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has important effects on the pathological effects of ILTV, caus- et al., 1987; Harris et al., 1990; Tal-Singer et al., 1991; Huemer et
ing more severe lesions and anticipated death in infected chicken al., 1992, 1993; Hung et al., 1994; Kostavasili et al., 1997; Rux et
embryos, as well as playing a role in systemic viral spread (Li et al., 2002; Hook et al., 2006; Awasthi et al., 2009). It has been pro-
al., 2016). A different viral strategy to modulate host responses is posed that this interaction may also occur between ILTV gC and
the host shut-off protein (encoded by UL41; Table 11.1) which C3/C3b and may help explain its immune-modulatory function
cleaves host mRNA during the very early stages of infection, (Pavlova et al., 2010). These interactions remain to be confirmed.
affecting, among others the expression of immune mediators
such as type I interferon (Taddeo and Roizman, 2006; Lin et al., Immune response
2010; Saffran et al., 2010; Su et al., 2015; Liu et al., 2016). How- In vivo and in vitro studies have indicated that ILTV glycoproteins
ever, the efficacy of this strategy in ILTV has been recognized to are the major immunogens in ILTV, which has led to a number
be limited in comparison to that of other herpesviruses, as only of viral-vectored vaccines expressing ILTV glycoproteins being
a few host-origin peptides are affected by ILTV infection at early developed and commercialized (see ‘Vaccines’). Experimental
time points of infection (Prideaux et al., 1992). works using mAbs raised against whole virus lysates have shown
Glycoprotein G is another host response modulation strategy that there are two major glycoprotein complexes, the first one
conserved in alphaherpesviruses. Glycoprotein G is a virulence corresponding to gC and the second one corresponding to gJ
factor in ILTV (Devlin et al., 2006b), which is expressed only as (York et al., 1987, 1990; Abbas et al., 1996; Veits et al., 2003a) (see
a secreted product (Kongsuwan et al., 1993a; Pavlova et al., 2010, ‘Molecular biology and viral genetics’). Both gJ and gC reacted
2013) and has the capacity to bind a wide range of human and strongly in Western blotting studies with a majority of chicken
murine chemokines, thus considered a viral chemokine binding antisera tested (York et al., 1987; York and Fahey, 1991; Veits et
protein (Devlin et al., 2010). Similar vCKBP have been described al., 2003a), and cell-mediated immune responses (measured as a
in other alphaherpesviruses and in poxviruses (Alcami, 2007; delayed-type hypersensitivity reaction) in chickens vaccinated 4
Van De Walle et al., 2008). Chemotaxis assays have demonstrated weeks earlier were also observed when chickens were inoculated
that the expression of ILTV gG can inhibit the chemotaxis of with gC and gJ (York and Fahey, 1990). When the same affinity-
heterophils in vitro, while in vivo infection studies comparing purified glycoproteins were administered as vaccines (together
immunological responses towards infection with gG-deficient with additional yet uncharacterised proteins of 74 and 50 kDa)
and gG-expressing ILTV revealed alterations in the numbers of B, they were capable of eliciting detectable antibody titres 4 weeks
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CD4 and CD8α lymphocyte subsets, as well as heterophils infil- after two doses of the glycoproteins in the majority of vaccinated
trating the tracheal mucosa, where the expression of gG shifted chickens, and also delayed hypersensitivity reactions. After chal-
the adaptive immune response away from cell-mediated responses lenge with virulent virus the majority of glycoprotein-vaccinated
and towards antibody production (Devlin et al., 2010), which has chickens had no detectable ILTV antigen in their tracheas after
been considered less important in protection (see below). Recent three to five days (York and Fahey, 1991). Following from these
studies have also demonstrated that gG has a direct impact on the results, vaccination with viral-vectored vaccines carrying ILTV
transcription of cytokines and chemokine ligands that is associ- glycoproteins has been proven to be an effective alternative to
ated with ILTV infection, where the transcription of the chicken traditionally attenuated ILTV vaccines, at least in areas of low
IL-8 orthologues, chCXCLi1 and chCXCLi2 (among others), is field challenge. As these vaccines are not capable of preventing
altered during in vitro and in vivo infections due to the presence of challenge viral replication in the trachea as efficiently as chicken-
gG (Coppo et al., 2018). These changes in cytokine transcription embryo-origin (CEO) vaccines, it has been hypothesized that the
help explain some of the changes in the leucocyte populations lack of a local immune responses associated with the administra-
recruited to the sites of infection, as observed earlier. tion route used for these recombinant vaccines (subcutaneous, in
A further immune modulation strategy is conferred through ovo, or via the wing-web) may play a role in this limitation (Coppo
ILTV gC (UL44). Glycoprotein C has a yet undefined role in et al., 2013).
ILTV cell entry (see Molecular biology and viral genetics section) Early studies investigating immune response against ILTV
but has been found to have immune-modulatory functions. In vivo determined that antibody responses were less important for
infection studies comparing immunological responses to infec- protection than cell-mediated immune responses (Fahey et al.,
tion with a gC-deficient ILTV or a gC-expressing ILTV revealed 1983; Fahey and York, 1990). Vaccination of bursectomised
that the lack of gC was associated with increased numbers of (by a combination of surgical and/or chemical treatment with
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antigen presenting cells (MHCII /Bu1 ) over the first 7 days cyclophosphamide) chickens resulted in less severe clinical sings
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after infection, while the numbers of B cells (Bu1 /MHC II ) and and fewer mortalities than vaccination in intact chickens, and
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CD4 , CD8 lymphocytes remained the same over this period, both groups of birds took the same time to clear the vaccine virus
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but increased after 21 days of infection. Interestingly, the numbers from the trachea (Fahey and York, 1990). This is interesting as
of all the lymphocyte subsets investigated consistently increased it highlights the deleterious effect that antibody may have in the
to higher levels after challenge in those pre-immunized with the pathogenesis of ILTV and indicates that antibody is not impor-
gC-deficient ILTV compared with those immunized with wild- tant in the response against attenuated vaccine virus without prior
type ILTV (Pavlova et al., 2010). The gC expressed by HSV can ILTV exposure. When vaccinated chickens were challenged with
interact with the C3/C3b central component of the complement, virulent ILTV, those that were bursectomised were capable of
thus inhibiting complement fixation (Fries et al., 1986; Eisenberg withstanding infection at similar levels to those of intact chickens