Influenza A and B Virus-Triggered Epithelial–Mesenchymal Transition Is Relevant to the Binding Ability of NA to Latent TGF-β

Wenxian Yang,Heqiao Li,Wenhui Fan,Xiaoyuan Bai,Lei Sun,Wenjun Liu,Huizi Li,He Zhang

doi:10.3389/fmicb.2022.841462

Abstract

Epithelial–mesenchymal transition (EMT) is an important mechanism of lung tissue repair after injury, but excessive EMT may lead to pulmonary fibrosis, respiratory failure, and even death. The EMT triggered by influenza A virus (IAV) and influenza B virus (IBV) is not well understood. We hypothesized that there was difference in EMT induced by different influenza virus strains. Here we discovered that both IAV [A/WSN/1933 (H1N1), WSN] and IBV (B/Yamagata/16/88, Yamagata) infection caused EMT in mouse lung and A549 cells, and more EMT-related genes were detected in mice and cells infected with WSN than those infected with Yamagata. Neuraminidase (NA) of IAV is able to activate latent TGF-β and the downstream TGF-β signaling pathway, which play a vital role in EMT. We observed that IAV (WSN) triggered more activated TGF-β expression and stronger TGF-β/smad2 signaling pathway than IBV (Yamagata). Most importantly, WSN NA combined more latent TGF-β than Yamagata NA in A549 cells. Collectively, these data demonstrate that both IAV and IBV induce TGF-β/smad2 signaling pathway to promote EMT, which might depend on the binding ability of NA to latent TGF-β.

Highlights

These data demonstrate that both influenza A virus (IAV) (WSN) and influenza B virus (IBV) (Yamagata) infection cause Epithelial–mesenchymal transition (EMT) in mouse lung, and more EMT-related genes are detected in mice infected with WSN than those infected with Yamagata
Virus-triggered EMT is believed to contribute to the progression of disease, including pulmonary fibrosis and cancer
It has been reported that IAV induces EMT-mediated pulmonary fibrosis in mice (Shatskaya et al, 2017), whether other strains of IAV or IBV could trigger EMT is still unknown

Summary

Introduction

Influenza virus infection will lead to acute and severe respiratory diseases (Donaldson et al, 2009; Gaitonde et al, 2019; Liu et al, 2021) and be accompanied by other common complications such as acute respiratory distress syndrome (Chow et al, 2019), secondary bacterial pneumonia (Estenssoro et al, 2010; Farias et al, 2010; Rice et al, 2012; Bai et al, 2021), and pulmonary fibrosis (Qiao et al, 2009; Shatskaya et al, 2017). TGF-β is the most common cytokine that induces EMT. TGF-β is secreted by virtually all cells in a biologically inactive form termed latent TGF-β. Latent TGF-β is composed of an amino-terminal latency-associated peptide (LAP) that remains non-covalently. IAV and IBV Trigger EMT associated with the carboxy-terminal mature TGF-β molecule (Ballesteros et al, 2015). The release of mature TGF-β from the LAP is necessary to bind to cellular receptors and activate the TGF-β/smad2/3 signaling pathway, leading to alveolar epithelial cells changing from cuboidal to an elongated spindle shape (Gonzalez and Medici, 2014; Lamouille et al, 2014; Yao et al, 2019)

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Conclusion