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members), virus egress (BST2/tetherin) and ISGs that have a functional similarities with mammalian viperin (Goosens et al.,
broad range of antiviral activity such as Mx (Verhelst et al., 2013). 2015).
Our equivalent knowledge of the avian IFN system lags behind, The interferon induced transmembrane proteins (IFITM)
but recently comprehensive studies of chicken IRGs have been have been ascribed roles in diverse biological processes, such as
produced (Giotis et al., 2016; Röll et al., 2017). In addition to immune cell signalling, germ cell homing and maturation, and
common IRGs shared between mammals and chickens, chickens bone mineralization. Some members of the IFITM family are
have unique IRGs whilst key innate immune genes expected from effectors of the immune system and are widely involved in restrict-
mammals are absent. Comparative genomic analysis indicates for ing entry of a broad range of viruses into cells. These genes are
example that IRF3 is absent in the chicken, but other transcrip- part of a larger family called the Dispanins, which have a common
tion factors such as AP-1, IRF7 and NF-κB, that are activated double transmembrane domain configuration. In both humans
upon sensing of viral nucleic acids, are present. Therefore, it is and chickens, five IFITM genes have been identified, IFITM1,
likely that the signalling pathway is functional and induces type 2, 3, 5 and 10, but the avian nomenclature does not necessarily
I IFN, pro-inflammatory cytokines and activation of IRGs to reflect their human orthologues. chIFITM1 is barely detectable
mount an antiviral state. in tissues and upon infection or cellular stress it is hardly induced.
Although genomic analyses have identified many chicken When expressed in a human cell line chIFITM1 localizes to the
IRGs, their function is still incomplete and often contradictory early endosomes, which is in contrast to human IFITM1 which is
results are demonstrated based on in vitro functional assays. plasma membrane bound. Based on features such as membrane
Myxovirus resistance (Mx) proteins are IFN-induced GTPases, localization and lack of an N-terminal extension, it was suggested
which convey a number of activities, including antiviral actions that an inversion might have occurred within the locus and con-
against a wide range of RNA viruses by blocking early stages of cluded that chIFITM2 is analogous to human IFITM1 (Smith et
the replication cycle, endocytosis and apoptosis. Chicken Mx is al., 2015). Based on cellular localization of chIFITM2 shown in
mainly located in the cytoplasm and is the most studied ISG in the plasma membrane this inversion conclusion has been con-
birds. In humans and chickens two Mx GTPases have been found, firmed (Bassano et al., 2017). Subsequently, it was shown that
MxA and MxB. Chicken Mx is highly polymorphic (Ko et al., duck IFITM1 localizes on the plasma membrane, like human
2004a), but its antiviral activities remain somewhat controversial IFITM1, highlighting further classification difficulty in avian
in chicken, based on both in vitro and in vivo studies (reviewed in IFITMs (Blyth et al., 2016). Expression at the cell surface is con-
Goossens et al., 2013; Santhakumar et al., 2017b). Despite strong sistent with the ability to restrict viral entry. IFITM2 and 3 localize
induction of Mx by IFN, chicken and duck Mx do not limit rep- to late endosomes and lysosomes where they preferentially affect
lication of influenza virus (Bazzigher et al., 1993; Benfield et al., viruses that utilize the endocytic pathway to invade host cells. The
2010; Schusser et al., 2011) and other IRGs are proposed to be IFITM proteins alter the lipid composition of the membrane and
likely to contribute to an antiviral state. decrease membrane fluidity. IFITM1, 2 and 3 have been shown
Protein kinase R (PKR) is a serine/threonine protein kinase to block viral membrane hemifusion (when the outer membranes
and binds dsRNA. PKR inhibits translation of cellular and viral of the two lipid bilayers have fused but the inner membranes are
mRNA and this inhibition of protein synthesis within the infected still intact), and thus subsequent viral replication (Li et al., 2013).
cells gives rise to its antiviral activities against a wide spectrum In vitro studies indicated that chicken and duck IFITMs are also
of DNA and RNA viruses (Balachandran et al., 2000). Similar potent inhibitors of viruses (Smith et al., 2013), but in vivo expres-
to Mx, PKR is polymorphic and induces antiviral effects to VSV sion and regulation differs significantly upon infection with HPAI
infection (Ko et al., 2004b), but failed to protect chickens against (Smith et al., 2015). Ducks strongly up-regulate IFITM1, 2 and
highly pathogenic influenza virus (Daviet et al., 2009). 3, whereas expression in chickens hardly changes and, in addition
2’–5′-oligoadenylate synthetase (OAS) is an IFN induced to other mechanisms, this differential response may contribute
enzyme and is stimulated by dsRNA. The antiviral activity is to the species-specific resistance to influenza. In general, higher
exerted through the cleavage of viral RNA transcripts and host expression levels can be observed for chIFITM2 and chIFITM3
RNAs (Silverman, 2007). Studies in chickens have found that upon stimulation (IBDV, ALV, IFNα, H5N2, H5N1, H5N3,
there is only one OAS gene in the chicken; however, there appears IRF7) suggesting a key role for these two proteins as antiviral
to be two alleles: OAS-A and OAS-B (Yamamoto et al., 1998). IFITMs compared with chIFITM1, expression of which is more
The antiviral activity has been described against West Nile and limited (Bassano et al., 2017). IFITM5, although expressed upon
Vaccinia virus (Tag-El-Din-Hassan et al., 2012). IFN stimulation in human, is exclusively expressed in osteoclasts.
In mammals, viperin has been shown to inhibit viral protein In contrast, in ducks it has been detected in lung tissue and was
and/or RNA biosynthesis for a number of different viruses. up-regulated upon infection with HPAI alongside IFITM1,
In addition, viperin can localize to the ER, disrupts lipid rafts 2 and 3 (Smith et al., 2015; Blyth et al., 2016). The function of
and thereby through inhibiting the trafficking of soluble virally chIFITM10 still remains to be elucidated (Okuzaki et al., 2017).
encoded proteins, it impairs viral replication and restricts viral Once an IFN response is initiated, the regulation and desen-
budding (Wang et al., 2007; Hinson and Cresswell, 2009; Jiang sitization of the response must be tightly controlled and occur in
et al., 2010). More recently, chicken viperin was shown to display parallel to prevent excessive inflammatory responses. Several neg-
antiviral activity against influenza and IBDV in addition to vari- ative control mechanisms have been described for mammals and
ous synthetic ligands and based on its structure it is likely to have similar early desensitization mechanisms seem to be applicable