Influenza A virus PB1-F2 protein: An ambivalent innate immune modulator and virulence factor

Abstract

Influenza A virus (IAV) causes not only seasonal respiratory illness, but also outbreaks of more severe disease and pandemics when novel strains emerge as a result of reassortment or interspecies transmission. PB1-F2 is an IAV protein expressed from the second open reading frame of PB1 gene. Small as it is, PB1-F2 is a critical virulence factor. Multiple key amino acid residues and motifs of PB1-F2 have been shown to influence the virulence of IAV in a strain-and host-specific manner, plausibly through the induction of apoptotic cell death, modulation of type I IFN response, activation of inflammasome, and facilitation of secondary bacterial infection. However, the exact role of PB1-F2 in IAV pathogenesis remains unexplained.Through reanalysis of the current literature, we redefine PB1-F2 as an ambivalent innate immune modulator that determines IAV infection outcome through induction of immune cell death, differential modulation of early-and late-type I IFN response, and promotion of pathogenic inflammation. PB1-F2 functions both intracellularly and extracellularly. Further investigations of the mechanistic details of PB1-F2 action will shed new light on immunopathogenesis of IAV infection.

PB1-F2 protein of highly pathogenic influenza A (H7N9) virus selectively suppresses RNA-induced NLRP3 inflammasome activation through inhibition of MAVS-NLRP3 interaction

“…15,16 PB1-F2, an antigenic nonstructural IAV protein localized to mitochondria, 17,18 is known to be a virulence factor that modulates innate immune response and NLRP3 inflammasome activity. 19,20 Intranasal administration of PB1-F2 peptide to mice or extracellular application to macrophages exacerbates NLRP3 inflammasome activation, resulting in excessive production of IL-1 and IL-18 as well as severe pulmonary inflammation. [21][22][23] Hyperactivation of NLRP3 inflammasome by PB1-F2 requires PB1-F2 aggregation, phagocytosis, and lysosomal acidification.…”

Accessory Gene Products of Influenza A Virus

“…In other circumstances, the presence, or precise sequence of PB1-F2 does affect pathogenesis (Zamarin et al 2006;Conenello et al 2007;Schmolke et al 2011;Leymarie et al 2014), but no overall simple conclusion can be drawn as to whether PB1-F2 expression leads to exacerbation or amelioration of disease. This almost certainly reflects viral strain-and host-dependent effects and is reviewed elsewhere (Kamal et al 2018;Cheung et al 2020). Consistent with virus-derived variation, not all IAV strains possess a full-length (defined as ≥87 codon) ORF; in general, avian strains of IAV tend to have fulllength genes, whereas human and swine viruses (notably including the H1N1pdm09 virus) often do not (Zell et al 2007;Pasricha et al 2013;Kamal et al 2018).…”

“…www.perspectivesinmedicine.org that are reviewed in more detail elsewhere (Kamal et al 2018;Cheung et al 2020). Despite much effort at molecular characterization of PB1-F2 in vitro, attemptsto elucidate in vivo function have given conflicting results.…”

Role of Post-translational Modifications in Influenza A Virus Life Cycle and Host Innate Immune Response

“…PTMs are involve in regulating innate immune signaling, and many viruses have evolved various mechanisms to usurp PTMs to counteract this host defense response (Calistri et al, 2014). For influenza virus, the activities of the immune-regulatory proteins, including NS1 (Nogales et al, 2018) and the accessory proteins PA-X (Levene and Gaglia, 2018;Nogales et al, 2018) and PB1-F2 (Cheung et al, 2020), are finely modulated by various PTMs to antagonize host innate immune responses.…”

“…PB1-F2, another accessory protein, is a 90-amino acid protein that is encoded as an internal open reading frame on the PB1 gene of some influenza viruses. It contributes to the pathogenesis and comorbidity of influenza viruses mainly through manipulating apoptosis and innate immune responses, and enhancing the secondary bacterial infection (Cheung et al, 2020). Loss of PB1-F2 ubiquitination enhances PB1-F2 stability, polymerase activity, and IFN antagonism (Kosik et al, 2015).…”