Discussion
Oncogenic OaPVs infect only ovine species. Accordingly, all benign and malignant OaPV-related tumors have been described exclusively in sheep. OaPVs have never been associated with any pathology in other domestic animals. This study shows, for the first time, that cross-species transmission by both Delta and epitheliotropic DyokappaOaPVs occurs between sheep (Ovis aries ) and cattle (Bos taurus ). All OaPV genotypes were detected through both DNA detection and transcriptionally active forms in PBMC samples from healthy cattle. Transcripts of E oncogenes as well as the L1 gene were peculiar molecular findings of this study, which suggested that the biological properties of OaPVs might be characterized by inducing both abortive and productive infections in cattle.
The scant information on the epidemiology of OaPV infections is the reason for the poor understanding of the biological significance of these viruses in cattle. PV transmission by blood in sheep and other species appears to be a key event in their pathology and epidemiology (Cutarelli et al., 2021b). It has been suggested that the blood infected with PV yields infections at permissive sites with detectable viral DNA, RNA transcripts, and viral proteins (Cladel et al., 2019; Syrjänen and Syrjänen, 2021). Similar to humans, it is conceivable that ecological factors can influence the virulence of several PVs from different genera, and the concomitant ecological changes in different hosts linked to the human domestication of farm animals, including sheep, may have increased their susceptibility to OaPV cross-species transmission and/or simply increased the frequency of physical contact to grant OaPVs improved access to a potential new host.
PVs have a long history of co-divergence with their hosts, and hence, these viruses are relatively more host-specific than other viruses (Geoghegan et al., 2017). Indeed, to date, Bovine Delta -PVs have been the only PVs responsible for documented cases of natural cross-species transmission leading to carcinogenetic events via oncoproteins encoded by E genes (IARC, 2017; Roperto et al., 2013). Most OaPV-harboring cattle in this study have in common highlands rich in bracken ferns with sheep that live in the same geographical zones. Close physical proximity and/or sharing of grazing lands may be a prerequisite for PV types to cross host-species barriers, as suggested by the detection of various BPVs in other hoofed domestic animals (de Villiers et al., 2004; Cutarelli et al., 2021; Roperto et al., 2021). It is conceivable that animal husbandry practices and/or mammalian sympatry may contribute toward the cross-species transmission of OaPVs. This is corroborated by the fact that a high prevalence of OaPVs was found in cattle sharing large enclosures with sheep, which facilitates direct and indirect contacts. Therefore, our study strengthens the assumption that cross-species transmission may occur among related hosts inhabiting the same geographic areas (Parrish et al., 2008). Successful cross-species transmission has been suggested to occur among phylogenetically related hosts, likely because they share fewer divergent cell receptors (Murthy et al., 2013). Indeed, it is believed that the closer the phylogenetic relationship between hosts, the more likely it is that a pathogen will be able to jump between them with appropriate exposure. Immunosuppressants of bracken coupled with more frequent exposure between sympatric hosts may help OaPVs jump host species, resulting in host switching.
OaPVs have also been detected in cattle from intensive dairy farms without any apparent contact with sheep. The cows were fed grass hay and corn silage prepared with grass and maize grown using irrigation water from the Volturno River. PVs have recently been detected and quantified in surface water of rivers (Iaconelli et al., 2015). It has been shown that PVs can be detected in vegetables and irrigation water and long-term consumption of HPV-polluted water can be associated with cell transformation (Ghaffar et al., 2018; Itarte et al., 2021). Several PV genotypes of different genera are known to be responsible for oral infection; however, the information on associated risk factors is still limited (Wong et al., 2018). It is possible that polluted irrigation water may have played an overlooked role in the OaPV epidemiology. The molecular findings of this study appear to strengthen our suggestions since OaPV DNA has been detected and sequenced in hay as well as corn silage samples. However, further studies on virus isolation from these feed should be conducted to better understand the actual risk of virus transmission from feed. It is well known that PVs can survive without significant loss of infectivity during desiccation, as well as at low pH and high temperatures, chemical features that characterize these feed (Roden et al., 1997; Nielsen et al., 2021). Furthermore, a recent scientific report by the European Food Safety Authority (EFSA) showed that some viruses, including African swine fever virus (ASFV), can be transmitted through feed based on hay and maize (Nielsen et al., 2021).
As the number of cross-species transmissions continues to rise and viral diseases pose a continual threat to animal populations, understanding the ecological diversity of OaPV prevalence and genotype distribution among new host species in different geographical regions remain essential. The need to understand how PV transmit within a given species, as well as to new host species, has become increasingly important as the cross-species transmission of viruses from one host species to another is responsible for the majority of emerging infections that can profoundly affect animal health (Geoghegan et al., 2017).
Finally, both circulating OaPV DNA and OaPV RNA have been reported in the blood samples of cattle found healthy by ante- and post-mortem anatomo-clinical observations, confirming that blood represents an important primary route of PV infection and that OaPVs can disseminate to any organ via the bloodstream. We detected and sequenced OaPVs in the urinary bladder of healthy cattle (personal observations), which supports the hypothesis that OaPVs may contribute to the composition of the normal bladder microbiota of cattle. BPV and HPV DNA have also been reported in the blood of healthy cattle (De Falco et al., 2021a) and asymptomatic blood donors (Vergara et al., 2019). It has been suggested that there is an actual likelihood that HPVs could reach epithelial target sites in the blood, which might explain how and why HPVs are associated with tumors of several organs (Cladel et al., 2019; Syrjänen and Syrjänen, 2021 Vergara et al., 2019; Conceição Gomes Nascimento et al., 2021). Accordingly, PV transmission by blood represents a conceptually novel idea, and if accepted more generally, this would change the current thinking about the modes of PV spread, including HPV within the host (Cladel et al., 2019; Roperto et al., 2013; Syrjänen and Syrjänen, 2021). In this context, a naturally occurring OaPV infection may be an additional animal model that sheds light on the PV biology, including issues related to viral tropism in the One Health approach.
Data Availability All relevant data are within the manuscript and its Supporting information files.
Funding: This research was partially supported by Istituto Zooprofilattico Sperimentale del Mezzogiorno. The funders of the work did not influence study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Conflict of interest statement: The authors have declared that no competing interests exist.
Author Contributions: Francesca De Falco and Anna Cutarelli: Methodology; Data curation; Formal Analysis, Investigation: Bianca Cuccaro: Formal analysis; Investigation; Cornel Catoi and Esterina De Carlo: Validation; Visualization; Writing – original draft; Sante Roperto: Conceptualization, Supervision, Validation, Visualization, Data curation; Funding Acquisition, Writing – original draft; Writing – review and editing