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Infectious Laryngotracheitis Virus | 329

epizootiology’). Increased mucosal thickness due to ILTV infec- failed to result in viral reactivation. The sites of ILTV latency are
tion has been reported and may contribute to reduced luminal the trachea, as demonstrated by isolation of virus from tracheal
diameter (Guy et al., 1990; Devlin et al., 2006b). Respiratory organ cultures from carrier chickens (Bagust, 1986); and trigemi-
mucins which play an important role in the prevention/contain- nal ganglia, as this was the only tissue examined that resulted
ment of infections at the airway interface (Vareille et al., 2011) positive for ILTV DNA in carrier birds (Williams et al., 1992).
have also been postulated to contribute to narrowed tracheal In vivo studies that have examined the trigeminal ganglia have
lumen (Linares et al., 1994). However, experimental work has detected ILTV in this tissue as early as 5 days pi (Bagust et al.,
shown that the main respiratory mucins (Muc5AC and Muc5B) 1986; Oldoni et al., 2009), by isolation or molecular methods,
appear not to be that important during the acute phases of ILTV but the virus has never been isolated from latently infected indi-
infection, as they were only scarcely found in tracheas of ILTV viduals (Bagust, 1986; Williams et al., 1992). Latency associated
infected chickens. Instead, epithelium desquamation and DNA transcripts have not been described for ILTV however, putative
extracellular traps are the main components of the mucoid plugs LATs have been identified through nucleotide sequence analysis
observed during ILTV infection of the trachea. DNA extracel- of the ICP4 gene (Johnson et al., 1995b). The work that has inves-
lular traps were induced in heterophils exposed to ILTV in vitro, tigated the transcription and function of ILTV miRNA (mapped
consequently, the authors have hypothesized that heterophils are antisense to ICP4) has also suggested that they may play a role
the source of DNA extracellular traps in vivo as well (Reddy et al., in the establishment and/or maintenance of ILTV infections, as
2017). these miRNA (I5 and I6) are capable of directly cleaving ICP4
While different viral strains show different tissue tropism transcripts, thus possibly altering the balance between latent and
within the upper respiratory tract (Kirkpatrick et al., 2006a), lytic infection (Waidner et al., 2011), but this has not been con-
they can also replicate with different efficiencies in these tissues firmed. The development of a reliable ILTV latent infection model
(Oldoni et al., 2009; Lee et al., 2015) leading to varying levels of and tools to detect and differentiate latent infection from lytic
virulence and disease severity. It is interesting to note that in the infection using molecular methods or viral culture techniques
study reported by Kirkpatrick et al. (2006a), the viral strain that will help to close the gap in our knowledge of ILTV latency. It is
caused the highest mortality did not have a particular predilec- likely that the increasing availability of high throughput sequenc-
tion for tissues of the upper respiratory tract, and only caused ing technologies will facilitate the identification of LATs in sites
mild lesions in the trachea and limited viral shedding in tracheal of latent infection.
swabs, which further supports the idea that ILTV is a systemic
disease. Studies using tracheal and conjunctival mucosal explants Viral strategies to modulate host responses
have determined that ILTV has a limited capacity (compared An interesting finding from the work published by Reddy et al.
with other alphaherpesviruses) to invade the mucosae beyond (2014) was that ILTV infection blocked apoptosis in infected
the epithelium basement membrane, and this happened more cells, an observation that has also been made during infections
efficiently in conjunctival than in tracheal mucosal explants, with other herpesviruses (Wang et al., 2011; Chang et al., 2013;
which the authors suggest may be a reflection of the specific tissue Guo et al., 2015; Li et al., 2015). Further recent work has deter-
tropism of the viral strain used in experimental studies (Reddy mined that ILTV infection induced the phosphorylation and
et al., 2014). It is also possible that the basement membrane of activation of the proto-oncogene tyrosine-protein kinase Src and
the conjunctiva may be more prone to be penetrated by ILTV the focal adhesion kinase (Fak), which work in concert through
than that of the tracheal epithelium. In any case, the capacity of a positive feedback loop, to prolong the survival of infected cells,
ILTV (although limited) to penetrate the basement membrane thus maintaining ILTV replication at high levels. In vitro inhibi-
in any of the infected mucosae is consistent with haematologi- tion of Src through silencing RNA or a chemical compound
cal distribution of the virus, and also with detection of ILTV in resulted in increased ILTV virulence evidenced by increased cell
extra-respiratory tissues at later stages of infection (5–9 days pi) death, cytopathic effect, and cell necrosis and apoptosis, but also
(Bagust et al., 1986; Oldoni et al., 2009). limited viral replication, as inhibition was associated with a sig-
nificant reduction in viral replication. These results were validated
Latent infection in ovo, where chemical treatments to inhibit Src or Fak resulted
Very little is known about ILTV latent infection, despite its great in increased ILTV-related embryo death and hepatic lesions as
importance in the epizootiology of the disease. An ILTV car- well as reduced viral replication in a dose dependant manner (Li
rier state was firstly described which suggested that ILTV, like et al., 2016). Herpesviruses are well known for their capacity to
other herpesviruses, was capable of establishing latent infections modulate host responses towards infection, however, the viral fac-
(Hughes et al., 1987). Since then, reactivation of infection has tors responsible for the induction of this pathway remain unclear,
been reported several times (Hughes et al., 1989, 1991b; Coppo as this is the first time Src and Fak have been implicated in the
et al., 2012), and has been associated with stressors such as onset modulation of host responses towards any herpesvirus. Further to
of lay and re-housing with unfamiliar birds (Hughes et al., 1989). this, recent work has demonstrated that ILTV initiates apoptosis
Interestingly, the administration of immunosuppressive drugs in uninfected cells adjacent to infected cells through the paracrine
such as dexamethasone (Bagust, 1986; Hughes et al., 1989) or repression of p53, a molecule that is involved in anti-cancer and
cyclophosphamide (Bagust, 1986; Williams et al., 1992) has anti-viral responses. The induction of apoptosis in bystander cells