The Streptococcus pyogenes fibronectin/tenascin-binding protein PrtF.2 contributes to virulence in an influenza superinfection

Abstract

Influenza A virus (IAV) and Streptococcus pyogenes (the group A Streptococcus; GAS) are important contributors to viral-bacterial superinfections, which result from incompletely defined mechanisms. We identified changes in gene expression following IAV infection of A549 cells. Changes included an increase in transcripts encoding proteins with fibronectin-type III (FnIII) domains, such as fibronectin (Fn), tenascin N (TNN), and tenascin C (TNC). We tested the idea that increased expression of TNC may affect the outcome of an IAV-GAS superinfection. To do so, we created a GAS strain that lacked the Fn-binding protein PrtF.2. We found that the wild-type GAS strain, but not the mutant, co-localized with TNC and bound to purified TNC. In addition, adherence of the wild-type strain to IAV-infected A549 cells was greater compared to the prtF.2 mutant. The wild-type strain was also more abundant in the lungs of mice 24 hours after superinfection compared to the mutant strain. Finally, all mice infected with IAV and the prtF.2 mutant strain survived superinfection compared to only 42% infected with IAV and the parental GAS strain, indicating that PrtF.2 contributes to virulence in a murine model of IAV-GAS superinfection.

Adaptation of the group A Streptococcus adhesin Scl1 to bind fibronectin type III repeats within wound‐associated extracellular matrix: implications for cancer therapy

“…To our knowledge, direct binding to the FnIII repeats in either fibronectin or TnC by F2 protein has not been reported. A recent study showed that a protein F2‐deficient mutant of an M3‐GAS strain bound significantly less TnC compared with the wild‐type parental organism, which was restored by in ‐ trans complementation (Herrera et al , ). It should be noted that the M3 strain used in this study, MGAS315, does not expresses the Scl1 adhesin (Bachert et al , ).…”

“…Two streptococcal proteins have been reported to bind to TnFnIII: protein H (Frick et al, 1995) and protein F2 (Herrera et al, 2018). The M-like protein H binds factor H and IgG, as well as the neural cell adhesion molecule (N-CAM), which contains FnIII repeats (Hemperly et al, 1986).…”

“…Group A Streptococcus (GAS) strains MGAS5005-M1 and MGAS6183-M41, as well as their scl1-inactivated isogenic mutants were used in this study (Hoe et al, 1999;Lukomski et al, 2000;Han et al, 2006a;Caswell et al, 2007). Briefly, both mutants were generated by allelic replacement with nonpolar resistance cassettes, encoding spectinomycin (MGAS5005 Δscl1) and erythromycin (MGAS6183 Δscl1) resistance.…”

Tenascin-C in Heart Diseases—The Role of Inflammation

“…Furthermore, TNC may modify the disease state of viral infection by interacting with other pathogens. For example, TNC binds to Streptococcus pyogenes (group A Streptococcus; GAS) and may increase GAS colonization, leading to GAS-influenza-A superinfection [ 135 ].…”

Secondary streptococcal infection following influenza

“…For example, NA of IAV has been reported to activate TGF‐β, 87–89 a multifunctional cytokine known to promote upregulation of host adhesion molecules, including fibronectin and integrins. Because S. pyogenes possesses several fibronectin‐binding proteins, including PrF1/SfbI 99 and FbaA, 102,103 the bacterium can utilize fibronectin–integrin interactions to adhere to and invade IAV‐infected cells. Besides, TGF‐β has been shown to be a positive regulator of the integrin signaling pathway that evokes cytoskeletal rearrangement and bacterial internalization 89 .…”