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that IBDV VP4 suppresses GILZ degradation by inhibiting GILZ gain sufficient time for its replication but inducing apoptosis in
ubiquitylation, therefore allowing the accumulation of GILZ, host cells at a later stage of IBDV infection to facilitate its release.
which suppresses the activation of NF-κB, leading to the sup- It can be proposed that IBDV VP5 plays different roles at differ-
pression of type I interferon expression (Fig. 7.3). These findings ent stages of viral infection, depending on the binding affinity of
reveal a new mechanism employed by viruses to suppress type I target proteins with VP5 and the quantity of VP5 expressed in
interferon expressions in host immune response. Furthermore, as the cytoplasm. In this case, mathematic biology may be required
mentioned above, the dsRNA-binding ability of VP3 that stabi- to uncover the multi-functions of VP5. Of note, even though
lizes the virus structure, may also contribute to the blockage of VP5 is not required for IBDV replication in host in vitro and in
viral dsRNA interacting to MDA5 (Fig. 7.3), a well-known pat- vivo, it might act as an important antigen to induce cell-mediated
tern recognition receptor (PRR) that detects viral RNA in the immune response in chickens. Since the majority of researches on
cytoplasm and initiates innate immune response (Ye et al., 2014). host response to IBDV infection have been focused on humoral
These findings suggest that IBDV survives in host cell from innate immunity, the significance of cell-mediated immunity against
immune response by at least two strategies: one is to suppress the IBDV might be underestimated. It is worthwhile investigating the
type I interferon expression via VP4 binding to GILZ, and the role of cell-mediated immunity in control of IBD and particularly
other is to block the recognition of viral dsRNA by MDA5 via the role of VP5 as an antigen in cell-mediated immunity against
VP3. Even though IBDV has evolved to employ VP4-mediated IBDV.
suppression of innate immunity as one of the important strategies
to escape from the host response, VP4 might also be targeted by Survival skills of IBDV in host cells
host cellular factors to restrict viral growth as demonstrated by IBDV, like most of pathogens, evolved with varied survival skills
the experimental evidence that host cell protein CypA interacts that help them to replicate and spread successfully in hosts. These
with viral VP4 and inhibits the replication of IBDV (Wang et al., survival skills employed by IBDV include manipulations of apop-
2015). The interaction of VP4 with cellular targets look like much tosis, autophagy and suppression of type I interferons for its own
more complex than anticipated, and the exact role of VP4 in cell benefit.
response needs to be further unravelled.
VP5, a non-structural protein that was originally identified in Manipulation of apoptosis
IBDV infected cells (Mundt et al., 1995), is not essential for viral Apoptosis, a process of programmed cell death, is responsible for
replication in cell culture (Mundt et al., 1997) and in chickens the massive depletion of lymphocytes from BF, leading to immu-
(Qin et al., 2010). It was found that accumulation of VP5 within nosuppression in IBDV-infected chickens (Lam, 1991, 1997;
the host plasma membrane induced cell lysis (Lombardo et al., Vasconcelos and Lam, 1994, 1995). In addition to the rapid loss
2000), suggesting that VP5 is involved in IBDV-induced cell of B cells in the BF, a high level of apoptosis is found in chicken
death. Using a reverse genetic system, Yao and his colleague spleen and peripheral blood lymphocytes during IBDV infection
found that VP5 serves as an apoptotic inducer as evidenced (Vasconcelos and Lam, 1994; Lam, 1997). IBDV, as a non-
by the decreased level of cell death in the cells infected with an enveloped dsRNA virus, is unable to utilize membrane budding
IBDV VP5 deficient mutant (Yao et al., 1998; Yao and Vakharia, for viral release, but uses VP5-dependent non-lytic egress mecha-
2001). Several cellular proteins have been identified to interact nism at an early stage of infection or apoptosis at a later stage of
with VP5, including p85alpha subunit of PI3K (Wei et al., 2011), infection to facilitate viral release (Li et al., 2012; Méndez et al.,
voltage-dependent anion channel 2 (VDAC2) (Li et al., 2012), 2017; Qin et al., 2017), suggesting that other factors, in addition
and receptor of activated protein kinase C 1 (RACK1) (Lin et to VPs, are involved in cell death during IBDV infection. In par-
al., 2015). It was found that VP5 inhibits apoptosis at the early ticular, the release of the VP5-deficient virus progeny is associated
stage of virus infection via interaction with p85alpha subunit of to cell death (Méndez et al., 2017). Experimental evidence show
PI3K (Liu and Vakharia, 2006; Wei et al., 2011), suggesting that that apoptosis induced by IBDV VP2 or VP5 is highly associated
VP5-mediated anti-apoptosis is an important event to support with viral release (Li et al., 2012; Qin et al., 2017). It seems that
viral replication in the early stage of IBDV infection. However, apoptosis occurring during IBDV infection is initiated or manipu-
VP5 induces apoptosis at the later stage of IBDV infection via lated by the virus rather than by the host because the destruction
interaction with VDAC2 to facilitate viral release (Li et al., 2012). of the host cells contributes to the viral release late in the life cycle
In addition, VP5, VDAC2 and (RACK1) forms a complex that (Lombardo et al., 2000), which is obviously beneficial to IBDV
modulates the apoptosis (Lin et al., 2015). VDAC2 was indis- rather than to the host. Interestingly, as mentioned above, VP5
pensable to the release of cytochrome c and the activation of inhibits cellular apoptosis via interaction with p85alpha subunit
caspase-9 or -3, which led to apoptosis during IBDV infection, of PI3K early during IBDV infection so as to gain sufficient time
while RACK1, an antiviral protein, was suggested to be on behalf for its replication and release by non-lytic egress mechanism but
of the counteractions of host (Qin and Zheng, 2017). Qin and induces apoptosis via interaction with VDAC2 in host cells at a
his colleague reported that VP5-deficient mutant IBDV caused later stage of infection to facilitate its release. Thus, the timing
reduced bursal lesion of SPF chicken compared with the paren- for induction of apoptosis needs to be tightly controlled by the
tal virus, indicating that VP5 induces tissue damage (Qin et al., virus during infection, and IBDV has evolved with such capability
2010). Thus, VP5 is a crucial viral component exploited by IBDV for survival. Employment of cellular apoptosis by IBDV for viral
for inhibiting cellular apoptosis early during IBDV infection to release seems to be the survival skill of this virus, and both the