Four-month-old, male, X-SCID rat (Rattus norvegicus).Rats within this colony were under clinical and pathologic investigation after a positive serology result for Pneumocystis carinii during routine quarterly sentinel surveillance. Few rats displayed evidence of mild to moderate respiratory distress and were sacrificed for follow-up P. carinii PCR and lung histopathologic evaluation. Lesions in the lungs suggested another viral etiologic agent in addition to P. carinii, and a full pathology evaluation was performed on two more rats.

Gross Description:  

Characteristic gross findings expected for the X-SCID strain (1) were present in all rats examined and consisted of severe thymic hypoplasia, unidentifiable lymph nodes, and hypoplastic spleens. All adult rats had mild crusting of the rostral nasal turbinates and multifocal, 1-2 millimeter diameter, white-tan foci on the pleural surface and fewer within the parenchyma on cut section. Few similarly-sized red foci were also present on the pleural surface and throughout the parenchyma.

Histopathologic Description:

Harderian gland:  There is severe atrophy and loss of the glandular acini with replacement by fibrous connective tissue. The epithelium of remaining glands is often necrotic or attenuated and infiltrated by mixed inflammatory cells composed of lympho-cytes, plasma cells, macrophages, and fewer neutrophils and mast cells. These inflammatory cells are present surrounding glands, ducts, and extend into fibrous connective tissue.  There are increased numbers of intralobular and interlobular ducts which are dilated and lined by hyperplastic or attenuated epithelium and multifocally contain sloughed cells and cellular debris.  Occasionally, ductal and acinar epithelial cells contain eosinophilic to amphophilic intranuclear inclusion that are up to 35µm in diameter and are sometimes surrounded by a clear halo.

Morphologic Diagnosis:  

Harderian gland:  Acinar atrophy, diffuse, severe, with fibrosis, lymphoplasmacytic inflammation, ductal hyperplasia, and epithelial intranuclear inclusion bodies.

Lab Results:  

Rats within this colony tested positive for Pneumocystis carinii via serology and PCR of nasal swabs. After histopathology was performed, additional PCR tests were submitted for rat cytomegalovirus and mouse adenoviruses 1 & 2. An additional PCR for polyomavirus was performed with primers designed using a target a region of the VP1 gene that is partially conserved among polyomaviruses, including those found in mice and hamsters; all follow-up PCR tests were negative.


Acinar atrophy/Rat polyomavirus

Contributor Comment:  

Additional histopathologic lesions, including epithelial necrosis, hyperplasia, dysplasia, and intranuclear inclusion bodies, were present in the nasal cavity, lung, salivary gland (parotid and submandibular), prostate gland, and uterus. Immunohistochemistry of the organs listed above showed strong staining with the pan-polyomavirus marker, PPIT.6 The virus was subsequently isolated from the salivary and Harderian glands of rats within this colony and sequenced. This is a novel polyomavirus phylogenetically distinct from the rat polyomavirus isolated and sequenced from feral Norway rats in 2015.2 Polyomaviruses (PyVs) are a family of DNA tumor viruses that are known to infect a variety of mammals, birds, and fish.1  Most mammalian polyomaviruses cause subclinical infections with life-long persistence in their natural immune competent hosts. However, when the host immunity is compromised, the virus can reactivate and cause disease.5 Until this discovery, five distinct PyVs have been identified in rodent hosts: murine PyV, mouse pneumotropic virus, hamster PyV, Mastomys PyV, and Rat PyV, whose full genomes are available in the GenBank database.2 The first polyomavirus in rats was described as a wasting disease in athymic nude rats by Ward, et al, in 1984.7 Inclusion bodies were described in the salivary glands, Harderian glands, lungs, and nasal glands, similar to those present in this colony.7  Also, similar to the previously described report is the fact that X-SCID rats are severely immune suppressed.3  This strain has severely hypo-plastic lymphoid organs and markedly decreased T cells, B cells, and NK cells, making them an excellent model for xenotransplantation studies.3  This severe immune suppression makes them particularly susceptible to viral infections like PyV.  It is not yet clear where these rats were infected with the virus or whether immune competent rats can be infected, show clinical symptoms, or have histologic lesions when infected with this novel Rat PyV. A full description of pathology findings and genomic sequencing information for this novel virus is pending publication (Rigatti and Toptan, et al).

JPC Diagnosis:  

Harderian gland: Dacryoadenitis, necrotizing and histiocytic, chronic, diffuse, moderate to severe, with edema and occasional epithelial intranuclear inclusion bodies, X-SCID rat, Rattus norvegicus.

Conference Comment:  

The contributor provides an outstanding description and synopsis of the lesions of a novel polyomavirus (PyV) infection in an X-SCID rat.  Particularly striking are the characteristic large, prominent epithelial intranuclear viral inclusions that marginate the chromatin and often enlarge the nucleus; there is variation among the slides in the number of intranuclear inclusions present. As mentioned by the contributor, the majority of mammalian PyVs cause subclinical infections with life-long persistence in immune competent natural hosts, much like herpesviruses.4 However, when the host immunity is compromised, such as in this particular strain of rat, the virus can cause disease. Polyomaviruses are of particular research interest, and murine PyVs are used as models of persistent virus infection in human disease.1,2,3,6 The most well-known human PyVs, BK virus and JC virus, are associated with severe disease in immunosuppressed human patients; and Merkel cell PyV is associated with Merkel cell carcinoma, a rare and highly aggressive neoplasm of neuroendocrine cells of the skin.2 The virus has long been established as potentially carcinogenic, causing many different types of tumors in experimental systems, hence the name poly(many)-oma(tumor)-virus.

Conference participants noted that this case nicely demonstrates cytomegaly, karyomegaly, and glassy intranuclear inclusions characteristic of PyV infection in the Harderian gland. Many participants noted that rat cytomegalovirus infection can cause similar inclusions in the Harderian gland of rats, with large eosinophilic “owl-eye” inclusions that marginate the chromatin.4  However, PyV inclusions in tissue have a homogenous basophilic or amphophilic appearance, which is distinct from cytomegalovirus and adenoviral inclusions.4 Participants also discussed that sialodacryoadenitis virus, a highly contagious betacoronavirus, which can cause similar lesions in the Harderian gland of rats; however, that virus does not result in the formation of intranuclear inclusions.4 Attendees discussed some other significant PyVs of veterinary importance, including simian virus 40 (SV40) which caused progressive multifocal leukoencephalopathy in immunosuppressed rhesus macaques; the Mesocricetus auratus PyV1 which induces trichoepithelioma and lymphoma in hamsters; the K virus and murine pneumotropic virus in mice; Procyon lotor PyV1 which causes high-grade neuroglial olfactory tumors in raccoons; Aves PyV1 that results in budgerigar fledgling disease in psittacine birds; and goose hemorrhagic PyV1, the cause of hemorrhagic nephritis and enteritis in anseriform birds.1-7 The conference moderator cautioned participants that, while inclusions present in the intra-orbital Harderian gland are due to viral infection, pseudoinclusions and syncytial cells in the exorbital lacrimal gland are part of its normal anatomy and should not be confused for viral cytopathic effect. In addition, participants noted numerous mast cells within the interlobular connective tissue, which is also a normal finding in rats. The moderator further observed that within the adjacent eye the retinal epithelium lacks pigment, indicating that this rat is an albino. As a result of the lack of pigmentation, albino rats are much more susceptible to retinal degeneration and cataract formation induced by ultraviolet light as compared to normally pigmented animals. Degenerative changes may also occur in the Harderian glands of rats exposed to high-intensity lights.4


1. Buck CB, Van Doorslaer K, Peretti A, Geoghegan EM, Tisza MJ, An P, Katz JP, Pipas JM, McBride AA, Camus AC, McDermott AJ, Dill JA, Delwart E, Ng TF, Farkas K, Austin C, Kraberger S, Davison W, Pastrana DV, Varsani A. The ancient evolutionary history of polyomaviruses. PLos pathogens. 2016; 19:12(4):e1005574.
2. Ehlers B, Richter D, Matuschka FR, Ulrichd RG. Genome sequences of a rat polyomavirus related to murine polyomavirus, rattus norvegicus polyomavirus 1. Genome Announc. 2015; 3(5):e00997-15.
3. Mashimo T, Takizawa A, Voigt B, Yoshimi K, Hiai H, Kuramoto T, Serikawa T. Generation of knockout rats with x-linked severe combined immunodeficiency (X-SCID) using zinc-finger nucleases. PLoS one. 2010; 5(1):8870.
4. Percy DH, Barthold SW. Rabbit. In: Pathology of Laboratory Rodents and Rabbits, 4th ed., Ames, IA: Blackwell Publishing; 2016:122,161.
5. Stevens H, Bertelsen MF, Sijmons S, Van Ranst M, MaesP. Characterization of a Novel Polyomavirus Isolated from a Fibroma on the Trunk of an African Elephant (Loxodonta africana). PLoS one. 2013; 8(10):1-9.
6. Toptan T, Yousem SA, Ho J, Matsushima Y, Stabile LP, Fernández-Figueras MT, Bhargava R, Ryo A, Moore PS, Chang Y. Survey for human polyomaviruses in cancer. JCI Insight. 2016; 1(2):85562.
7. Ward JM, Lock A, Collins Jr MJ, Gonda MA, Reynolds CW. Papovaviral sialoadenitis in athymic nude rats. Lab Animals. 1984; 18:84-89.

Click the slide to view.

1-1. Lung, X-SCID rat.

1-2. Eye, with Harderian gland, X-SCID rat.

1-3. Harderian gland, X-SCID rat.

1-4. Harderian gland, X-SCID rat.

1-5. Harderian gland, X-SCID rat.

1-6. Harderian gland, X-SCID rat.

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