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.