JPC SYSTEMIC PATHOLOGY

URINARY SYSTEM

January 2024

U-V09

 

Signalment (AFIP #2329759): 2-year-old male rhesus monkey.

 

HISTORY: This 2-year-old male rhesus monkey was born at the primate center and entered in a study of simian immunodeficiency virus pathogenesis. He was inoculated with SIVmac251 and died 1 year later.

 

HISTOPATHOLOGIC DESCRIPTION: Kidney: There is diffuse, mild to moderate expansion of the interstitium by fibrous connective tissue separating and surrounding tubules and scattered individual and rare aggregates of lymphocytes and plasma cells. Tubules are multifocally atrophic, ectatic, or contain pale eosinophilic granular material (protein) or few sloughed epithelial cells. Tubules display one or more of the following changes: lined by swollen epithelial cells with slightly basophilic cytoplasm that pile up to 4 layers (hyperplasia, regeneration), or are attenuated, or have swollen, vacuolated cytoplasm (degeneration), or are shrunken, hypereosinophilic, with pyknotic nuclei (necrotic). Multifocally there are rare 6-8 µm, round to angular, basophilic intranuclear viral inclusion bodies in tubular epithelial cells and the parietal epithelial cells of Bowman’s capsule. Multifocally, glomeruli have segmental hypertrophic parietal and visceral epithelial cells or synechia.

 

MORPHOLOGIC DIAGNOSIS: Kidney: Nephritis, tubulointerstitial, lymphocytic, chronic, diffuse, moderate, with tubular degeneration, necrosis, and regeneration, moderate interstitial fibrosis, and epithelial intranuclear viral inclusions, Rhesus monkey (Macaca mulatta), primate.

 

ETIOLOGIC DIAGNOSIS: Polyomaviral nephritis

 

CAUSE: Simian virus 40

 

SYNONYMS: Vacuolating agent infection, Simian papovavirus infection, Simian polyomavirus, Progressive multifocal leukoencephalopathy, Polyomaviral interstitial pneumonia, Papovaviral tubulointerstitial nephritis

 

GENERAL DISCUSSION: 

• Member of the Polyomavirus genus of the family Polyomaviridae, nonenveloped, circular, double-stranded DNA virus
• Latent infection in feral and captive Asian macaques (rhesus, cynomolgus, Japanese, and Formosan rock macaques; old world primates); high incidence of infection
• Overt disease only in immunocompromised individuals, such as those co-infected with SIV
• Lesions in brain, kidney and lung and other tissues
• Oncogenic in non-host species 
• Zoonotic potential is controversial, but some reports support the potential in those in close contact with nonhuman primates (zoo workers)

 

PATHOGENESIS:

• Disease symptoms result from reactivation of latent infection that originally occurred early in life (in kidney, CNS and circulating lymphocytes) or primary infection later in life during periods of immunosuppression
• Proposed that renal lesions predominate in macaques acquiring infection during immunosuppression and CNS lesions predominate following a recrudesce of latent infection 
• Readily transmitted; most animals >1 year are seropositive in conventional colonies; may be associated with mild respiratory illness; shedding occurs in nasopharyngeal secretions, urine and feces; in the immunocompetent natural host, the virus remains latent, primarily in renal tissue   
• Transmission via urine is suspected 
• Large and small T (tumor) antigens à bind to viral regulatory sequences > facilitate transcription of late viral genes 

 

TYPICAL CLINICAL FINDINGS:  

• Asymptomatic in immunocompetent individuals
• Clinicopathologic: Mild hypochromic, microcytic anemia, moderate BUN and creatinine elevations

 

TYPICAL GROSS FINDINGS:  

• Kidneys: Multiple linear petechiae in inner cortex and medulla
• Lung: Patchy firm, red areas that do not collapse and have a frothy fluid 
• Brain: Multifocal to coalescing 1-3 mm gray-white, translucent foci in white matter of cerebrum and brainstem

 

TYPICAL LIGHT MICROSCOPIC FINDINGS:

• Kidney: Collecting tubules lined by hypertrophic or hyperplastic epithelium in inner cortex and medulla; there are occasionally large deeply basophilic intranuclear viral inclusion bodies in tubular epithelial cells; may also be present in sloughed tubular epithelial cells/casts; there is chronic nonsuppurative tubulointerstitial nephritis, fibrosis, glomerular sclerosis, and atrophy
• Lung: Proliferative interstitial pneumonia, with intranuclear inclusions within hypertrophied type 2 pneumocytes
• Brain: Multifocal to confluent regions of demyelination; cerebral white matter and subependymal regions; Multifocal to coalescing areas of demyelination of cortical white matter and in subependymal regions; large basophilic intranuclear inclusions in oligodendrocytes and astrocytes; gitter cells and astrocytes predominate
  1. SIV infected macaques with AIDS: Distinct SV40-induced meningoencephalitis without demyelination; astrocyte infection predominates
  2. SV clones with unique neuron tropism have been developed

 

ULTRASTRUCTURAL FINDINGS: 

 

ADDITIONAL DIAGNOSTIC TESTS: 

• Demyelination confirmed with luxol fast blue
• IHC, ISH, or EM to confirm SV40
• Serology is of little value since most rhesus monkeys are seropositive

 

DIFFERENTIAL DIAGNOSIS: 

Viruses causing inclusion bodes can be differentiated based on size, using electron microscopy, or antigenic or genetic composition using virus-specific immunohistochemistry

• Adenovirus: Very large basophilic intranuclear inclusion bodies with a “smudgy” appearance that fill the nucleus within mesenchymal cells; uncommon cause of tubulointerstitial nephritis in nonhuman primates
• Cytomegalovirus: Large basophilic intranuclear inclusions with a clear halo (“owl eye”) within epithelial cells
• Herpesvirus simiae (B virus): Eosinophilic inclusion bodies
• Other herpesviruses

 

COMPARATIVE PATHOLOGY:

• Hamsters: Oncogenic in suckling hamsters when experimentally infected; tumor type based on age and method of inoculation
• Humans: Contamination of rhesus kidney cell cultures by SV40 used in the early production of polio vaccines; brain lesions resemble progressive multifocal leukoencephalopathy (PML) in humans with JC virus reactivation 
• Other polyoma viruses

• Budgerigar fledgling disease: A highly contagious and fatal disease of young budgerigars and non-budgerigar psittacines with karyomegalic cells with prominent intranuclear inclusion bodies in many tissues
• Hamster polyoma virus: Causes transmissible lymphoma in hamsters; can occur in epizootics; trichoepitheliomas also possible. 
• Equine polyomavirus infection: Marked interstitial nephritis and tubulitis; INIB in tubular epithelial cells in distal nephron; can affect other organs

• Raccoons: Novel raccoon polyomavirus is associated with neuroglial brain tumors; olfactory tract and bulb; some extend into the nasal cavity

• K virus of mice: Experimental disease; oral inoculation of neonatal mice causing respiratory distress and death

 

REFERENCES:

1. Barthold SW, Griffey SM, Percy DH. Pathology of Laboratory Rodents and Rabbits. 4^th ed Ames, IA: John Wiley & Sons, Inc; 2016:176-177.
2. Cianciolo RE, Mohr FC. Urinary system. In: Maxie MG, ed. Jubb, Kennedy, and Palmer’s Pathology of Domestic Animals. Vol 2. 6th ed. St. Louis, MO: Elsevier; 2016:432.
3. Delaney MA, Treuting PM, Rothenburger JL. Rodentia. In: Terio KA, McAloose D, St. Leger J, eds. Pathology of Wildlife and Zoo Animals. London, UK: Academic Press; 2018:506-507.
4. Fahey MA, Westmoreland SV.  Nervous System Disorders of Nonhuman primates and Research Models.  In: Abee CR, Mansfield K, Tardif S, Morris T, eds. Nonhuman primates in biomedical research: Diseases. Vol 2. 2nd ed. London, UK: Elsevier; 2012:739-740.
5. King, NW. Simian Virus 40 Infection. In: Jones, T.C., Mohr, U., Hunt, R.D. eds. Nonhuman Primates I. Monographs on Pathology of Laboratory Animals. Berlin, Heidelberg: Springer;1993:37-38.
6. Reavill DR, Dorrestein G. Psittacines, Coliiformes, Musophagiformes, Cuculiformes. In: Terio KA, McAloose D, St. Leger J, eds. Pathology of Wildlife and Zoo Animals. London, UK: Academic Press; 2018:786-788. 
7. Wachtman L, Mansfield K. Viral diseases. In: Abee CR, Mansfield K, Tardif S, Morris T, eds. Nonhuman Primates in Biomedical Research: Diseases. Vol 2. 2nd ed. London, UK: Elsevier; 2012:30-33.

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