Page 19 - Avian Virology: Current Research and Future Trends

12 | Perez et al.

into the cytoplasm. Subsequently, the vRNPs are transported into assembly of vRNPs-M1 into virus particles for final budding at
the nucleus by the importin α/β transport pathway through the the plasma membrane (Martin and Helenius, 1991a,b; Helenius,
nuclear pore complex (Martin and Helenius, 1991b; Gabriel et 1992; Simpson-Holley et al., 2002; Ohkura et al., 2014).
al., 2008, 2011; Boulo et al., 2011; Hudjetz and Gabriel, 2012).
Once in the nucleus, the vRNPs initiate the process of transcrip- Effect on the host cell – cellular signalling
tion and replication (Fig. 1.2) (reviewed in Krug et al., 1989). pathways, innate immune responses, and
Two different populations of positive sense RNAs are synthe- apoptosis
sized from the vRNA templates: messenger RNAs (mRNAs) and The innate immune response against IAV in birds is driven by
complementary RNAs (cRNAs). Viral mRNAs are capped and different effector cells and molecules to limit infection and to
polyadenylated (Plotch et al., 1981; Ulmanen et al., 1983; Beaton initiate adaptive immune response. The major host cell signal-
and Krug, 1986; Krug et al., 1989). Capping of viral mRNAs is ling pathways altered by influenza viruses are: Toll-like receptor
unique to influenza viruses: PB2 binds to the 5′ cap structure of (TLR) and retinoic acid– inducible gene I (RIG-I) signalling
the host’s pre-mRNAs, which are subsequently cleaved at 10–13 cascades, NF-kB signalling, PI3K/Akt pathway, MAPK pathway,
nucleotides downstream from the 5′ end by the PA’s endonuclease and PKC/PKR signalling (Pahl and Baeuerle, 1995; Flory et al.,
activity. These short 5′ capped oligonucleotides serve as primers 2000; Root et al., 2000; Pleschka et al., 2001; Hale et al., 2006;
for transcription by PB1 (Braam et al., 1983.). As transcription Ehrhardt and Ludwig, 2009; Gack et al., 2009; Gaur et al., 2011;
progresses, viral mRNAs are polyadenylated by a ‘stuttering’ Shim et al., 2017). These pathways are important for viral entry,
mechanism that involves the vRNP complex on a short template viral replication, viral propagation and apoptosis, and are involved
polyuridine tract, which is located 17–22 nucleotides before the in antagonizing the host antiviral response. Interestingly, RIG-I
5′ end in the vRNAs (Hay et al., 1977; Robertson et al., 1981). is missing in galliformes but present in anseriformes (although
Because influenza viral mRNAs are structurally identical to caution is necessary since not every galliformes or anseriformes
those produced by the host cell, the virus must hijack the cellular species has been analysed). Acute-phase proteins (APP) are one
translation machinery. In addition to the cap-snatching process, of the first players of the innate immune response. These include
NS1 and PA-X can effectively shut off cellular protein synthesis surfactant protein A (SP-A) and chicken lung lectin (cLL), which
by a variety of mechanisms (Khaperskyy and McCormick, 2015). are two of the lectins present in chickens that are associated with
Interaction of the viral proteins with host’s initiation factors (i.e. IAV neutralization and clearance. Like their mammalian ortho-
eIF4A, eIF4E and eIF4G), and the viral polymerase with the logues, SP-A and cLL are thought to bind specific motifs on IAV
C-terminal domain of the largest subunit of the DNA-dependent HA and NA (Hogenkamp et al., 2006). Previous studies have
RNA polymerase II also contributes to the inhibition of cellular shown that cLL is associated with decreased haemagglutination
translational pathways (Hutchinson and Fodor, 2012). activity of IAV (Hogenkamp et al., 2008), and therefore reducing
It is commonly accepted that nuclear accumulation of newly virus attachment to the host cells. SP-A and cLL are produced by
synthesized NPs triggers the switch from primer-dependent to non-epithelial cells in tracheal and bronchial epithelium and have
primer-independent transcription to produce cRNAs, which been found up-regulated in the trachea and down-regulated in the
are full length copies of the vRNAs (Shapiro and Krug, 1988; lung after infection with IAV (Hogenkamp et al., 2006).
Krug et al., 1989; Newcomb et al., 2009). The cRNAs are neither Influenza A viral pathogen-associated molecular patterns
capped nor polyadenylated and serve as the bona fide templates (PAMPs) are first recognized by macrophages, heterophils, and
for synthesis of progeny vRNAs (McGeoch et al., 1976). Accu- dendritic cells through pathogen recognition receptors (PRRs).
mulation of NEP correlates with cRNA and vRNA accumulation These PRRs include toll-like receptors (TLRs), retinoic acid-
and reduction of viral mRNA levels. NEP’s role in regulating viral inducible gene-I (RIG-I)-like receptors (RLRs), and nucleotide
RNA populations does not depend on the region involved in oligomerization (NOD)-like receptors (NLRs). TLR3 and TLR7
nuclear export (Robb et al., 2009). Furthermore, the discovery are intracellular PRRs that recognize IAV RNA and have been
of regulatory small RNAs led to the uncovering of IAVs-derived described in chickens and ducks (Philbin et al., 2005; MacDonald
small viral RNAs (svRNAs) of 22–27 nts in length. These svRNAs et al., 2008; Downing et al., 2010; Jiao et al., 2012; Chen et al.,
correspond to the 5′ end of each of the vRNA segments. Expres- 2013). While TLR7 recognizes IAV ssRNA and interacts with
sion of svRNAs requires the polymerase complex, NP and NEP. TRIF/MYD88 adaptor molecules, TLR3 recognizes dsRNA
Association of svRNAs to the polymerase complex appears signif- and interacts with TRIF. Activation of either pathway, leads to
icant for the switch to vRNA synthesis (Perez et al., 2010). Newly activation of interferon regulatory factor 7 (IRF7) or nuclear
synthesized polymerase subunits and NP migrate to the nucleus factor-κB (NF-κB), which migrate to the nucleus and initiate
to produce progeny vRNA from cRNA templates (Bullido et al., transcription of IFN type I and pro-inflammatory cytokines such
2000). Concomitantly, increased expression of HA, NA and M1 as IL-1β (Chen et al., 2013; Iwasaki and Pillai, 2014; Mishra et al.,
proteins is observed later in the infection cycle. NEP associates 2017). Activation of IRF7 and NF-κB can be achieved by RIG-I
with progeny vRNPs and M1 to promote nuclear export through (ducks) or melanoma differentiation-associated gene 5 (MAD5)
the crm1 pathway. Also, the interaction with Rab11 enables the (chickens). RIG-I and MAD5 recognize the 5′ triphosphate from
vRNPs to be carried by the vesicular transport system, moving IAV RNAs and then interact with mitochondrial antiviral signal-
through the cytoplasm by the microtubule network (Chou et al., ling (MAVS), which leads to the phosphorylation of IRF7 and
2013). The HA, NA and M2, associated with lipid rafts, mediate NF-κB, and further gene expression (Barber et al., 2010; Cheng et