Page 303 - Avian Virology: Current Research and Future Trends

294 | Corredor and Nagy

Figure 10.5 Induction of the inflammatory response by adenovirus. Adenovirus infections induce inflammatory responses during virus
attachment through cell surface receptors (e.g. CAR), penetration (recognition of viral ds DNA by either mammalian TLR-9 or chicken TLR-22
in the endosome) or recognition of the viral DNA by NOD-like receptors (NALP3). Viral attachment and penetration activate the NF-kB
pathway for the expression of inflammatory cytokines. Recognition of viral DNA in the cytosol leads to the production of IL-1 and IL-18.
IL-1 binds to IL-1R, which in turn, activates the NF-kB pathway. (© Thaci, B., Ulasov, I.V., Wainwright, D.A., and Lesniak, M.S. Oncotarget,
2011;2:113–121 This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits
unrestricted use, distribution and reproduction in any medium, provided the original author and source are credited.)

Mastadenovirus E1A 243R stabilizes p53 and stimulates Viruses have evolved mechanisms that counteract the
p53-mediated apoptosis early in infection as a consequence of antiviral responses and apoptosis signalling. Counteraction of
unscheduled cell cycle progression (Nakajima et al., 1998). It is not IFN signalling occurs at different levels upon virus infection.
clear whether the pro-apoptotic role of Gam-1 is p53-dependant or For example, mastadenovirus E1A proteins, and probably
independent. The role of Gam-1 in modulating apoptosis has not Gam-1 and ORF22 protein by direct or indirect mechanisms,
been determined in the context of infection in avian cells. However, inhibit the formation of the ISGF3 complex (Anderson and
transfection assays using primary human skin fibroblasts and con- Fennie, 1987), which is important for the expression of the
tinuous cell lines suggest that Gam-1 has pro- and anti-apoptotic IFN-stimulated genes (ISGs). As also previously mentioned,
roles that could be determined by its expression levels and cell-type FAdV-1 Gam-1 inactivates HDAC1, either through complex-
(Chiocca et al., 1997; Wu et al., 2007). For instance, transfected ing with p120 E4F transcription factor or inhibiting sumoylation
human 293T and HeLa cells overexpressing Gam-1 undergo cell (Colombo et al., 2002). Class I HDACs, including HDAC1, are
cycle arrest and caspase 3-dependent apoptosis (Wu et al., 2007), required for the expression of ISGs mediated by STAT1- and/
while moderate expression levels counteracts TNF-induced apop- or STAT2-dependent IFN signalling (Chang et al., 2004).
tosis in primary human fibroblasts and induces E2F-mediated cell However, HDAC1 can also down-regulate the expression of
cycle progression in chicken embryo fibroblasts (CEF) and human inflammatory genes (e.g. IL-12p40, COX-2, IFN-β) (Falken-
293 and A549 cells (Lehrmann and Cotten, 1999). berg and Johnstone, 2014). As mentioned previously, PML,
Type I IFN signalling is the first line of defence against virus known for its antiviral functions, is disrupted by Gam-1
infections. The expression of type I IFNs and cytokines in (Colombo et al., 2002) and significantly up-regulated by type
response to infection has been mostly studied in human adeno- I and II IFNs (Everett and Chelbi-Alix, 2007). Therefore,
viruses and some aviadenoviruses. FAdV infections result in these observations suggest the indirect role of FAdV-1 Gam-1
the up-regulation of pro-inflammatory cytokines that seems to in modulating the IFN signalling and expression of inflamma-
be tissue type- and time-dependent (Deng et al., 2013; Grgić et tory genes through inactivation of HDAC1 and disruption of
al., 2013a,b). For example, transcription of IFNγ is up-regulated PML.
in liver and spleen of chickens infected with FAdV-4 at 3 days Adenoviruses also counteract apoptosis pathways through
post-infection (dpi), whilst this cytokine is significantly down- various mechanisms. FAdV-1 Gam-1 inhibits TNF-α-induced
regulated in the same tissue at 10 dpi (Grgić et al., 2013a). The apoptosis through NF-κB in primary human fibroblasts by a
cytokines expressed in response to FAdV infection is described mechanism that differs from that of the mastadenoviral E1B
in detailed in ‘Immune response’ section. 19K (Chiocca et al., 1997). As mentioned previously, avian