Naturally Occurring Swine Influenza A Virus PB1-F2 Phenotypes That Contribute to Superinfection with Gram-Positive Respiratory Pathogens

Abstract

A combination of viral, bacterial, and host factors contributes to the severity and overall mortality associated with influenza virus-bacterium superinfections. To date, the virulence associated with the recently identified influenza virus protein PB1-F2 has been largely defined using models of primary influenza virus infection, with only limited assessment in models of Streptococcus pneumoniae superinfection. Specifically, these studies have incorporated isogenic viruses that differ in the PB1-F2 expressed, but there is still knowledge to be gained from evaluation of natural variants derived from a nonhuman host species (swine). Using this rationale, we developed the hypothesis that naturally occurring viruses expressing variants of genes, like the PB1-F2 gene, can be associated with the severity of secondary bacterial infections. To test this hypothesis, we selected viruses expressing variants in PB1-F2 and evaluated outcomes from superinfection with three distinct Gram-positive respiratory pathogens: Streptococcus pneumoniae, Staphylococcus aureus, and Streptococcus pyogenes. Our results demonstrate that the amino acid residues 62L, 66S, 75R, 79R, and 82L, previously proposed as molecular signatures of PB1-F2 virulence for influenza viruses in the setting of bacterial superinfection, are broadly associated with enhanced pathogenicity in swine in a bacterium-specific manner. Furthermore, truncated PB1-F2 proteins can preferentially increase mortality when associated with Streptococcus pyogenes superinfection. These findings support efforts to increase influenza virus surveillance to consider viral genotypes that could be used to predict increased severity of superinfections with specific Gram-positive respiratory pathogens.

Amyloid Assemblies of Influenza A Virus PB1-F2 Protein Damage Membrane and Induce Cytotoxicity

“…Similarly, infection of mice with IAV expressing PB1-F2 was reported to significantly enhance the predisposition to secondary bacterial infections (25,26). We observed no effect of PB1-F2, either amorphous or amyloidal, on E. coli growth and only an ephemeral inhibitory effect on B. subtilis growth.…”

“…Likewise, PB1-F2 can disturb the inner membrane of mitochondria, which induces apoptosis. Other functions of PB1-F2 have been also reported: PB1-F2 co-localizes in the nucleus of infected epithelial cells and up-regulates viral polymerase activity (19,20); PB1-F2 may be implicated in inflammation and can modify the host pro-inflammatory response induced by IAV infection (11,21,22); PB1-F2 may inhibit the IFN pathway induction through interacting with the mitochondrial antiviral signaling protein, MAVS (23,24); PB1-F2 was also shown to enhance the predisposition to secondary bacterial infection (11,25,26).…”

Seasonal H3N2 influenza A virus fails to enhanceStaphylococcus aureusco-infection in a non-human primate respiratory tract infection model

“…That said, we were surprised by our findings in NHPs, because numerous studies using rodent models have demonstrated that antecedent IAV infection causes a significant increase in morbidity and mortality following secondary S. aureus respiratory tract infection. [26][27][28][29] There are several possible explanations for the noted differences.…”

Emergence of Highly Pathogenic Avian Influenza A(H5N1) Virus PB1-F2 Variants and Their Virulence in BALB/c Mice

“…Several possible mechanisms have been suggested, including mitochondrial targeting and proapoptotic activity (8,9,19), enhancing PB1 function (20), and inhibition (21)(22)(23)(24)(25)(26)(27) or enhancement (28) of the IFN-␤ response. PB1-F2 has also been linked to bacterial infections following IAV infection (29)(30)(31)(32). However, most of these phenotypes have been difficult to generalize to all strains of virus and across host models tested.…”