Influenza viral neuraminidase primes bacterial coinfection through TGF-β-mediated expression of host cell receptors

Area of Science:

• Immunology
• Virology
• Microbiology

Background:

• Influenza infection increases susceptibility to secondary bacterial pneumonia, a leading cause of mortality.
• The precise molecular mechanisms driving bacterial coinfection following influenza remain unclear.
• Influenza A virus (IAV) neuraminidase (NA) is known to enhance bacterial adherence and activate TGF-β.

Purpose of the Study:

• To investigate the role of TGF-β signaling in IAV-mediated secondary bacterial infections.
• To determine if IAV NA-induced TGF-β activation contributes to increased bacterial adherence by up-regulating host cell adhesion molecules.

Main Methods:

• Flow cytometry was used to analyze fibronectin and α5 integrin expression in human lung epithelial cells after IAV or NA treatment.
• TGF-β signaling inhibition was employed to assess its effect on IAV-promoted bacterial adherence.
• Mouse models were utilized to evaluate the impact of IAV infection on bacterial lung colonization in wild-type and TGF-β signaling-deficient mice.

Main Results:

• IAV infection and recombinant NA treatment increased fibronectin and α5 integrin expression in lung cells, which was reversed by TGF-β inhibition.
• Inhibition of TGF-β significantly reduced the adherence of fibronectin-dependent bacteria, such as group A Streptococcus (GAS), to IAV-infected cells.
• IAV infection enhanced GAS lung colonization in wild-type mice but not in mice lacking TGF-β signaling.

Conclusions:

• IAV NA activates TGF-β signaling, leading to increased expression of cellular adhesins (fibronectin and integrins).
• This mechanism enhances bacterial binding and colonization, contributing to secondary bacterial pneumonia after influenza.
• Targeting TGF-β signaling and cellular adhesins presents a potential therapeutic strategy for preventing influenza-associated coinfections.