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seldom fatal (O’Connor et al. 1993; Pronost et al. 2010). The numerous publications describing clinical signs and lesions caused by the experimentally derived highly virulent horse-adapted VBS of EAV reflect a severe fatal infection that is not representative of the disease caused by field strains of the virus in circulation over the past decades. Following respiratory infection, initial viral replication
occurs in alveolar macrophages and bronchiolar epithelial cells within 24 h post-infection (hpi) (Crawford and Henson 1973). During the initial 48 hpi, EAV rapidly localises in the regional lymph nodes, especially those associated with the respiratory tract (bronchial lymph nodes), and viral shedding in nasal secretions is initiated and typically lasts for 7–14 days, although it can extend to up to 21 days post-infection (dpi) (McCollum et al. 1971, 1988). Within 72 hpi, a cell-associated viraemia develops, which frequently extends for 3–19 dpi, and the virus is distributed throughout the body, replicating in macrophages, vascular smooth muscle cells, and endothelial cells and causing a systemic panvasculitis (Bryans et al. 1957b; Prickett et al. 1973; Lopez et al. 1996; MacLachlan et al. 1996; Del Piero 2000a; Balasuriya et al. 2013). Hence, the clinical manifestations of EVA reflect endothelial cell injury and increased vascular permeability. The characteristic histologic feature of EVA is a severe necrotising panvasculitis of small vessels. Affected muscular arteries show foci of intimal, subintimal and medial necrosis with oedema and infiltration with lymphocytes and neutrophils (Prickett et al. 1973; Lopez et al. 1996; MacLachlan et al. 1996; Del Piero 2000a).
Recent ex vivo (i.e. mucosal explants) and in vitro studies
to elucidate the early events in the pathogenesis of EAV infection demonstrated that virus localises in CD3+ T lymphocytes, CD172a+ myeloid cells, and a small population of IgM+ B lymphocytes found in the connective tissue (Vairo et al. 2013a). Interestingly, the virus was not detected in epithelial cells from the upper respiratory tract during the early phase of infection (Vairo et al. 2013a,b). These studies have shown that the nasopharynx and tubal–nasopharyngeal tonsils play an important role as primary sites of EAV replication during early infection, and high viral titres were detected during the first 7 dpi (Vairo et al. 2012). In addition, in vitro and in vivo studies have demonstrated increased transcription of genes encoding proinflammatory mediators (interleukin [IL]-1b, IL-6, IL-8 and tumour necrosis factor-a) following EAV infection, suggesting that these cytokines are critical in determining the severity of the disease (Moore et al. 2003b). Recently, it has been demonstrated that experimental inoculation of horses with in vitro CD3+ T lymphocyte susceptible or resistant phenotype could express different levels of proinflammatory and immunomodulatory cytokine mRNAs. Furthermore, horses possessing the in vitro CD3+ T lymphocytes resistant phenotype tend to develop more severe clinical signs compared to the horses with CD3+ T lymphocyte susceptible phenotype (Go et al. 2012b). Equine arteritis virus infection of pregnant mares can result
in abortion, and aborted fetuses are usually partially autolysed at the time of expulsion. Even though not fully understood, it is speculated that abortion occurs as a consequence of vasculitis of myometrial blood vessels, that leads to placental dysfunction and chorionic detachment (Del Piero 2000a). Aborted fetuses may exhibit interlobular pulmonary oedema, pleural and pericardial effusion, and petechial and ecchymotic haemorrhages on the serosal and
mucosal surfaces of the small intestine (Del Piero 2000a). Even though microscopic lesions in tissues from aborted fetuses are only occasionally detected (Johnson et al. 1991), viral antigen can be detected in the trophoblastic epithelium, chorioallantoic mesenchyma, pneumocytes, alveolar macrophages, thymic epithelium, splenic reticular cells, endothelial cells, renal interstitial cells, cells within glomeruli, rare tubular epithelial cells, and enterocytes by immunohistochemical staining (Lopez et al. 1996; Del Piero et al. 1997; Del Piero 2000a; Carossino et al. 2016a). With the exception of infected stallions, viral clearance
usually occurs by 28 dpi and is coincident with the appearance and rise in serum neutralising antibodies (McCollum 1969a; Fukunaga et al. 1981). However, a recent study has reported that infectious virus could still be recovered from tonsils of experimentally infected animals by 28 dpi (Vairo et al. 2012). EAV exclusively persists in the reproductive tract of carrier stallions (mainly the ampullae of the vas deferens) (Neu et al. 1988; Carossino et al. 2016b). The mechanism of persistence and cellular tropism of EAV in the long-term carrier stallion remain to be elucidated.
Immune response
Natural and experimental EAV infections induce a robust and protective immune response. Even though the innate immune response has not been comprehensively characterised, recent studies have demonstrated that EAV inhibits type I interferon (IFN) production and, thus, subverts the innate immune response (Go et al. 2014). It has been shown that 3 nonstructural proteins (nsp1, 2 and 11) have the capacity to block IFN synthesis, with nsp1 exerting the strongest effect. Following infection, both EAV-specific complement-fixing
(CF) and neutralising antibodies (VN) develop (McCollum 1969b; Fukunaga and McCollum 1977) and provide long- lasting immunity and protection from reinfection with most (if not all) viral strains. Both CF and VN antibodies develop between 7 and 14 dpi, and peak either after 2–3 weeks or 2–4 months post-infection, respectively (Fukunaga and McCollum 1977; Balasuriya et al. 1999b, 2002a, 2005; Balasuriya and MacLachlan 2004). CF antibodies steadily decline by 8 months post-infection, while neutralising antibodies persist for 3 years or more (Gerber et al. 1978b). Both structural proteins (GP5, M and N) and nonstructural proteins (nsp2, nsp4, nsp5 and nsp12) induce humoral immunity (Hedges et al. 1998; MacLachlan et al. 1998; Go et al. 2011b). GP5 contains 4 major neutralisation sites (A–D), and GP5-M heterodimerisation is essential for induction of antibody responses and protection (Balasuriya et al. 1995, 1997, 2002a). Despite the presence of high neutralising antibodies, EAV
persists in the reproductive tract of carrier stallions (Balasuriya et al. 2013, 2014). Therefore, viral evolutionary mechanisms take place during persistent infection in the reproductive tract, leading to the emergence of genetic variants with distinct neutralisation phenotypes due to amino acid substitutions in major viral neutralisation sites and, thus, conferring the ability of the virus to successfully escape humoral immunity (escape mutants) (Balasuriya et al. 1999a, 2001, 2004a; Hedges et al. 1999; Zhang et al. 2010a; Miszczak et al. 2012). Foals born to immune mares are protected against clinical EVA by passive transfer of VN antibodies in
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