Page 389 - Avian Virology: Current Research and Future Trends

380 | Vervelde and Kaufman

STAT1 and STAT2 and together with IRF9 leads to the forma- and IL28B] whereas IFNλ4 is only found in individuals who
tion of the ISGF3 complex (Takaoka and Yanai, 2006). Chicken cannot clear hepatitis C virus (O’Brien et al., 2014). They share
IFNα/β bind to the same receptor of IFNAR1/IFNAR2, but they homology with type I and II IFNs but also with homology to the
differentially regulate ISGs in chickens (Qu et al., 2013). Chicken IL-10 family. Type III IFNs signal through a receptor complex
IFNα induced a more potent antiviral state than IFNβ which consisting of IL-10Rβ and IL-28Rα which is expressed on epi-
might be related to their differential binding affinity to IFNAR1 thelial cells, hepatocytes, keratinocytes and cells of the myeloid
and IFNAR2 (Pei et al., 2001) and regulation of IFNAR1 and lineage. Downstream signalling occurs through the JAK/STAT
IFNAR2 during embryonic development (Karpala et al., 2012). pathways (similar to type I IFNs), however there are significant
Tissue and time specificity in response to intravenous adminis- differences in the patterns of ISGs induced compared with
tration of IFNα was recently demonstrated in chickens, with a fast those induced by type I IFNs. Type III IFNs constitute antiviral
peaking response in the spleen and a slower but sustained reac- defences, activated by both RNA and DNA viruses, at the early
tion in the lung, leading to time specific reaction of IRGs (Röll stage of infection even before the type I IFNs are produced,
et al., 2017). Time specific responses and induction of IRGs are indicating a second anti-viral defence mechanism distinct from
also common in cultured primary cells such as CEFs (Giotis et al., type I IFNs. Various cells produce type III IFNs including epi-
2016). Receptor binding rapidly induces an antiviral state within thelial cells, macrophages and dendritic cells and triggering can
minutes which peaks approximately 5–8 hours later. The half-life occur through TLR3 (reviewed by Galani et al., 2015). IFNλ acts
reported for human IFNα (4–6 hours) and IFNβ (1–2 hours) is locally on epithelial cells to prevent virus spread without acti-
much longer than the terminal half-life of chicken type I IFNs vating inflammation, which is in contrast to type I IFNs which
(≈ 36 minutes), which could be attributed to a higher metabolic are strong inducers of inflammation. Viral load is the key factor
rate in birds (Radwanski et al., 1987; Röll et al., 2017). Whether in alarming the immune system and assessment of the level of
this affects the downstream responses is not known. danger, inducing the appropriate magnitude and type of immune
Differential responses that are described in literature should be response. The relative contribution of type I and type III IFNs
interpreted with care, because the use of immortalized cell lines is determined by the viral load. If type III IFN is able to limit
is common practice and these findings could be due to intrinsic the spread of virus, as shown during sublethal IAV infection,
functional components of cell lines, specific tissues or timing of prolonged antiviral defences in neutrophils are induced without
the responses (Röll et al., 2017; Giotis et al., 2016). For example, activation of inflammation. Higher viral loads thereafter activate
type I IFNs did not induce TLR3 up-regulation in the macrophage type I IFNs, which in turn may lead to immunopathology (Galani
cell line HD11, but up-regulation was observed upon stimulation et al., 2017).
of the fibroblast cell line DF-1 (Karpala et al., 2008a). In chicken and duck, only one copy of IFNλ was identified
and shows high homology with human IFNλ3 and also signals
Type II IFN through IL-28Rα (Karpala et al., 2008b; Yao et al., 2014; Reuter et
IFNγ is the only known member of type II IFN to be found in al., 2014). Similar to mammals, IL-28Rα expression in chicken is
both mammals and birds. Although it is associated with having higher on epithelial cells or tissues rich in epithelium. Moreover,
antiviral potential, it is regarded as a bridge between innate and the functions of type III IFN that have been studied are conserved,
adaptive responses and a hallmark of T-helper 1 (Th1) responses. likely playing a dominant role in the antiviral responses at epithe-
The antiviral effects of IFNγ have been demonstrated by small lial surfaces, demonstrated in vivo, in ovo and in vitro against NDV,
inferring RNA knockdown in several studies including against IBV and AIV (Reuter et al., 2014; Santhakumar et al., 2017a).
MDV and AIV (Haq et al., 2013b; Yuk et al., 2016). Rapid up- Both chicken and duck IFNλ are capable of inducing ISGs (Mx
regulation of IFNγ during early responses in the absence of type I and OAS) in vitro (Masuda et al., 2012; Yao et al., 2014).
IFNs has been described for IBV (Ariaans et al., 2009; Vervelde et The IFN response to virus infection in mammals is relatively
al., 2013a). In contrast to humans, chicken IFNγ up-regulates the well understood, but new proteins involved in this pathway con-
expression of Mx similar to type I and type III IFNs (Holzinger tinue to be identified (reviewed by Garcia-Sastre, 2011; Raftery
et al., 2007; Masuda et al., 2011). IFNγ has many different roles and Stevenson, 2017). Although of great importance, PAMPs will
in addition to its antiviral role as shown by a plethora of immu- trigger a much broader range of innate responses than just the
nostimulatory and immunomodulatory effects. It is an important IFN pathway.
macrophage-activating factor, it mediates nitric oxide production,
up-regulates MHC class I and II expression, orchestrates matura- IRGs
tion and differentiation of various cell types and is also involved Studies in mammals have demonstrated the presence of hun-
in T-helper 1 (Th1) responses. IFNγ is produced during innate dreds of IRGs. Decades of research and with the relatively recent
responses by natural killer (NK) cells, macrophages and epithelial emergence of transcriptomic technologies, many comprehensive
cells, and during the adaptive responses by CD4 cells Th1 and overviews of IRGs have been published (Schoggins et al., 2011;
cytotoxic CD8 T-cells. Rusinova et al., 2013; Schneider et al., 2014; www.interferome.
org, the database of IFN regulated genes). IRGs generally target
Type III IFN conserved aspects of viral infections at all stages of the infection,
Four type III IFNs have been identified in humans called IFNλ1, including ISGs that affect nucleic acid integrity (OAS/RNAse
IFNλ2, and IFNλ3 [also known as interleukin-29 (IL-29), IL28A L), virus entry (IFITM3), protein translation (PKR, IFIT family