PB1-F2 amyloid-like fibers correlate with proinflammatory signaling and respiratory distress in influenza-infected mice

• Published in: The Journal of biological chemistry 2021-07, Vol.297 (1), p.100885-100885, Article 100885
• Main Authors: Chevalier, Christophe, Leymarie, Olivier, Sedano, Laura, Da Costa, Bruno, Richard, Charles-Adrien, Maisonnasse, Pauline, Réfregiers, Matthieu, Jamme, Frédéric, Le Goffic, Ronan
• Format: Article
• Language: English
• Subjects: amyloid; Biochemistry, Molecular Biology; Human health and pathology; Immunology; Infectious diseases; inflammation; influenza virus; Innate immunity; Life Sciences; lung injury; Microbiology and Parasitology; PB1-F2; Pulmonology and respiratory tract; Virology; virulence factor
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1016/j.jbc.2021.100885

PB1-F2 is a virulence factor of influenza A virus known to increase viral pathogenicity in mammalian hosts. PB1-F2 is an intrinsically disordered protein displaying a propensity to form amyloid-like fibers. However, the correlation between PB1-F2 structures and the resulting inflammatory response is unknown. Here, we used synchrotron-coupled Fourier transform-IR and deep UV microscopies to determine the presence of PB1-F2 fibers in influenza A virus–infected mice. In order to study the correlation between PB1-F2 structure and the inflammatory response, transgenic mice expressing luciferase under the control of an NF-κB promotor, allowing in vivo monitoring of inflammation, were intranasally instilled with monomeric, fibrillated, or truncated forms of recombinant PB1-F2. Our intravital NF-κB imaging, supported by cytokine quantification, clearly shows the proinflammatory effect of PB1-F2 fibers compared with N-terminal region of PB1-F2 unable to fibrillate. It is noteworthy that instillation of monomeric PB1-F2 of H5N1 virus induced a stronger inflammatory response when compared with prefibrillated PB1-F2 of H1N1 virus, suggesting mechanisms of virulence depending on PB1-F2 sequence. Finally, using whole-body plethysmography to measure volume changes in the lungs, we quantified the effects of the different forms of PB1-F2 on respiratory parameters. Thus, we conclude that PB1-F2–induced inflammation and respiratory distress are tightly correlated with sequence polymorphism and oligomerization status of the protein.