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the MLP increases late in infection. Homologues to ADP have al., 2011). Alternatively, virus attachment triggers the MEK1/2
not been identified in avian adenoviruses. and ERK1/2 signalling that also leads to the activation of NF-kB
The third mechanism of virus release in mastadenoviruses (Fig. 10.5). Virus-induced endosome rupture can further
involves the viral E1B 55K and E4ORF6 proteins forming ubiq- enhance the expression of pro-inflammatory genes such as IL-1α
uitin complexes with elongins P/C-Cul-RBX1 to promote the (Di Paolo et al., 2009). PRRs that recognize virion components
degradation of integrin α3. The viral E4ORF1 protein interacts with (proteins and nucleic acid) can be membrane-bound (cell surface
PDZ-domain-containing members of the membrane-associated and endosomal compartments) and cytoplasmic. Toll-like recep-
guanylate kinase protein family. These protein interactions render tors (TLRs) are among the membrane-bound PRRs. Endosomal
cells with decreased attachment to their substratum and disrup- internalization and partial disassembly of the virion exposes the
tion of junctions in epithelial cells that seems to aid virus spread. viral DNA to TLR-9, which is absent in chicken cells (Temperley
The fourth mechanism involves the disruption of tight et al., 2008). TLR-21 is the functional homologue to mammalian
junctions of epithelial cells by free fibre trimers released upon TLR-9 (Brownlie et al., 2009; Keestra et al., 2010) that may rec-
infection that may aid cell lysis. ognize the avian adenovirus genome. The adenoviral genome in
mammalian cells can be also sensed directly by cytoplasmic PRRs
such as DNA-dependent activator of IFN-regulatory factors
Effects on the host cell, signalling (DAI), IFN gamma inducible protein 16 (IFI16), absent in mela-
pathways and apoptosis noma 2 (AIM2), or indirectly by retinoic acid-inducible gene I
In general, adenovirus infection in susceptible cells results in (RIG-I) and nucleotide-binding oligomerization-like receptor
cytopathic effect (CPE), which often consists of morphological family, pyrin domain-containing protein 3 (NLRP3) (Cheng et
changes, decrease ability to attach to the cell culture flask surface al., 2007; Thaci et al., 2011). DAI, IFI16, RIG-I and AIM2 acti-
and enlarged nuclei. At the latest stage of infection, cell debris vates the IFN response, whilst NLRP3 induces apoptosis via IL-1
results as a consequence of virus-induced cell lysis. Adenovi- and IL-18 (Thaci et al., 2011). Chicken cells express NLRP3 (Ye
ruses increase glycolysis in continuous cell lines resulting in an et al., 2015), but not DAI, RIG-I, IFI16 and AIM2 (Santhakumar
increased production of acid (Berk, 2013). et al., 2017).
Diagnosis of adenovirus infections in part relies on nuclear Activation of IFN signalling through PRRs is cell-type
morphological changes due to intranuclear inclusions. These dependent. For example, human myeloid dendritic cells (mDCs)
inclusions are initially Feulgen negative and eosinophilic but and plasmacytoid DC (pDCs) recognize the viral nucleic acid in
become Feulgen positive and basophilic as the infection pro- the cytoplasm and endosomes through DAI and TLR-9, respec-
gresses. In addition to clinical history and lesions, diagnosis of tively (Thaci et al., 2011). Therefore, it is likely that differential
inclusion body hepatitis (IBH) in poultry caused by some FAdVs IFN response can be also cell-type dependent in chickens or any
is aided by identifying inclusions in the hepatocytes of the liver. other avian species.
Cells have evolved numerous mechanisms to defend them- Viral gene transcription-dependent activation of IFN signal-
selves from external insults including virus infections. Such ling has been mostly described for human adenoviruses. As
defence mechanisms include activation of the innate immunity mentioned previously, dsRNAs, which are bioproducts during
mediated by pro-inflammatory gene products that results in virus replication, induce PKR-mediated global inhibition of
recruitment of immune cells such as natural killer cells (NK mRNA translation. PKR is also expressed in chicken cells (Ko et
cells) to the site of infection, induction of the acquired immune al., 2004). VA RNAs, in addition to its role on inactivating PKR,
response (T and B cells) and apoptosis. Activation of signalling stimulate IFN response through direct binding to RIG-I, which
pathways that leads to the expression of pro-inflammatory genes is a cytoplasmic PRR that also senses dsRNA (Minamitani et al.,
and apoptosis can be either independent or dependent of viral 2011). Though RIG-I is not expressed in chickens, recognition of
gene expression. Viral gene expression-independent mecha- dsRNA and VA RNAs may be mediated by cooperative actions
nisms involve cell surface perturbations during virus attachment, of other RIG-I-like receptors expressed in chicken cells, such as
endosome ruptures during virion disassembly and recognition melanoma differentiation-associated protein 5 (MDA5) and
of virion components by pattern recognition receptors (PRRs) laboratory of genetics and physiology 2 (LGP2) (Santhakumar
– either membrane bound or cytoplasmic. Viral gene expression- et al., 2017).
dependent mechanisms involve the induction of unscheduled E genes induce the expression of pro-apoptotic and heat-
cell cycle progression and stimulation of antiviral defences (pro- shock protein genes early in infection. As mentioned previously,
inflammatory cytokines and apoptosis) by early genes (Nakajima FAdV-1 Gam-1 and ORF22 are the only known avian adenovirus
et al., 1998; Di Paolo et al., 2009; Thaci et al., 2011). early genes known to induce cell cycle progression and to be
Perturbations on the cell surface, via interaction between functionally equivalent to mastadenovirus E1A genes. Gam-1
CAR and fibre proteins, activate the phosphoinositide 3-kinase also up-regulates hsp40 and hsp70 heat-shock proteins and dis-
(P13K). PI3K through yet-to-be-characterized effectors acti- rupts PML bodies by inhibiting PML sumoylation (Glotzer et al.,
vates the ERK1/2, JNK, MAPK and NF-κB resulting in the 2000; Colombo et al., 2002). Gam-1-deleted mutant FAdV-1 is
up-regulation of pro-inflammatory genes – such as IL-1α, TNF-α, replication-deficient, but its replication can be rescued by either
RANTES, IP-10, MIP-1α and MIP-1β – and induction of antivi- heat-shock or forced overexpression of hsp40 (Glotzer et al.,
ral innate immunity and apoptosis (Di Paolo et al., 2009; Thaci et 2000).