JPC SYSTEMIC PATHOLOGY
DIGESTIVE SYSTEM
November 2018
D-V14

Signalment (JPC #1199696):  Marmoset

HISTORY:  This animal died after a short, severe illness.  These marmosets were housed with a group of squirrel monkeys.

HISTOPATHOLOGIC DESCRIPTION:  Liver:  Approximately 40% of the section is characterized by random, multifocal to coalescing foci of hepatic cord architecture loss and replacement by eosinophilic cellular and karyorrhectic debris and few scattered degenerate neutrophils (necrosis).  At the periphery of the necrotic foci, hepatocytes are individualized and have either a hypereosinophilic cytoplasm and a pyknotic nucleus (necrotic) or a swollen, pale, vacuolated cytoplasm (degeneration), and contain a 5-12um, round, eosinophilic intranuclear inclusion body that peripheralizes the chromatin and is occasionally rimmed by a 2 um clear zone.  Randomly, there are few multinucleate hepatocytes (viral syncytia) that contain similar intranuclear inclusions within small, shrunken pyknotic nuclei.  Diffusely, remaining hepatocytes are mildly swollen with lacy cytoplasm or an intracytoplasmic vacuole that displaces the nucleus (glycogen type and lipid type vacuolar degeneration).

MORPHOLOGIC DIAGNOSIS: Liver:  Hepatocellular degeneration and necrosis, acute, random, multifocal to coalescing, with hepatocellular eosinophilic intranuclear viral inclusion bodies and rare viral syncytia, marmoset (Callithrix jacchus), nonhuman primate.

ETIOLOGIC DIAGNOSIS:  Herpesviral hepatitis

CAUSE:  Saimiriine Herpesvirus 1; SaHV1

ETIOLOGY SYNONYM:  Herpesvirus tamarinus (Herpes T); Herpesvirus platyrrhinae type 1; Marmoset herpesvirus; Herpesvirus M; Cebid herpesvirus 1; Saimirine herpes 1

GENERAL DISCUSSION:

• Herpesviruses are double-stranded DNA viruses that form a capsid within the host nucleus, require host cell lysis to complete viral replication, and persist in a latent form within the host
• The family Herpesviridae is divided into three subfamilies:
  • Alphaherpesvirus: Latency in nerves (typically sensory ganglia), grow rapidly, lyse host cells; has 4 genera:
    • Simplexvirus: human herpesvirus 1 and 2, macacine herpesvirus 1 AKA B virus, Saimiriine herpesvirus 1 AKA herpesvirus tamarinus
    • Varicellovirus: human herpesvirus 3 AKA Varicella-zoster virus, Cercopithecine herpesvirus 9 AKA simian varicella virus
    • Mardivirus: Gallid herpesvirus 2 AKA Marek’s disease virus
    • Iltovirus: Gallid herpesvirus 1, AKA infectious laryngotracheitis virus
  • Betaherpesvirus: Latency in secretory glands, kidneys, lymphoreticular cells, and other tissues but NOT neurons
  • Gammaherpesvirus: Latency in lymphocytes, may induce lymphoproliferation and/or lymphoid malignancy; includes Saimiriine Herpesvirus 2 (Herpesvirus Saimiri)
• SaHV1 is an alphaherpesvirus, genus Simplexvirus, first isolated from tamarins and is referred to as Herpesvirus tamarinus or Herpes T, though the squirrel monkey is the natural host
• Causes an acutely fatal disease in marmosets, tamarins, African green, owl, howler and spider monkeys; the natural host (squirrel monkey) is usually asymptomatic (reservoir host), where virus remains latent within sensory ganglia with periodic reactivation and shedding in oral secretions

PATHOGENESIS:

• Exposure of marmoset, tamarin, or owl monkey to carrier species à 7-10 day incubation period à disseminated necrotizing disease (skin, oral mucosa, numerous parenchymal organs) à death 24-72 hours after onset of clinical signs
• Intradermal and enteric routes of infection are associated with generalized disease (necrosis of epidermis, oral mucosa and numerous parenchymal organs), while aerosol inoculation results in pneumonitis; all exposure routes are fatal
• Alphaherpesviruses attach to the cell at specific receptor sites via a particular envelope glycoprotein, fuse with the plasma membrane, and release nucleocapsids into the cytoplasm à the DNA-containing core moves into the nucleus à viral DNA is transcribed by cellular DNA-dependent RNA polymerase II à viral multiplication in the nucleus à virus acquires a lipid envelope by budding through the nuclear membrane

TYPICAL CLINICAL FINDINGS:

• Squirrel monkey (reservoir host): infection is common but clinical disease is rare and limited to (rare) vesicles and ulcers of oral mucosa
• Marmosets, tamarins, and owl monkeys: epizootic fatal systemic disease with high mortality characterized by rhinitis, conjunctivitis, oral and labial vesicles and ulcers, anorexia and depression, and ulcerative dermatitis (especially of the face) sometimes with hyperesthesia and intense pruritus, with progression to death in 24-48 hours

TYPICAL GROSS FINDINGS:

• Lesions may be minimal due to acute death
• Ulcerations throughout the GI tract from the lips and oral cavity through the esophagus and small and large intestines, as well as dermal or labial ulcers
• Gray-white focal necrosis of the liver and other viscera
• Hemorrhage in the adrenal cortex and lymph nodes
• Edema of the eyelids and the periorbital area
• Swelling of the parotid salivary gland

TYPICAL LIGHT MICROSCOPIC FINDINGS:

• Multifocal full-thickness epidermal and/or mucosal necrosis with basophilic to eosinophilic intranuclear inclusion bodies (Cowdry type A) and viral syncytia adjacent to areas of necrosis; relative sparing of adnexa; inflammation may be minimal due to the acute lethality
• There may also be multifocal necrosis in other organs such as intestine, liver, spleen, lung, kidney, adrenal gland
• Degeneration of the ganglion cells of the myenteric (Auerbach’s) and submucosal (Meissner’s) plexus
• Occasionally, minimal encephalitis

ULTRASTRUCTURAL FINDINGS:

• Herpesviridae are large (120-200 nm), enveloped viruses within an icosahedral capsid
• Dense core 120-200 nm virions acquire an envelope by budding through the nuclear membrane (characteristic ultrastructural finding)

ADDITIONAL DIAGNOSTIC TESTS:

• Electron microscopy
• Molecular diagnostics, including IFA technique

DIFFERENTIAL DIAGNOSIS:

For hepatic necrosis:

• Herpes Simplex Virus 1 and 2 (human herpesvirus 1 and 2): essentially identical lesions, must be differentiated using virus isolation or molecular lesions; generalized fatal infection in marmosets, tamarins, owl monkeys, and tree shrews
• Callitrichid hepatitis (arenavirus): Affects tamarins, marmosets (Callitrichidae); jaundice, subcutaneous and intramuscular hemorrhage, hepatosplenomegaly, pleuropericardial effusions; hepatic necrosis, lymphocytic and neutrophilic infiltrates, acidophilic bodies, portal phlebitis; no intranuclear inclusion bodies
• Hepatitis A virus (picornavirus): Chronic periportal inflammation; slight focal hepatic necrosis with acidophilic bodies
• Monkeypox: cutaneous papules in African greens, macaques, intracytoplasmic inclusions; occasionally fatal in humans
• Tanapox: cutaneous papules in macaques and humans, intracytoplasmic & intranuclear inclusions
• Bacteria: Rarely occur as epizootics; Salmonella, Yersinia, Klebsiella, and Diplococcus

For oral ulcers:

• Herpes Simplex Virus 1 and 2 (human herpesvirus 1 and 2): Gross and histologic lesions identical to SaHV1
• Cercopithecine herpesvirus 9 (simian varicella virus): Hyperplastic epidermis with intranuclear inclusions
• Measles virus (paramyxovirus, genus morbillivirus): Koplik spots (raised white oral lesions), intranuclear and intracytoplasmic inclusions with syncytia

COMPARATIVE PATHOLOGY:

• The family Herpesviridae is divided into three subfamilies:
• Alphaherpesviruses of nonhuman primates:
  • Human herpesvirus 1 (herpes simplexvirus 1): Prototype alphaherpesvirus, has similar biological properties and may be closely related to Macacine herpesvirus 1; infected New World primates (marmosets, tamarins, owl monkeys) and rabbits die rapidly with epizootics of high morbidity and mortality with histopathological lesions indistinguishable from SaHV-1 although encephalitis may be a more frequent sequela; there are rare reports of mild lesions in gibbons, gorillas, tree shrews, orangutans, and chimpanzees
  • Macacine herpesvirus 1 (herpes B virus, herpes simiae): common, typically subclinical disease in natural host (macaques); in natural host causes oral and/or epidermal vesicles and rarely disseminated disease with multifocal hemorrhagic necrosis; lethal in humans (assume all macaques are infected); histologically, ballooning degeneration of keratinocytes progressing to vesiculation, syncytial cells and intranuclear inclusions may be prominent; lifelong latent infection in sensory ganglia with recrudescence associated with stress, breeding phase of cycle, immunosuppression, but not SIV infection
  • Cercopithecine herpesvirus 2 (simian agent 8): Genus Simplexvirus, infection is usually subclinical in African green monkeys
  • Papiine herpesvirus 2 (Herpesvirus Papio-2): Genus Simplexvirus, common (nearing 100% seroprevalence) subclinical infection of baboons; similar to Macacine herpesvirus 1 and HSV-1 in their natural host, disseminated disease has not ever been reported in adults (is rarely reported in infants), only one report of severe disease in a non-baboon and no reports of zoonosis
  • Cercopithecine herpesvirus 9 (simian varicella virus, see I-V16): Genus Varicellovirus, highly contagious infection of Old World primates that can result in significant morbidity and mortality; virus is similar to the human chickenpox etiologic agent; causes disseminated hemorrhagic vesicular exanthema (inguinal region first, spares palms and soles) with fever and may progress to pneumonia and hepatitis
  • Other significant alphaherpesviruses of other species:
    • Gallid herpesvirus 1: Avian infectious laryngotracheitis (see P-V11)
    • Gallid herpesvirus 2: Marek"s disease (formerly a gamma herpesvirus; see H-V01, I-V13, N-V08)
    • Psittacid herpesvirus: Pacheco’s disease (see D-V13, H-V03)
    • Anatid herpesvirus 1: Duck plague virus (see D-V10)
    • Bovine herpesvirus 1: Infectious bovine rhinotracheitis, infectious pustular vulvovaginitis and infectious balanoposthitis (R-V02)
    • Bovine herpesvirus 2: Bovine mammillitis/pseudo-lumpy skin disease
    • Bovine herpesvirus 5: Bovine herpes meningoencephalitis
    • Equine herpesvirus 1: Abortion, myeloencephalitis, rhinopneumonitis (see P-V10, R-V01)
    • Equine herpesvirus 3: Equine coital exanthema
    • Equine herpesvirus 4: Equine rhinopneumonitis
    • Suid herpesvirus 1: Aujeszky’s disease (pseudorabies, see N-V07, E-V01)
    • Canine herpesvirus 1
    • Feline herpesvirus 1: Feline viral rhinotracheitis (see P-V09)
    • Leporid herpesvirus 4: Acute death, edema, abortion, multifocal hemorrhage, intranuclear inclusion bodies (vs. rabbit calicivirus)
  • Betaherpesviruses (subfamily) of nonhuman primates:
    • Cytomegaloviruses (CMV), including macacine herpesvirus 2 (see P-V12, the most thoroughly characterized of the CMVs), cercopithecine herpesvirus 5, panine herpesvirus 2, aotine herpesviruses 1 and 2, human herpesvirus 5: Slowly cytolytic à cause cytomegaly with large cytoplasmic and nuclear viral inclusions (“cytomegalic inclusion body disease”; virus remains latent in secretory glands, kidneys, lymphoreticular cells, and other tissues but NOT neurons; infection is very common in macaques but disease is rare except in immunocompromised animals (e.g. infected with SIV, immunosuppressive drugs)
    • Other significant betaherpesviruses of other species: Species-specific viruses have been described in pigs (porcine inclusion body rhinitis, see P-V13), mice (mouse cytomegalovirus AKA murid herpesvirus 1, and mouse thymic virus), rats (murid herpesvirus 2), guinea pigs (guinea pig cytomegalovirus AKA cavid herpesvirus 2, see D-V12), elephants (elephantid betaherpesvirus 1 AKA elephant endotheliotropic herpesvirus 1), horses (equid herpesvirus 2), and cattle (bovine herpesvirus 4)
  • Gammaherpesviruses (subfamily) of nonhuman primates: generally species-specific
    • Genus Lymphocryptovirus: there are many lymphocryptoviruses, most are not well characterized; the human species is Human herpesvirus 4, AKA Epstein-Barr virus, to which some primates are experimentally susceptible
      • Macacine herpesvirus 4 (Rhesus lymphocryptovirus):; infects B lymphocytes and remains typically latent for life with occasional reactivation to a lytic cycle with virus shedding; SIV-infected macaques fail to adequately control viremia, and development of non-Hodgkin B-cell lymphomas has been described; B-cell lymphoproliferative disorder associated with latent lymphocryptovirus has been described following organ transplant in macaques (post-transplant lymphoproliferative disorder); there is cross-reactivity with Epstein-Barr virus for molecular diagnostic purposes
      • Callitrichine herpesvirus 3 (Marmoset lymphocryptovirus): Discovered in an investigation into B cell lymphomas in common marmosets; seroprevalence levels are similar across colonies but rate of lymphoma development differs; infection is usually asymptomatic
    • Genus Rhadinovirus:
      • Macacine herpesvirus 5 (rhesus radinovirus): Closely related to Kaposi’s sarcoma herpesvirus (human herpesvirus 8, causes highly vascular neoplasms of endothelial origin and lymphoproliferative disorders), tropic for B-lymphocytes which likely serve as site for latency, natural infection is typically asymptomatic although coinfection with SIV results in marked B cell lymphocytosis
      • Retroperitoneal fibromatosis herpesvirus (see D-V24): affects rhesus and pig-tailed macaques, most frequently co-infected with simian retrovirus 2 (SRV2)
      • Saimiriine herpesvirus 2 (herpesvirus saimiri, see H-V02): common in wild squirrel monkeys; no clinical signs in natural host, but causes lymphoma or lymphocytic leukemia in aberrant primate hosts
      • Ateline herpesvirus 2 and 3: common in spider monkeys, similar to saimiriine herpesvirus
    • Other significant gammaherpesviruses of other species: Limited host range; remain latent in lymphocytes and sometimes transform them to malignancy; serve as models for the study of herpesviruses and neoplasia; also malignant catarrhal fever group viruses (Alcelaphine herpesvirus 1 and Ovine herpesvirus 2, see D-V15 and S-V01)

REFERENCES:

1. Barthold SW, Griffey SM, Percy DH. Pathology of Laboratory Rodents and Rabbits. 4th ed. Ames, IA: Blackwell Publishing; 2016: 15-17, 122, 175, 219-220, 258-259.
2. Ojkic D, Brash ML, Jackwood MW, Shivaprasad HL. Viral diseases.  In: Boulianne M, ed.  Avian Disease Manual. 7th ed.  Jacksonville, FL: American Association of Avian Pathologists, Inc; 2013:30-38.
3. O’Toole D, Li H.  The pathology of malignant catarrhal fever, with an emphasis on ovine herpesvirus 2. Vet Pathol. 2014;51:437-452.
4. Wachtman L, Mansfield K. Viral diseases of nonhuman primates. In: Abee CR, Mansfield K, Tardif S, Morris T, Morris T, eds.  Nonhuman Primates in Biomedical Research.  London, UK: Academic Press; 2012: 7-26.
5. Zachary JF. Mechanisms of microbial infections. In: Zachary JF ed. Pathologic Basis of Veterinary Disease. 6th ed. St. Louis, MO: Elsevier; 2017: 212.

Click the slide to view.

---