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