Introduction
Papillomaviruses (PVs) are small, non-enveloped, double-stranded DNA
viruses infecting mucosal and cutaneous epithelia of mammals, reptiles,
birds, and fish (IARC, 2007; Willemsen et al., 2020). As part of the
commensal flora, these viruses can be found in the healthy skin and
mucosa in a latent state; reactivation occurs following the loss of
immunity, resulting in a persistent infection which causes oncogenic
risk, with occurrence of tumors at several body sites (Sichero et al.,
2019; Strickley et al., 2019).
Ovine papillomavirus (OaPV) infections occur in sheep and
are caused by four oncogenic
genotypes. OaPV1, OaPV2, and OaPV4 belong to the genus Delta -PV,
while OaPV3 belongs to the genus Dyokappa- PV
(http://pave.niaid.nih.gov/).
Ovine Delta- PV is characterized by marked tropism for both
mesenchymal and epithelial cells (Tore et al., 2017), whereas OaPV3
exclusively infects epithelial cells (Alberti et al., 2010). OaPVs have
sporadically been associated with ruminal fibropapillomas, papillomas,
papillomatosis, and fibropapillomas of the skin (Gibbs et al., 1970;
Vanselow et al., 1982; Norval et al., 1985; Trenfield et al., 1990;
Tilbrook et al., 1992; Hayward et al., 1993; Uzal et al., 2000).
Although it has been suggested that OaPVs may be responsible for the
progression of cutaneous papillomas to squamous cell carcinomas (SCCs)
in sheep (Vanselow et al., 1982), a novel OaPV, namely OaPV3, was only
recently identified in a high number of SCCs in sheep, suggesting that
OaPV3 could represent a key infectious agent in the onset of SCC in
ovine species (Alberti et al., 2010; Vitiello et al., 2015). OaPV3 and
OaPV4 are well-characterized molecularly, as they are the only OaPVs
identified in tumor samples from sheep. Indeed, it has been shown that
the E6 and E7 oncogenes of OaPV3 and OaPV4 can immortalize primary sheep
keratinocytes and regulate the levels of proliferative proteins such as
cyclin A and cyclin-dependent kinases (CDKs). However, it has been
suggested that only OaPV3 E7 can strongly promote the cleavage and
degradation of ovine retinoblastoma protein (pRb) (Tore et al., 2019).
Calpain-mediated cleavage of pRb may result in the dysregulation of E2F
transcription factors, which play crucial roles in the cell cycle, cell
proliferation, and viral replication (Darnell et al., 2007; Scarth et
al., 2021). OaPV1 and OaPV2 are not well characterized molecularly so
far; however, it has been postulated that they could be associated with
tumors in sheep. DNA sequences related to OaPV2 E5 have been found in
the mass of the buccal cavity of a pig, suggesting that similar to
bovine Delta -PVs, ovine fibropapillomaviruses may also be
responsible for cross-species transmission (Munday et al., 2020). Unlike
OaPV3 that induces cell transformation by the E6 and E7 oncoproteins
(Tore et al., 2019), ovine Delta -PVs may exert their main
oncogenic activity through the oncoprotein encoded by the E5 gene, as
verified in most artiodactyl fibropapillomaviruses (Munger and Howley,
2002). OaPV1, OaPV2, and OaPV4 are fibropapillomaviruses and belong to
the Delta -PV clade, which is known to encode the most highly
conserved E5 oncoproteins (Van Doorslaer, 2013); this is likely because
of the integration of the E5 ORF in the Delta- PV genus occurring
between 65 and 23 million years ago (Garcia-Vallvé et al., 2005).
Recently, the first systematic research on the molecular epidemiology of
OaPV infection was conducted in sheep and revealed a divergent
geographical prevalence of OaPV genotypes. Furthermore, this survey
showed a high prevalence of OaPV infection since OaPV DNA was found in
up to 76.4% of the peripheral blood of apparently healthy sheep (De
Falco et al., 2021b).
This study aimed to provide evidence of a novel cross-species
transmission and infection by OaPVs which were detected, quantified, and
found to be expressed in the peripheral blood mononuclear cells (PBMCs)
of cattle.