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Influenza A virus enhances ciliary activity and mucociliary clearance via TLR3 in airway epithelium.
Respir Res. 2020 Oct 27; 21(1):282.RR

Abstract

BACKGROUND

Viral respiratory tract infections, such as influenza A virus (IAV), are common and life-threatening illnesses worldwide. The mechanisms by which viruses are removed from the respiratory tract are indispensable for airway host defense. Mucociliary clearance is an airway defense mechanism that removes pathogens from the respiratory tract. The coordination and modulation of the ciliary beating of airway epithelial cells play key roles in maintaining effective mucociliary clearance. However, the impact of respiratory virus infection on ciliary activity and mucociliary clearance remains unclear.

METHODS

Tracheal samples were taken from wild-type (WT) and Toll-like receptor 3 (TLR3)-knockout (KO) mice. Transient organ culture of murine trachea was performed in the presence or absence of IAV, polyI:C, a synthetic TLR3 ligand, and/or reagents. Subsequently, cilia-driven flow and ciliary motility were analyzed. To evaluate cilia-driven flow, red fluorescent beads were loaded into culture media and movements of the beads onto the tracheal surface were observed using a fluorescence microscope. To evaluate ciliary motility, cilia tips were labeled with Indian ink diluted with culture medium. The motility of ink-labeled cilia tips was recorded by high-speed cameras.

RESULTS

Short-term IAV infection significantly increased cilia-driven flow and ciliary beat frequency (CBF) compared with the control level in WT culture. Whereas IAV infection did not elicit any increases of cilia-driven flow and CBF in TLR3-KO culture, indicating that TLR3 was essential to elicit an increase of cilia-driven flow and CBF in response to IAV infection. TLR3 activation by polyI:C readily induced adenosine triphosphate (ATP) release from the trachea and increases of cilia-driven flow and CBF in WT culture, but not in TLR3-KO culture. Moreover, blockade of purinergic P2 receptors (P2Rs) signaling using P2R antagonist, suramin, suppressed polyI:C-mediated increases of cilia-driven flow and CBF, indicating that TLR3-mediated ciliary activation depended on released extracellular ATP and the autocrine ATP-P2R loop.

CONCLUSIONS

IAV infection readily increases ciliary activity and cilia-driven flow via TLR3 activation in the airway epithelium, thereby hastening mucociliary clearance and "sweeping" viruses from the airway as an initial host defense response. Mechanically, extracellular ATP release in response to TLR3 activation promotes ciliary activity through autocrine ATP-P2R loop.

Authors+Show Affiliations

Second Division, Department of Internal Medicine, Hamamatsu University School of Medicine, 1-20-1 Handayama, Higashi-ku, Hamamatsu, Shizuoka, 431-3192, Japan.Second Division, Department of Internal Medicine, Hamamatsu University School of Medicine, 1-20-1 Handayama, Higashi-ku, Hamamatsu, Shizuoka, 431-3192, Japan. fujisawa@hama-med.ac.jp.Second Division, Department of Internal Medicine, Hamamatsu University School of Medicine, 1-20-1 Handayama, Higashi-ku, Hamamatsu, Shizuoka, 431-3192, Japan.Second Division, Department of Internal Medicine, Hamamatsu University School of Medicine, 1-20-1 Handayama, Higashi-ku, Hamamatsu, Shizuoka, 431-3192, Japan.Second Division, Department of Internal Medicine, Hamamatsu University School of Medicine, 1-20-1 Handayama, Higashi-ku, Hamamatsu, Shizuoka, 431-3192, Japan.Second Division, Department of Internal Medicine, Hamamatsu University School of Medicine, 1-20-1 Handayama, Higashi-ku, Hamamatsu, Shizuoka, 431-3192, Japan.Second Division, Department of Internal Medicine, Hamamatsu University School of Medicine, 1-20-1 Handayama, Higashi-ku, Hamamatsu, Shizuoka, 431-3192, Japan.Second Division, Department of Internal Medicine, Hamamatsu University School of Medicine, 1-20-1 Handayama, Higashi-ku, Hamamatsu, Shizuoka, 431-3192, Japan.Second Division, Department of Internal Medicine, Hamamatsu University School of Medicine, 1-20-1 Handayama, Higashi-ku, Hamamatsu, Shizuoka, 431-3192, Japan.Second Division, Department of Internal Medicine, Hamamatsu University School of Medicine, 1-20-1 Handayama, Higashi-ku, Hamamatsu, Shizuoka, 431-3192, Japan.Second Division, Department of Internal Medicine, Hamamatsu University School of Medicine, 1-20-1 Handayama, Higashi-ku, Hamamatsu, Shizuoka, 431-3192, Japan. Department of Clinical Pharmacology and Therapeutics, Hamamatsu University School of Medicine, 1-20-1 Handayama, Higashi-ku, Hamamatsu, 431-3192, Japan.Department of Cellular and Molecular Anatomy and International Mass Imaging Center, Hamamatsu University School of Medicine, 1-20-1 Handayama, Higashi-ku, Hamamatsu, 431-3192, Japan.Department of Virology and Parasitology, Hamamatsu University School of Medicine, 1-20-1 Handayama, Higashi-ku, Hamamatsu, 431-3192, Japan.Department of Virology and Parasitology, Hamamatsu University School of Medicine, 1-20-1 Handayama, Higashi-ku, Hamamatsu, 431-3192, Japan.Department of Cellular and Molecular Anatomy and International Mass Imaging Center, Hamamatsu University School of Medicine, 1-20-1 Handayama, Higashi-ku, Hamamatsu, 431-3192, Japan. Department of Anatomy and Developmental Biology, Graduate School of Biomedical and Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minamiku, Hiroshima, 734-8553, Japan.Second Division, Department of Internal Medicine, Hamamatsu University School of Medicine, 1-20-1 Handayama, Higashi-ku, Hamamatsu, Shizuoka, 431-3192, Japan.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

33109186

Citation

Kamiya, Yosuke, et al. "Influenza a Virus Enhances Ciliary Activity and Mucociliary Clearance Via TLR3 in Airway Epithelium." Respiratory Research, vol. 21, no. 1, 2020, p. 282.
Kamiya Y, Fujisawa T, Katsumata M, et al. Influenza A virus enhances ciliary activity and mucociliary clearance via TLR3 in airway epithelium. Respir Res. 2020;21(1):282.
Kamiya, Y., Fujisawa, T., Katsumata, M., Yasui, H., Suzuki, Y., Karayama, M., Hozumi, H., Furuhashi, K., Enomoto, N., Nakamura, Y., Inui, N., Setou, M., Ito, M., Suzuki, T., Ikegami, K., & Suda, T. (2020). Influenza A virus enhances ciliary activity and mucociliary clearance via TLR3 in airway epithelium. Respiratory Research, 21(1), 282. https://doi.org/10.1186/s12931-020-01555-1
Kamiya Y, et al. Influenza a Virus Enhances Ciliary Activity and Mucociliary Clearance Via TLR3 in Airway Epithelium. Respir Res. 2020 Oct 27;21(1):282. PubMed PMID: 33109186.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Influenza A virus enhances ciliary activity and mucociliary clearance via TLR3 in airway epithelium. AU - Kamiya,Yosuke, AU - Fujisawa,Tomoyuki, AU - Katsumata,Mineo, AU - Yasui,Hideki, AU - Suzuki,Yuzo, AU - Karayama,Masato, AU - Hozumi,Hironao, AU - Furuhashi,Kazuki, AU - Enomoto,Noriyuki, AU - Nakamura,Yutaro, AU - Inui,Naoki, AU - Setou,Mitsutoshi, AU - Ito,Masahiko, AU - Suzuki,Tetsuro, AU - Ikegami,Koji, AU - Suda,Takafumi, Y1 - 2020/10/27/ PY - 2020/07/30/received PY - 2020/10/21/accepted PY - 2020/10/28/entrez PY - 2020/10/29/pubmed PY - 2020/10/29/medline KW - Airway epithelium KW - Ciliary activity KW - Influenza A virus KW - Mucociliary clearance KW - TLR3 SP - 282 EP - 282 JF - Respiratory research JO - Respir Res VL - 21 IS - 1 N2 - BACKGROUND: Viral respiratory tract infections, such as influenza A virus (IAV), are common and life-threatening illnesses worldwide. The mechanisms by which viruses are removed from the respiratory tract are indispensable for airway host defense. Mucociliary clearance is an airway defense mechanism that removes pathogens from the respiratory tract. The coordination and modulation of the ciliary beating of airway epithelial cells play key roles in maintaining effective mucociliary clearance. However, the impact of respiratory virus infection on ciliary activity and mucociliary clearance remains unclear. METHODS: Tracheal samples were taken from wild-type (WT) and Toll-like receptor 3 (TLR3)-knockout (KO) mice. Transient organ culture of murine trachea was performed in the presence or absence of IAV, polyI:C, a synthetic TLR3 ligand, and/or reagents. Subsequently, cilia-driven flow and ciliary motility were analyzed. To evaluate cilia-driven flow, red fluorescent beads were loaded into culture media and movements of the beads onto the tracheal surface were observed using a fluorescence microscope. To evaluate ciliary motility, cilia tips were labeled with Indian ink diluted with culture medium. The motility of ink-labeled cilia tips was recorded by high-speed cameras. RESULTS: Short-term IAV infection significantly increased cilia-driven flow and ciliary beat frequency (CBF) compared with the control level in WT culture. Whereas IAV infection did not elicit any increases of cilia-driven flow and CBF in TLR3-KO culture, indicating that TLR3 was essential to elicit an increase of cilia-driven flow and CBF in response to IAV infection. TLR3 activation by polyI:C readily induced adenosine triphosphate (ATP) release from the trachea and increases of cilia-driven flow and CBF in WT culture, but not in TLR3-KO culture. Moreover, blockade of purinergic P2 receptors (P2Rs) signaling using P2R antagonist, suramin, suppressed polyI:C-mediated increases of cilia-driven flow and CBF, indicating that TLR3-mediated ciliary activation depended on released extracellular ATP and the autocrine ATP-P2R loop. CONCLUSIONS: IAV infection readily increases ciliary activity and cilia-driven flow via TLR3 activation in the airway epithelium, thereby hastening mucociliary clearance and "sweeping" viruses from the airway as an initial host defense response. Mechanically, extracellular ATP release in response to TLR3 activation promotes ciliary activity through autocrine ATP-P2R loop. SN - 1465-993X UR - https://www.unboundmedicine.com/medline/citation/33109186/Influenza_A_virus_enhances_ciliary_activity_and_mucociliary_clearance_via_TLR3_in_airway_epithelium L2 - https://respiratory-research.biomedcentral.com/articles/10.1186/s12931-020-01555-1 DB - PRIME DP - Unbound Medicine ER -
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