1 [/SUP], Yasuyuki Hashimoto[SUP] 1 [/SUP], Hironoshin Onizuska[SUP] 1 [/SUP], Sayaka Kashiwagi[SUP] 1 8 [/SUP], Tomoko Kamasaki[SUP] 1 8 [/SUP], Maho Amano[SUP] 1 [/SUP], Takeharu Nagai[SUP] 6 7 9 [/SUP], Takasuke Fukuhara[SUP] 2 8 3 4 5 [/SUP], Yoichiro Fujioka[SUP] 10 11 [/SUP], Yusuke Ohba[SUP] 12 13 [/SUP]
Affiliations
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 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.
Methods: 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.
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 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.
Conclusions: Intercellular calcium signaling plays a crucial role in the early expansion and establishment of IAV infection, presenting a potential target for IAV prophylaxis.
Keywords: Calcium imaging; Influenza A virus; Intercellular calcium wave propagation; P2Y1 antagonist.
. 2025 Aug 2;23(1):361.
doi: 10.1186/s12964-025-02357-y. The crucial role of intercellular calcium wave propagation triggered by influenza A virus in promoting infection
Fumiya Kozawa[SUP] 1 [/SUP], Tomokazu Tamura[SUP] 2 3 4 5 [/SUP], Naoki Takahashi[SUP] 1 [/SUP], Taishi Kakizuka[SUP] 6 7 [/SUP], Taro Ichimura[SUP] 7 [/SUP], Rumi Shimada[SUP] 1 [/SUP], Yasuyuki Hashimoto[SUP] 1 [/SUP], Hironoshin Onizuska[SUP] 1 [/SUP], Sayaka Kashiwagi[SUP] 1 8 [/SUP], Tomoko Kamasaki[SUP] 1 8 [/SUP], Maho Amano[SUP] 1 [/SUP], Takeharu Nagai[SUP] 6 7 9 [/SUP], Takasuke Fukuhara[SUP] 2 8 3 4 5 [/SUP], Yoichiro Fujioka[SUP] 10 11 [/SUP], Yusuke Ohba[SUP] 12 13 [/SUP]
Affiliations
- PMID: 40753252
- PMCID: PMC12317542
- DOI: 10.1186/s12964-025-02357-y
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 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.
Methods: 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.
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 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.
Conclusions: Intercellular calcium signaling plays a crucial role in the early expansion and establishment of IAV infection, presenting a potential target for IAV prophylaxis.
Keywords: Calcium imaging; Influenza A virus; Intercellular calcium wave propagation; P2Y1 antagonist.