Papillomavirus infection of ruminants

Current authors:
J S MUNDAY - Professor of Veterinary Pathology, BVSc, PhD, Dipl ACVP, School of Veterinary Science, Massey University, Tennent Drive, Palmerston North, Manawatu, 4410, New Zealand
S ROPERTO - Department of Veterinary Medicine and Animal Production, Naples University “Federico II”, Naples, Italy

GENERAL INTRODUCTION: PAPILLOMAVIRIDAE

Papillomavirus infections in bovines

There are currently 23 bovine papillomavirus (BPV) types that have been fully sequenced.³ These BPVs are classified within five genera; Deltapapillomavirus, Xipapillomavirus, Epsilonpapillomavirus, Dyoxipapillomavirus, and Dyokappapapillomavirus.¹⁵ Of these, the BPVs that have been most firmly established as a cause of disease in bovines are the DeltaPVs (especially BPV-1 and BPV-2) and the XiPVs (especially BPV-4). 

The DeltaPVs demonstrate some important differences to papillomaviruses in other genera. First is their ability to infect, and cause disease in, other host species. This wider host range allows these viruses to cause disease not only in bovines including cattle, water buffalo, and yak, but the DeltaPVs also cause equine sarcoids (BPV-1, -2, and -13)¹⁴ and feline sarcoids (BPV-14).³⁶ A second unique property of the DeltaPVs is their ability to infect and cause proliferation of both epithelial and mesenchymal cells.²⁵ It is probable that the unique ability to influence mesenchymal cell growth is due to the proteins produced by the DeltaPVs to influence cell growth. Unlike other papillomavirus types that promote epithelial growth and differentiation primarily through E7 protein-mediated inhibition of the retinoblastoma protein (pRb),³² the predominant oncoprotein of the DeltaPVs is the E5 protein.⁶⁴ This protein influences cell growth by activating the platelet derived growth factor-β receptor, phosphoinositide 3-kinase, tyrosine kinase c-Src,⁶ and the subunit D of the V1-ATPase proton pump.⁵⁰ In addition, the DeltaPV E5 protein promotes overexpression of the transcription factor E2F3 by downregulating pRb via calpain 3.⁴⁸

Transmission of papillomaviruses between animals is thought to most often occur from either direct contact or indirectly via environmental contamination. However, bovine DeltaPVs can also be found in semen of infected animals,²⁹ suggesting that sexual transmission of these papillomaviruses could also be possible. Additionally, productive infections of DeltaPVs have been demonstrated within the trophoblasts of the placenta in cattle and water buffaloes⁴⁶ and there is accumulating evidence that vertical transmission of papillomaviruses may be an important method of spread of DeltaPVs within ruminant species.

Cutaneous papillomas (warts)

Cutaneous papillomas are the most frequent clinical manifestation of papillomavirus infection in bovines and papillomas have been associated with numerous different papillomavirus types.⁴⁴ It was initially suggested that each bovine papilloma subtype was caused by a specific BPV type. However, more recent studies have demonstrated that most papillomas contain numerous BPV types,⁵⁵ making it difficult to determine which BPVs cause papillomas and which are present simply as a coincidental infection.

Cutaneous papillomas commonly affect cattle throughout the world and warts have been detected on up to a third of cattle at slaughter.²⁸ Bovine papillomaviruses have also been reported to cause cutaneous papillomas in water buffalo and yak.^{2, 56}

Papillomas typically develop on younger animals. While the epidemiology of infection remains poorly understood, this is likely due to BPV infection of an immunologically naïve animal. The lack of protective antibodies allows rapid replication by the BPV, marked epithelial hyperplasia, and the development of a visible papilloma.³³ After papilloma development, the body develops protective antibodies against the BPV type and an animal will be protected against further infections by this BPV type.^{17, 26} The development of a cell-mediated immune response results in lesion resolution.¹⁶ As with all papillomaviruses, infection is probably due to a combination of exposure to the BPV and the presence of skin microtrauma allowing the BPV access to the basal cell layer of the epidermis.⁵⁴ Bovine papillomaviruses can spread by direct contact and housed cattle develop papillomas more frequently than cattle on pasture. Indirect spread from the environment or from farming equipment is common. Genital papillomas are spread by venereal transmission.³⁵

Papillomas can develop anywhere on the body but appear to be most frequent around the head (Figure 1 and Figure 2). They also commonly develop on the penis and vulva and on the teats. Most animals will have multiple papillomas. An accumulation of keratin over the surface of the papillomas can result in a grey colour and a hard roughened surface. Ulceration is rarely observed, the lesions are not painful, and generally appear to be of little concern to the animal. Rarely teat papillomas can interfere with normal milking practices and predispose to mastitis while large genital papillomas can prevent mating.

Papillomavirus-induced cutaneous papillomas in bovines can be subdivided into squamous papillomas and fibropapillomas. A squamous papilloma develops as the marked epidermal hyperplasia that is caused by the papillomavirus infection results in folding of the epidermis. The folded epidermis forms an exophytic mass...