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DNA virusesLast modified on September 5, 2010 Viruses in boldface in the table below cause clinical disease in immunocompetent animals.
Other DNA viruses: Hepadnavirus: Hepatitis B, Woodchuck hepatitis Iridovirus: lymphocystis, polyhedral cytoplasmic viruses Viral morphologyNote in the following table that parvoviruses are the only single-stranded, non-enveloped DNA viruses, and that only the largest ones (herpes and pox) are enveloped.
Parvovirus (Family Parvoviridae)Parvoviruses are the smallest DNA viruses. They are ssDNA, non-enveloped viruses{3764} and are extremely resistant to temperature, pH, and drying{2764}. Many infections are inapparent. They have a predilection for mitotically active cells, although specific tissue tropism varies. A Special Topic Overview was published in LAS 46(4) on rodent parvoviruses{3799}. Incidental infections occur in several species. In humans, B19 is a parvovirus with tropism for erythroid precursors. The disease is known as “fifth disease” or “erythema infectiosum.” In immunosuppressed people it may cause transient aplastic crisis or chronic anemia.{3974} Mouse parvovirusesMice are infected with two parvoviruses, Minute Virus of Mice (MVM) and Mouse Parvovirus (MPV). There are 2 named strains of MVM: MVM-p (prototype) and MVM-i (immunosuppressive). The most common type of MPV is designated MPV-1a. Their continuing prevalence is likely due to their high infectivity, persistence in infected mice, resistance to the environment, and contamination of biologics{3799}. MVM: There are differences in the sites of virus replication and the ages of susceptible mice between the two parvoviruses. MVM-i infects infant mice, where it replicates in small intestine, lymph nodes, and the kidneys. Disease is acute and self-limiting.{4025} In clinical situations, MVM is usually asymptomatic. Virus is shed in feces and urine, so transmission occurs by oronasal exposure. MVM is common, highly contagious, chronic, subclinical and possibly latent or persistent. Because parvoviruses divide in lymphoid cells they can interfere with research. MVM has no predilection for the GIT according to one reference{3551}, although another states that MVM-1a replicates in small intestine but prefers the kidney{4025}. It is important to perform serological screening for MVM, and if found, the colony should be depopulated because of the virus’s insidious effects upon research.{3551} Parvoviruses have some anti-tumor properties, by unknown means, and may therefore be interesting vectors for tumor-targeted gene therapy. H-1 and MVMp, while capable of infecting Mastomys, can only be found in tissues for about 3 weeks, as opposed to persistent infection seen in the natural host. Antibody titers rise rapidly and remain elevated for at least one year. Infected neonates show signs of hair color changes (white or gray), growth disturbances, and in the case of MVMp, death at weaning age (>60%). Targets of the virus are likely intestine, liver, and hematopoietic cells. Because of the pathogenicity of mouse and rat parvoviruses for multimammate mice, they are not likely to be good candidates for parvoviral-vectored genes.{2375} MPV: MPV is among the most prevalent infectious agents in research institutions{4103}. It is subclinical and possibly latent{3763}. There are no clinical or histopathological signs of disease{4103}. It infects adults more than infants, and results in persistent infection--viral DNA can be detected for at least 9 weeks after infection. The virus does not replicate in the kidney, in contrast to MVM. Persistence in normally responsive tissues (i.e. lymphoid) could result in inappropriate responses to other antigens, making it necessary to clear research mice of this infection.{4025} MVM and MPV share non-structural antigens, such as NS-1 and NS-2, which are highly conserved in rodent parvoviruses{3799}. It follows that IFA using infected cells (which express both structural and non-structural antigens) works as a diagnostic tool, whereas HAI and ELISA for MVM (which use virus as the antigen) will not detect MPV in serum. MVM agglutinates mammalian RBCs, a feature that makes it easier to detect viral serotypes{3551}. The relationship between MPV and MVM can be shown in the following diagram: I used to have a drawing here but Microsoft kept fargling it up, so I deleted it. The viral capsid shares 98.4% of its identity between MVM-i and MVM-p. The non-structural regions (NS-1) are "inside" the capsid. There is 99.3% identity between the non-structural regions of MVM-i and MPV-1a.
Hansen et al{4025} studied humoral immunity to MVM-i and MPV-1a in Swiss-Webster mice to see if there was cross-protection between the two, and whether humoral immunity prevented persistence. They found that immunity to one virus did not provide protection against the other, whether this immunity was maternally-derived or exogenously administered. Even though there is much homology between the viruses in the non-structural regions, it is the capsid proteins that elicit humoral response. This is a predictable finding, but had not been previously demonstrated. Detection of MPV was the subject of an ACLAM-sponsored research study. The most common serologic tests for MPV are an ELISA using recombinant NS-1 and an IFA using MVM antigen. Confirmatory tests can be run using IFA and HAI that utilize cell-cultured MPV, and there is a PCR test to detect viral DNA in tissues. There are strain and age differences in the response to MPV, however, so sentinel mice should be carefully selected. Younger mice (4-8 weeks) have more rapidly-dividing cells, and so they may have better humoral response to the non-structural antigens that are detected by the rNS-1 ELISA. Some facilities leave sentinel mice in place for a couple of months, and these animals may not show seroconversion to the non-structural antigens if they were not exposed until they were 12 weeks of age. The IFA and HAI tests using MPV antigen seem to be the best ways to detect infected mice, but the response is somewhat dependent on the dose of virus used to infect them. High doses (5x105-106 TCID50) are needed to get a good response. C3H/HeN mice are good responders; ICN, BALB/c and DBA/2 mice are pretty good; and C57BL/6 require high doses and still they don't all seroconvert. One explanation may be the T-helper phenotype (Th1 vs. Th2) of the mouse strain. BALB/c, for example, generate a Th2 response to antigens that do not elicit strong T helper-directing signals.{4103} PCR used to detect viral DNA may be a superior screening test in labs that do not have access to MPV IFA or HAI testing. Mesenteric lymph nodes are the tissues of choice, rather than small intestine, as the virus appears to remain in these lymphoid tissues for months. The exception seems to be the DBA/2 strain, which does not show a strong persistence of viral DNA in lymphoid tissues.{4103} Fluorogenic PCR ("real-time" PCR) assays are being developed that are rapid, sensitive and can be performed on feces and cage swabs as well as cell culture materials (thereby replacing the MAP test usually used). These tests detect all rodent parvoviruses (MVM, MPV and HaPV).{4581} Rat parvovirusesTaxonomy: Rats carry three parvoviruses:
All three are common. RPV shares no common structural antigens (VP1 and VP2) with the other two groups.{3799} This means that tests such as HI, which use virus, will detect RV and H-1, but will not detect RPV. All three parvoviruses can be detected with tests such as IFA, which use infected cells expressing both structural and conserved non-structural (NS1 and NS2) antigens.{4208} Transmission: Rat parvoviruses are common in laboratory colonies, especially breeding colonies. Its pathogenicity for fetal rats was exploited early on as a model for virus-induced congenital anomalies.{4254} Transmission is oronasal, transplacental, or by fomites. Infected infants (pre-weaning age) develop persistent infection and can transmit the virus for up to 10 weeks. If infected after weaning, humoral immunity develops and they usually clear the virus within 4 weeks.{4208, 4254} Usually the disease is picked up by detecting seroconversion, which begins 1-2 weeks after exposure by inhalation or contact{3799}. A newer reference{4254} states that adult rats develop humoral antibody in 7-10 days. This is significant because, if experimentally infected on day 9 of pregnancy with high viral doses, dams will transmit virus to the fetuses within 5 days, i.e. before the dam has developed humoral immunity. The pups will be infected and are capable of transmitting infection to others for at least 16 weeks after birth. In contrast, breeding females that were infected as infants will transfer maternal antibody to their pups, protecting them from infection for 14-16 weeks. But those females are also persistently infected, and may transmit virus to their mates. Virus can be found in the lung and kidney, sites conducive to viral excretion.{4254} Immunodeficient rats excrete virus indefinitely{3799}. Pathogenesis: Only RV has been associated with disease, although it is usually subclinical. Experimental infections use high doses of virus (i.e. 105 TCID50). The virus has broad tissue tropism for dividing cells, so clinical signs are variable. Disease conditions that might be seen vary with viral dose, and may include:
In a rare spontaneous outbreak reported in 1983, clinical signs in young rats included dyspnea, ruffled hair coats, muscular weakness and cyanotic scrotums.{4208, 4752} Unlike dogs and cats, rat parvoviruses do not cause intestinal lesions. Jacoby{4254} found virus by immunohistochemistry in vascular smooth muscle cells, with some signal also detected in pneumocytes and renal tubular epithelium. Rat parvoviruses have all been contaminants of rat cell lines or transplanted tumors. They interfere with T cell responses to transplanted mammary adenocarcinoma, provoke the onset of diabetes mellitus in diabetes-resistant BB/Wor rats, and cause immunosuppression in Lewis rats without altering the CD4:CD8 ratio{3799}. Diagnosis: Amphophilic intranuclear inclusions may be found in hepatocytes, Kupffer cells, endothelial cells and biliary epithelium.{2764} Seroconversion can be detected with complement fixation (CF), hemagglutination inhibition (HI), virus neutralization, or immunofluorescent antibody (IFA). RPV antibody has been detected only by IFA. {4208} RV capsid (VP2) protein was used in an ELISA for experimental studies. In situ hybridization was also used on paraffin-embedded tissues{4254}. Differential diagnosis includes bacterial (Pseudomonas) septicemia, chronic wasting due to Mycoplasma pulmonis, trauma, and nutritional causes of reproductive problems.{4208, 4752} Control: Since there may be significant but obscure effects on research results, depopulation is the recommended control method.{2764} Case presentation:Rat virus {4752}
Rabbits: Parvovirus was found first in clinically normal rabbits in Japan. Later it occurred in rabbits in the U.S. and Switzerland, the significance of which is unknown. As with mice, interference with research results is of concern.{3768}{3773} Hamsters: A parvovirus epizootic of high mortality was reported in Syrian hamsters (Mesocricetus auratus). Suckling and weaned hamsters had malformed and missing incisor teeth with necrosis and inflammation of the dental pulp and alveolar bone osteoclasts. Other signs included a domed cranium, pot-bellied appearance, and small testes{3799}. There was multifocal cerebellar and cerebral hemorrhage in suckling SPF hamsters inoculated with this new virus. It is now believed to be an example of cross-species transmission of mouse parvovirus 3 from mice.{4773} These hamsters seroconverted to rat Toolan H1 parvovirus.{3775} MVM in hamsters has teratogenic effects such as causing mongoloid deformities{3551}. Control measures should take into account prenatal infection and persistence of infectious virus in animals. Chemical decontamination of the environment, heat sterilized caging, culling of seropositive animals, and caging in filter-top cages may help.{3799} Aleutian disease in ferrets: The disease in ferrets has a different course from the disease in mink. Mink die acutely with immune-mediated vasculitis, glomerulonephritis and hypergammaglobulinemia. In ferrets the disease is insidious, taking up to 2 years to develop. In the late stages, ferrets are hypergammaglobulinemic; serum protein will be 8-9mg/dl with >20% gammaglobulins. Splenomegaly and lymphadenopathy are seen, and the kidneys are brownish-tan. Unique infiltrates composed entirely of plasmacytes are found in several organs (renal interstitium, hepatic portal area, splenic red pulp, lymph nodes and bone marrow). Terminally, vasculitis and hypergammaglobulinemia cause clotting defects with petechial hemorrhages and hematuria (“Bing cherry bladder”). There is no treatment and no vaccine for this disease.{3767}{3567} Aleutian disease is diagnosed best by counter-immunoelectrophoresis. An Army mock board exam quoted AJVR 57:1753-57, 1996. Jackson, M., et al. Click here to read a Fascicle about Aleutian disease in mink, used as a model for glomerulonephritis, arteritis and dysgammopathies. Cats: Feline panleukopenia is caused by a parvovirus; it is interesting, in light of the hamster situation, to note that infection of kittens in utero may lead to cerebellar hypoplasia.{3776} The virus has a predilection for mitotically-active cells, so induction of defects depends on when the infection occurs. It primarily infects cells of the external granular layer of the cerebellum that are dividing during late gestation and early neonatal periods. This leads to loss of the internal granular layer because the cells can't migrate there. Purkinje cells may also be affected.{4105} Dogs: Canine parvovirus can be diagnosed by detection of either antibody or virus in feces. If myocarditis occurs, intranuclear inclusions may be seen in myocardium.{3776} Erythema multiforme major is defined as erythematous patchy lesions with ulcerations on less than 10% of the body surface, and with more than one mucosa affected. It can be associated with drug reactions, but also with epitheliotropic viruses such as distemper, papilloma, parvovirus and herpesvirus. There was a first case report of a dog with erythema multiforme in a Great Dane puppy with parvovirus diarrhea and skin lesions on her toes, pressure points, mouth and vagina. In humans, EM is usually caused by herpes simplex or parvovirus B19. Histologically there is apoptosis of keratinocytes, in proximity to infected lymphocytes, as there was also in this canine case.{4057} NHPs: A simian parvovirus has been described by O’Sullivan, with only transient anemia reported to occur in type-D retrovirus-infected cynomolgus macaques (Macaca fascicularis).{3770} The virus has also been diagnosed in a pigtail macaque infected with KUSHIV-1B (an experimental chimeric virus related to SIVmac 239). The female macaque developed severe chronic progressive anemia six weeks after viral inoculation. The diagnosis was made presumptively on the basis of giant pronormoblasts and eosinophilic inclusions in erythroid precursors; it was confirmed by dot-blot.{4124} Confirmation can also be made by PCR and/or in situ hybridization.{3974} Hepadnaviridae (Hepatitis B-like)The genus Orthohepadnavirus infects mammals, especially man (HBV), woodchuck and ground squirrel (Spermophilus beecheyi). Avihepadnaviruses infect birds such as the Pekin duck and heron. Hepadnaviruses are reported as either enveloped{3777} or nonenveloped{3764} with a circular dsDNA genome. They are transmitted by parenteral exposure, such as drug abuse and sexual contact.{3958} In general they replicate in hepatocytes, producing acute hepatitis and later a chronic hepatitis which may lead to primary hepatocellular carcinoma in humans. There is a human vaccine which was developed despite being unable to propagate the virus in cell culture, through the use of chimpanzees.{3958} Primary hepatocellular carcinoma is a common cause of death in captive woodchucks, probably a sequel to chronic hepatitis. A virus similar to human HBV has been found in their serum. The virus has been characterized and designated woodchuck hepatitis virus.{3560} Hepatitis B can infect chimpanzees, gibbons, gorillas and possibly (one report) cynomolgus macaques; however there are usually no clinical signs with only elevated transaminases. Histologically there is chronic periportal inflammation and focal hepatocyte necrosis.{3770,4780} It is one of the most common lab-acquired infections.{3950} Adenovirus (Family Adenoviridae; adeno=gland)Adenoviruses are small, non-enveloped, icosahedral, dsDNA viruses that most often cause only subclinical or even inapparent disease. They were initially discovered in adenoids of military recruits with upper respiratory tract disease and conjunctivitis{3777}. The hallmark lesion of the adenovirus family is the production of large intranuclear inclusion bodies, which can be seen in nearly every species.{3764} In general they have a predilection first for the respiratory tract, and secondarily the enterocytes of the small intestine. Diagnosis is based on serology. Adenoviruses have been used extensively as viral vectors for gene transfer, partially because they act as good adjuvants. While this may be a disadvantage for gene delivery because of host immune response, it is a real advantage for DNA vaccine delivery. Adenoviruses enter the cell by endocytosis and proceed to the nucleus. These vectors generally result in robust transfection, but for a limited period of time (days-weeks) due to host defenses. An alternative approach is to use primate serotypes, to which humans would not normally be already immune. These have been used to deliver rabies and HIV antigens. Adenovirus vectored genes have been successfully used in humans, and have an impressive safety record.{4751} Adeno-associated viruses (AAV) are also small non-enveloped viruses, but they are single-stranded. They are naturally replication-defective and depend on helper function from adenoviruses or herpesviruses. But as they are completely non-pathogenic and also remain latent in infected cells, they have different applications from adenoviruses, i.e. correction of genetic defects. Mice: Murine adenoviruses
infect both animals and cell cultures, producing intranuclear inclusions.
Unlike some other adenoviruses, murine adenoviruses are not hemagglutinating or
oncogenic{3551}. There are two adenoviruses that infect mice. MAd-1 (also called FL) is rapidly fatal in infant mice but causes no disease in adults or weanling-age mice. Necrotic, infected tissues containing intranuclear inclusions include the brown fat, myocardium, adrenal cortex, salivary glands and kidneys. According to Barthold{3763} this virus is probably extinct. MAd-2 (also called K-87) is non-pathogenic and localizes to the intestine where it also produces intranuclear inclusions. However, experimentally-inoculated mice can excrete virus in the urine for at least 2 years. Diagnostically, K-87 antiserum neutralizes both strains, but FL antiserum is weak in neutralizing K-87. The prevalence of mouse adenovirus is much less than other viruses, and Caesarean rederivation is effective in getting rid of it.{3551} Rats: Adenovirus seroconversion is common in rats. It is cross-reactive with, or maybe even the same as, MAd-2.{2764} Infectious canine hepatitis is caused by canine adenovirus type 1 and is a polytropic infection. Most cases are subclinical, but in a few disease develops. After acquisition of virus, usually by the oropharynx, it spreads via epithelium to lymph nodes and spreads to liver, kidneys, vascular endothelium and the eye. In some dogs chronic progressive hepatitis develops even though virus is no longer present. In others there may be vomiting, tonsillar enlargement and lymphadenopathy. In severe cases dogs collapse and die peracutely with only pain and hyperthermia, and occasionally hematemesis and diarrhea. Some dogs develop "blue eye", or uveitis, and this can be a sequel to vaccination with CAV-1. Virus is shed for months in the urine, having localized in first glomerular, then tubular epithelium. The hallmark of histology is large intranuclear inclusions, seen in hepatocytes and sometimes glomeruli. Once it was found that CAV-2, which causes mild respiratory disease, cross-protects against CAV-1, the vaccines were changed to contain only CAV-2, since it does not cause uveitis.{3769} NHPs (macaques, African greens, baboons, chimpanzees, squirrel monkeys and cotton-top tamarins) can be infected with adenovirus, and there are some case reports in the literature. Disease is usually subclinical, but frequently viral inclusions may be found incidentally in intestine and lung. Chronic pancreatitis may cause abdominal masses in Macaca mulatta. Intranuclear inclusions vary from small red to large blue smudges.{3770} Occasionally electron microscopy of feces is used, but since most infected NHPs are shedders a positive EM is nondiagnostic.{3777} Rabbits: Adenovirus was isolated from young rabbits in Hungary in 1979. There was no cytopathic effect in cell culture, so acridine orange was used to detect virus. There was partial CF and ID response to human adenovirus. Serologic survey of rabbits in Canada revealed antibodies to bovine adenovirus-1. Experimental inoculation of rabbits with human adenovrius-5 resulted in persistent lymphoid infection for 1 year, but no disease.{3773} Guinea pigs: Following up on an outbreak of low morbidity, high mortality respiratory disease in guinea pigs in 1981, healthy 6-7-week-old Ibm:GOHI guinea pigs were infected intranasally with virus. Disease was not induced in any of the 18 animals. However, there were intranuclear inclusion bodies in nasal mucosal exudate and a weak cross-reaction with MAd1 and 2. PCR was used to detect viral DNA in specimens. Inclusions were present only in the nasal mucosa (site of infection) and a few lungs. When they put an infected guinea pig with 5 others, only 2 developed virus in nasal specimens. The authors concluded that GPAdV induces transient subclinical infection of the upper respiratory tract in healthy guinea pigs. After a 6-day incubation virus is shed by aerosol for 10 days. There must be other factors involved in reported disease outbreaks.{3774} If disease occurs in guinea pigs from adenovirus, there is gross lung consolidation, necrotizing bronchitis and bronchiolitis with desquamation of epithelial cells. Respiratory epithelial cells contain distinctive amphophilic to basophilic inclusions 7-15µm in diameter.{3775} In hamsters, young animals <4 wks old have developed antibodies to MAd-2 (K87) with inclusions in villar enterocytes, goblet cells and sometimes crypt epithelium. Hamsters are asymptomatically infected.{3775} Adenovirus in hamsters has more often been used in cancer research.{3771} Birds: Marble spleen disease in pheasants is caused by an avian adenovirus, causing peracute death. The virus may be the same as the one causing hemorrhagic enteritis in turkeys. The only signs are large mottled spleens and pulmonary edema. Intranuclear inclusions in the spleen support the diagnosis. Another avian adenovirus causes quail bronchitis, with coughing, sneezing, and huddling in young chicks. Mortality usually ranges from 50-60%. It may be confused with pulmonary aspergillosis, but that disease causes granulomas.{3568} Papovaviridae (papilloma-polyoma-vacuolating)Papovaviruses are non-enveloped dsDNA viruses and have the capacity to transform cells.{3764} They are typically resistant to heat and dessication. Rabbit (Shope) papillomavirus is the type species of the genus Papillomavirus.{3773} The taxonomy has now changed, and Papovaviridae has been replaced with Papillomaviridae and Polyomaviridae. PolyomaviridaeSV40: the type species of the family Polyomaviridae. This natural polyomavirus of rhesus macaques is latent and widespread in captive macaques, but causes disease only in immunocompromised animals. Transmission is via shedding in the urine. It is the "rhesus equivalent of human JC virus." Primary disease in immunocompromised rhesus macaques consists of pneumonia, nephritis and meningoencephalitis. A reactivated latent infection causes a syndrome called progressive multifocal leukoencephalopathy. In those animals, respiratory spread causes pneumonia, then renal tubular necrosis. When it infects the oligodendrocytes and astrocytes, demyelination and encephalitis occur, especially around the ventricles. Large basophilic inclusions (similar to those caused by adenoviruses, but much smaller) may be seen in the lung, oligodendroglia and renal tubular epithelium.{3770, 4150}K virus of mice: This causes in most cases a latent, chronic disease with low prevalence and low antibody titers, making diagnosis very difficult. It is easily eliminated by basic good husbandry. The virus infects endothelial cells of villus lamina propria, and disseminates through the bloodstream to pulmonary and hepatic vascular sites.{3763} Signs of disease are highly variable when they occur. Usually, passive immunity protects neonates, but after weaning mice can develop dyspnea and die within 24 hours. Asymptomatic mice shed virus in secretions. Gross lesions are limited to the lungs and sometimes to vascular endothelium of other organs such as liver, kidney and jejunum. Histologically, swollen nuclei and intranuclear inclusions are seen with H&E stain. Livers can develop a “Swiss cheese appearance” due to membrane-lined spaces. Differential diagnosis includes MHV and ectromelia; the intranuclear inclusions in K virus disease are a helpful marker. MHV's classic lesion is the vascular endothelial syncytium, rather than a hypertrophic lesion{4032}. Virus isolation can be accomplished by cerebral inoculation of newborn mice and hemagglutination testing. A new PCR has been developed that is far more sensitive and yields results more rapidly.{4591} If infection is found in a colony, rederivation is indicated (above statement about easy elimination makes this questionable).{3551}
Rat polyomavirus: Sialoadenitis was noted in an NIH colony of rnu/rnu rats with wasting syndrome. It caused intranuclear inclusions in epithelial cells of the parotid duct. There was no cross-reaction with other papovaviruses such as K virus or polyoma virus of mice.{3763} Hamster Polyomavirus (HaPV): There was much confusion about this virus at first, because some thought it caused outbreaks of lymphoma and others thought it caused epitheliomas. Turns out both are correct. In naive populations, explosive outbreaks (up to 80%) of lymphoma occur, an otherwise rare tumor in hamsters. Lymphomas usually arise in the mesentery rather than the spleen, causing wasting and sometimes palpable abdominal masses. Sometimes the tumors infiltrate hepatic sinusoids. Affected hamsters may also have epitheliomas of haired skin ("reminiscent of" trichoepitheliomas according to Barthold). Lymphomas will not have infectious virus, but the epitheliomas will. The major means of transmission is via the urine, even in older hamsters with asymptomatic infections. As in mice, initial viremia involves multiple organs, but it remains persistent in the kidneys. HaPV has been known to wipe out entire colonies of inbred hamsters. The virus may be environmentally resistant, even after thorough decontamination.{4773} PapillomaviridaeRabbit polyomaviruses: Two distinct papillomaviruses have been found in rabbits, neither of which causes significant disease. One (Shope papillomavirus) causes wartlike growths on cottontail rabbits, spread by arthropods. It was originally described in Sylvilagus floridanus rabbits in the Midwest, but also occurs in California cottontails (S. bachmani). Infected cottontails carry 1-10 warts on the skin of the inner thighs, belly, neck and shoulders. Shope papillomavirus was the first virus recognized to be oncogenic in mammals{3773}. One-fourth of lesions transform into squamous cell carcinoma. Inclusion bodies have not been demonstrated (unlike rabbit oral papillomavirus, ROPV, see below). In Oryctolagus cuniculus, warts occur on the ears and eyelids, where they can also transform into squamous cell carcinoma. One much-investigated transplantable malignant carcinoma, the VX2/V-2/V2 carcinoma, was derived from multiple passages of this virus. The other virus (ROPV) causes oral papillomas in young domestic rabbits 2-18 months old, which are found on the ventral surface of the tongue and contain intranuclear inclusions. It is not known to transform.{3561}{3768}{3773} [Note: Shope fibroma is caused by a leporipoxvirus similar to myxoma virus.] NHPs: Oral, cutaneous or genital mucosal lesions are caused by papillomavirus in NHPs. In chimpanzees, a papovavirus causes oral mucosal lesions as a benign condition termed focal (oral) epithelial hyperplasia. {3770} Reptiles and Fish: Papilloma-like viruses were found in lesions from Bolivian side-neck turtles (Platemys platycephala). The lesions were circular and papular, and some coalesced to form larger lesions, all on the head. There were no inclusions.{3570} A disease called papilloma of brown bullhead (Ictalurus nebulosus) has been noted causing papillomas on the head and lips.{3571}Family HerpesviridaeHerpes viruses (herpes=creeping) are large enveloped viruses containing dsDNA which mature by budding through the nuclear membrane. Common features of the herpesviridae include:{3777}
There are three subfamilies:{3764}{3777} Alphaherpesviruses (herpes simplex-like)
Betaherpesviruses (cytomegalovirus causing low-grade infection)
Gammaherpesviruses, which are lymphoproliferative and some are oncogenic
AlphaherpesvirusesHerpesvirus B (cercopithecine herpesvirus 1, H. simiae): This is the frequently-worried-about-and-for-good-reason disease of Asian macaques causing vesicles on the lips, in the oral cavity and on the genitalia, as well as conjunctivitis. The virus is transmitted by biting, sexual behavior, and by fomites. The percentage of infected animals increases rapidly as they approach sexual maturity. The percentage of animals showing oral lesions is very low (2.3%), and the disease in macaques is usually mild and self-limiting. Lesions resolve within 10-14 days.{3777} Generalized disease may occur in young or immunocompromised animals. Such disseminated disease is usually fatal, with widespread, hemorrhagic necrosis of the liver, lung, brain and lymphoid organs. Intranuclear inclusions and syncytial cells are found associated with lesions. B virus should be included in the differential diagnosis of multifocal, necrotizing hepatitis in macaques. In a single outbreak in bonnet macaques, respiratory signs (coryza, rhinorrhea, cough and conjunctivitis) occurred, with high morbidity and mortality from hemorrhagic interstitial pneumonia and hepatic necrosis.{3777} The virus establishes latency in the sensory ganglia. Viral shedding is not associated with the stress of quarantine, parturition or breeding; nor has it been commonly seen in experimental SIV-inoculated macaques{3777}. Activities involving the use of tissues, body fluids, and primary tissue cultures from macaques should be done at BSL2. Material known or suspected to contain large amounts of virus must be handled using BSL3 conditions; cultures of virus are maintained at ABSL4. Studies with animals experimentally infected with the virus should be conducted at ABSL3.{3950} Recently it has been suggested that a safe and equally reliable serologic test for the virus uses herpesvirus papio-2, which has fewer zoonotic implications.{3777} Herpes simplex I has commonly been used as an antigen to screen for herpes B infection, due to the safety concerns of generating herpes B antigen for ELISA testing. However, herpesvirus 2 of baboons may also be used as the antigen. HVP2 is a biosafety level 2 pathogen. HVP2 was equal to herpes B in both sensitivity and specificity when tested on 448 serum samples from a variety of species. It was better than HSV1 because it accurately detected more positive samples. Background reactivity was actually less (compared to B virus) when using HVP2.{4176} Efforts are underway to develop colonies of herpes-B-free macaques. Repeated testing is necessary because of (a) chronically infected and immunologically unreactive animals, and (b) animals may be in the early stages of disease prior to seroconversion. In small facilities, animals may be acquired as seronegative and housed individually. Periodic testing is recommended as a component of colony management.{3777} In humans, signs of herpes infection include intensely pruritic vesicular dermatitis at the inoculation site, followed by lymphangitis and lymphadenopathy. Neurologic signs include fever, paresthesia, muscle weakness and conjunctivitis, followed by ascending myelitis. Humans may also (rarely) be asymptomatically infected and have recurrent infections with vesicular rash and respiratory signs.{3777} Herpes B is fatal in owl monkeys, marmosets (Callithrix jacchus), African greens, gibbons, black and white colobus (Colobus abysinnicus), capuchin (Cebus apella), and patas monkeys (Erythrocebus patas).{3770}{3777} An outbreak of herpetic disease in a zoo colony of DeBrazza's monkeys in 1981 was successfully diagnosed as having been caused by a fourth genotype of herpes B in 2000. Tissue blocks and material from a monkey that survived the initial infection for 12 years were used to document the presence of the virus. During the initial outbreak, 3 of 8 monkeys died from septicemia. Signs included ulcerations on the tongue, palate, and hind feet initially, progressing to severe diarrhea and facial edema. Conjunctivitis, epiphora and bilateral corneal opacity were observed in another animal for 38 days. The tongue ulcers consisted of rough-bordered erosions 1-3 cm in diameter; a few progressed to regions of central ulceration overlaid by fibrinopurulent exudate. Two adults that died had multifocal adrenocortical necrosis.{3656} Simian Agent 8 (SA8, cercopithecine herpesvirus 2, Herpes papionis) is endemic in African green monkeys, and is related to herpes B, Herpes papio 2, HSV-1 and 2. No human infections have been recorded. It is rarely reported in cercopithecoids.{3770} Herpesvirus papio 2 is endemic in baboon colonies and was previously thought to be the same virus as SA8. It causes similar lesions in baboons to H. simiae in macaques, and may be a good model for human herpes simplex 2. Lesions are usually located on the genitals, but also occur less frequently in the oral mucosa. Many baboons are asymptomatic carriers. Neonatal infection can result in pulmonary alveolitis and hepatic necrosis.{3770} It has been suggested as an alternative antigen for testing of sera for antibodies to B virus.{3777} Simian varicella virus is actually a group of closely-related viruses (Liverpool vervet virus, patas herpesvirus, Medical Lake macaque virus, and Delta herpesvirus) all antigenically similar to human varicella-zoster. Latency is common. Epizootics affect several species of cercopithecoids including patas monkeys, African green monkeys, and macaques. Epizootics occurred with high morbidity and mortality between 1966-1970 at three primate centers in the US. A herpetic rash may occur with rapid progression to death in 48 hours. Vesicles develop on the skin, oral mucous membranes and esophagus. Signs include fever, lethargy, vesicular skin rash, pneumonia and hepatitis. After experimental inoculation, neutrophilic leukocytosis occurred along with decreased platelets and increased liver enzymes and BUN. There is focal necrosis with intranuclear inclusion body formation in liver, lung, spleen, lymph nodes, adrenal, bone marrow and the GI tract; the disease must be differentiated from measles using clinical and histologic signs. A PCR is available that can be run on skin or blood samples.{4148} The virus becomes latent in ganglia. No transmission to humans has occurred.{3770}{3777} I have an undocumented statement that New World NHPs develop diarrhea if infected with SVV. Herpes simplex causes latent or active infection in humans; they can transmit it to NHPs, and the monkeys can transmit it to each other. Local lesions such as oral vesicles, conjunctivitis and keratitis may occur in gibbons (Hylobates lar), tree shrews (Tupaia glis), or chimpanzees (Pan sp.). Owl monkeys, tree shrews, lemurs, marmosets, and tamarins may develop generalized disease which is indistinguishable from H. tamarinus except that encephalitis occurs more often. Either HSV-1 or HSV-2 causes the same symptoms. Morbidity and mortality are high. Intranuclear inclusions and syncytia are found.{3770}{3777} Herpes tamarinus (platyrrhinae{2765}{3777}): In its natural host, the squirrel monkey, no lesions or rarely oral vesicles occur. It causes fatal generalized disease in owl monkeys, marmosets, and tamarins, with vesicular rash, oral vesicles and ulcers. Eosinophilic inclusions and occasional syncytial cells are seen.{3770} Natural infection in callitrichids such as Saguinus is often fatal, with a broad spectrum of lesions. The virus causes disseminated necrosis of skin, oral mucosa, and numerous parenchymal organs. Because of the rapidity of disease progression, areas adjacent to lesions may have relatively little in the way of inflammation. Intranuclear inclusions may be either basophilic or eosinophilic, although they both contain virus. Lesions are indistinguishable from those of H. simplex in these species. Squirrel monkeys must be housed separately from callitrichids!{2765} Feline herpesvirus-1 (feline viral rhinotracheitis (FHV-1): The two most important respiratory pathogens of the cat are FHV-1 and feline calicivirus (a picornavirus), with Chlamydia psittaci running far behind as a secondary pathogen. FHV-1 causes sneezing, coughing, fever and hypersalivation, followed by photophobia, chemosis, serous discharge and depression. Occasionally the eyes may develop ulcerative keratitis; oral ulcers and pulmonary lesions are rare. However, in kittens, FHV-1 can cause necrotizing bronchitis, bronchiolitis, and pneumonia. Intranuclear inclusions seen in respiratory epithelium are considered diagnostic. Rule-outs for the kittens include calicivirus (which usually affects only the upper respiratory tract and does not form inclusions), T. gondii (2-3 micron trophozoites would have been seen in cells), primary bronchial pneumonia (which is rare in cats but may be caused by Pasteurella or Bordetella), Chlamydia psittaci (which doesn't cause severe disease), fungal disease (Cryptococcus neoformans, Blastomyces dermatitidis and Coccidioides immitus can be ruled with histology), parasitic (Aelurostrongylus abstrusus and Paragonimus kellicotti can also be ruled out histologically), and aspiration (macrophages would be seen in the inflammatory areas, and perhaps fat vacuoles depending on the material aspirated.){4031}{3776}{4649} Infectious laryngotracheitis (ILT): This virus causes inflammation of the larynx and trachea in domestic fowl, pheasants and pea fowl. The larynx may become blocked by hemorrhagic and later caseous material, containing intranuclear inclusions in the tracheal epithelium (pathognomonic). A vaccine is available.{3568} Marek’s disease (range paralysis) is caused by avian herpesvirus 2, and used to be the most common lymphoproliferative disease in chickens. It is progressive, the virus being a slowly cytopathic herpesvirus. Subclinical infection with viral shedding is common. Infection is transmitted by inhalation of dander, which contains infectious virus from feather follicle epithelium. Lesions result from infected T lymphocytes (leukemia or in situ proliferation) and inflammatory responses to lysed non-lymphoid cells. Four overlapping syndromes occur: (1) neurolymphomatosis or classic Marek's disease, in which one or more peripheral nerve trunks are grossly enlarged causing asymmetric paralysis of legs or wings; (2) acute Marek's, which occurs in explosive outbreaks of ataxia, paralysis and sudden death, and in which lymphomatous lesions are seen in the gonads; (3) ocular lymphomatosis with graying of the iris due to infiltration with transformed lymphocytes; and (4) cutaneous Marek's, in which round nodular lesions affect the feather follicles. Marek’s must be differentiated from lymphoid leukosis (retrovirus) but can be done based on the following: (a) only Marek’s affects the nerves, causing paralysis, (b) Marek’s causes gray eye, feather follicle inflammation and muscle tumors, and (c) only LL causes tumors in the bursa of Fabricius.{3568} Diagnosis is based on history, signs and lesions. Viral antigen is demonstrated by IF, and antibody by AGID, VN or indirect IF. Avian leukosis may occur in the same flock or even the same bird. Although there is a vaccine, birds continue to be infected. Disease in vaccinates is not as common as in non-vaccinates. Neurologic disease continues to occur at decreased incidence in vaccinated flocks. Control is difficult to achieve practically; some genetic protection is afforded in birds with the B21 alloantigen on their RBCs. All-in, all-out management is best in chickens.{3764} BetaherpesvirusesCytomegaloviruses differ from alphaherpesviruses in several respects. They cause cytolysis only slowly, and virus particles accumulate in the cytoplasm and the nucleus. Therefore, cytoplasmic inclusions are sometimes seen. The virus causes enlargement of the nucleus and cytoplasm (cytomegaly). They are mostly cell-associated rather than cytolytic. They are limited in host range. Latency is established not in neurons, but in glandular tissues, lymphoreticular tissues and kidneys.{3777} Murine cytomegalovirus (MCMV): This virus is common only in wild mice, and is nonexistent in laboratory stocks. Natural infection is asymptomatic in immune-competent mice. Experimental inoculation of neonates causes lethal multisystemic necrosis and inflammation{4756}. Its significance was as a potential model for human disease. It is the only virus to cause latent infection in mice. It infects salivary glands preferentially.{3763} The diagnosis may be established by demonstrating enlarged cells with intranuclear inclusions, particularly in the salivary glands.{3551} Mouse thymic virus (MTV): Prevalence and signs are the same as in MCMV, except that the virus preferentially attacks T cells in the thymus causing thymic necrosis. It is often a contaminant of MCMV cultures.{3768} Cytomegaloviruses may induce immunosuppression, and make the animal more susceptible to opportunistic infections.{3551} Rat cytomegalovirus: As in mice, this virus exists only in wild rats, in which it causes mild nonsuppurative inflammation in salivary gland acinar and ductal epithelium. Its histology can be confused with normal exorbital gland morphology.{3763} NHPs: Species affected include white-lipped tamarins (Saguinus fuscicollis), squirrel monkeys (Saimiri sciuris), macaques, baboons (Papio), African green monkeys (Cercopithecus aethiops), capuchins (Cebus), woolly monkeys (Lagothrix), and chimpanzees (Pan). Cytomegaloviruses are highly species-specific. Although infection is widespread in macaques, there is no disease except in fetal and immunodeficient (i.e. SIV or SRV-infected) NHPs, in which it is a common opportunistic infection. In SIV-infected macaques the virus may reactivate as a terminal opportunistic infection with severe CD-4+ T cell depletion. This shares many features of human AIDS. Generalized disease is similar to other betaherpesviruses, with CNS and respiratory signs: meningitis, pneumonia, arteritis, enterocolitis, orchitis and focal hepatic and splenic necrosis. The intranuclear inclusions are characteristic large basophilia, and there are also granular eosinophilic cytoplasmic inclusions in mesenchymal cells (contrast to other herpesviruses which affect epithelia). Infection of the fetus may occur, as in humans. CMV has also been associated with accelerated GVH disease in humans, as well as being incriminated in arteriosclerosis in the general population.{3770}{3777} Guinea pig cytomegalovirus: This causes “big cells with big nuclei with big inclusions” according to the POLA notes. Natural infection with CMV occurs in humans, NHPs, rats and the guinea pig. The disease may be subclinical, latent or persistent. In the guinea pig it resides in the salivary glands, kidneys and liver. Salivary glands may be swollen and inflamed. Lesions are often noted incidentally at necropsy. Histologically, there are large eosinophilic intranuclear inclusions and occasional small intracytoplasmic inclusions in ductal epithelial cells, particularly in the submaxillary salivary glands.{3775}{3559} Chinese hamsters (Cricetulus griseus) may be infected with a CMV producing disease similar to that in guinea pigs. Acinar cells of the submaxillary salivary gland are more affected than the ductal cells, though. Intranuclear and occasionally intracytoplasmic inclusions are found.{3775} Channel catfish virus: This is a disease that occurs when fingerlings are stressed by high temperatures, low oxygen and/or handling. The most prominent sign is a dark red to black enlarged spleen; other signs include abdominal distension, exophthalmia, hemorrhage at the base of the fins and straw-colored ascites. Diagnosis is based on signs; cell-free filtrates will cause syncytia in cell culture in 24 hours. Treatment is to improve management practices and eliminate positive fish.{3779} GammaherpesvirusesWithin the subfamily Gammaherpesvirinae there are two genera: Lymphocryptovirus
and Rhadinovirus. Lymphocryptoviruses lack strict species-specificity.
The NHP viruses share approximately 35-45% homology with human EBV. Generally,
Old World monkeys are commonly infected with EBV-like viruses, whereas New
World monkeys and prosimians are less often infected.{3777}
Lymphocryptovirus
Epstein-Barr virus (to which rhesus lymphocryptovirus is related) in humans is usually latent, but may cause infectious mononucleosis with fever, lymphadenopathy, pharyngitis and atypical circulating lymphocytes. EBV is associated with Burkitt’s lymphoma (as a result of translocation of protooncogenes), nasopharyngeal carcinoma, Hodgkin's disease, and oral hairy leukoplakia (usually not visible, but there is hyperkeratotic parakeratosis). Burkitt's lymphoma and oral hairy leukoplakia may also occur in rhesus macaques. Most cynos are infected with EBV-like virus by one year of age. Baboons may develop malignant lymphoma as well. EBV-like virus causes lymphoma and squamous proliferative lesions in immunodeficient NHPs. Epithelial lesions (oral, genital, cutaneous) resemble hairy leukoplakia in humans, and contain basophilic intranuclear inclusions. Latency is poorly understood, but expression of viral proteins such as latent membrane proteins (LMP-1, 2a and 2b) may influence subsequent disease development. Human infection with simian EBV-like lymphocryptoviruses has not been reported.{3770}{3777} Marmoset lymphocryptovirus: Between 1992 and 1996, 16 cases of lymphoproliferative disease occurred in common marmosets (Callithrix jacchus) at the Wisconsin Regional Primate Research Center. The typical signs were weight loss, inappetance and diarrhea; in some there was a palpable abdominal mass. All were necropsied. The abdominal masses were enlarged mesenteric lymph nodes. Neoplastic round cells (B lymphocytes) were found in large numbers in mesenteric nodes, jejunum, duodenum, ileum and colon. Liver, kidney and lungs were affected in some. Serology revealed that 52/84 marmosets in the colony responded positively to Epstein Barr virus. Some spleens responded immunohistochemically to EBV latent membrane protein-1, which is essential to B cell transformation. Virus isolation was apparently not attempted. The cause was presumed to be a herpesvirus because PCR on tissues showed the presence of two highly-conserved herpesvirus genes, DNA polymerase and terminase. Substantial homology with human EBV was demonstrated. The authors concluded that they have described a new virus in marmosets, which can be placed most appropriately in the genus Lymphocryptovirus in the gammaherpesvirus family.{3780} Herpesvirus sylvilagus (Hinze herpesvirus lymphoma, leporid herpesvirus 1{3773}): Found in wild rabbits (S. floridanus) only, and not transmissible to Oryctolagus to date, despite several attempts. It was isolated from primary kidney cell cultures derived from apparently healthy, trapped wild cottontails in Wisconsin in the late 1960s. A serologic survey in Wisconsin turned up 6/101 positives in wild cottontail rabbits. It is a proposed model for EBV, causing leukocytosis, lymphocytosis and monocytosis. There is also myocarditis, hydropericardium, interstitial pneumonia and lymphocytic myositis. Nonlymphoid organs such as lung and kidney undergo prominent lymphoid hyperplasia.{3768}{3561}{3773} Herpesvirus cuniculi (leporid herpesvirus 2) was isolated from primary kidney cell cultures derived from Oryctolagus cuniculus. It was originally isolated during attempts to find the etiologic agent of chicken pox in the 1920s. Other investigators working on rheumatic fever and scarlet fever also isolated this virus, at about the same time, in Europe. It is as yet an unclassified herpes virus. Until the 1970s it was believed to be unable to cause disease, but there have been two reports of disease since then. One was in rabbits with respiratory disease, in which herpesvirus was cultured from the nares. The other situation involved acute death in Oryctolagus from two rabbitries. Under experimental conditions, intradermal inoculation caused local erythema with occasional generalized reactions (anorexia, diarrhea, emaciation, fever and skin vesicles). Lesions are microscopic only: edema with intense mononuclear inflammation, and large eosinophilic intranuclear inclusions. "The absence of reported cases could be attributed to the relative rarity of disease or to lack of intensive etiologic investigation of cases which do occur."{3773} Rabbits are also susceptible to human herpes simplex, and develop necrotizing meningoencephalitis following exposure to infected humans. Murine herpesvirus-68 was originally isolated from bank voles in Slovakia. It infects the lungs for the first week or so, then moves to the spleen where it infects B cells. After 18-24 months, about 10% of the cases develop high-grade lymphomas. If cyclosporin A is given the incidence rises to 60%. The tumors resemble Hodgkin’s lymphomas, and this is a suggested model for Epstein-Barr virus infection in rodents.{3973} Rhadinovirus
Herpes saimiri (Cebid herpes 2): In NHPs, H. saimiri, a rhadinovirus which is found in >85% of all squirrel monkeys, causes fatal disease in callitrichids (marmosets and tamarins). The squirrel monkey is the host, with high incidence but no disease. Its significance is as a predictable model of lymphoma or leukemia in other NHPs, such as marmosets (Saguinus and Callithrix), owl monkeys (Aotus), African greens (Cercopithecus aethiops), howlers (Alouatta carage), and spider monkeys (Ateles geoffroyi). In these hosts, there are leukemic infiltrates of immature lymphocytes in the liver, kidney, spleen, lymph nodes, adrenals and other organs. A protein termed “saimiri transformation-associated protein” has been studied. Three types of clinical picture ensue, depending upon survival time: (1) in animals which survive less than 40 days, a disseminated necrosis of vital organs with lymphoma occurs; (2) in those surviving 50-150 days there is less aggressive lymphoma with lymphocytic leukemia; and (3) in those surviving >150 days there may be localized, well-differentiated lymphoma (i.e. retrobulbar lymphoma){3777}. There are NO inclusion bodies. H. saimiri can experimentally infect rabbits, and will transform human T lymphocytes in vitro.{3770}{2765} Herpes ateles: In its natural host, Ateles geoffroyii, no lesions are produced. However, the virus causes lymphomas in marmosets and owl monkeys with lymphadenopathy, hepatomegaly and splenomegaly.{3770} Rhesus rhadinovirus is another gammaherpesvirus closely related to human herpes 8 or Kaposi’s sarcoma-associated virus. Many M. nemestrina and M. mulatta are seropositive, and there is a potential association with retroperitoneal fibromatosis, which is more often associated with SRV infection. {3770}
Lucké Renal AdenocarcinomaThis tumor does not affect laboratory frogs but is of interest as a model of herpesvirus-induced cancer. It affects leopard frogs (Rana pipiens). There are usually no clinical signs until the tumors get large enough to cause bloating. Growth of the tumors is tied to temperature: at 22-25°C or above viral replication does not occur, the so-called summer or calid tumor. When frogs hibernate at temperatures of 5-10°C the tumor enters the algid phase with viral replication and massive tumor cell cytolysis. At necropsy the kidneys have single or multiple white nodules that vary in size from 1mm to masses causing abdominal distension. Metastases are found in the lung, liver and other viscera.{3569} Family IridoviridaeThese dsDNA viruses (iridae=iridiscent) are enveloped and are found mainly in frogs (genus Ranavirus) and fish (genus Lymphocystivirus). African swine fever virus used to be in this family, but it now has no family designation and exists all by itself.{3764} Lymphocystis: Despite the name, this virus causes large nodules of fibroblasts to form, particularly on external surfaces such as skin and fins. Each cell is surrounded by a hyaline capsule. Wild fish are more often affected in the cooler months. There is no treatment.{3779,3982} Polyhedral Cytoplasmic Viruses (FV1, FV2, FV3, LT, TEV): First isolated in cell cultures of renal tumors, these viruses are related to the iridoviruses. They do not cause overt disease in adult frogs, nor do they cause tumors. However, in bullfrog tadpoles 3-60 days of age, subcutaneous edema and acute death are common. Histologically there is edema, petechial hemorrhage and focal coagulative necrosis. Isolation and culling of tadpoles are the only treatments.{3569} Family PoxviridaeThe poxviruses are dsDNA enveloped viruses that reproduce in the cytoplasm using a virus-associated transcriptase. They are the largest and most complex of all viruses. They are termed “complex” because there is no special type of symmetry in the nucleocapsid. The core is dumbbell-shaped with two lateral bodies. There are two subfamilies, the Entomopoxvirinae of insects and the Chordopoxvirinae of vertebrates. Within the latter family are several genera. Within each genus there is much cross-reactivity and cross-protection, as well as frequent genetic recombination. Poxviruses are extremely resistant to the environment and may survive for years in dried scabs. Disease is transmitted by introduction through skin abrasion (orf), by droplets (sheeppox), or through mechanical transmission by biting arthropods (swinepox, fowlpox, myxomatosis). All poxviruses are associated with skin lesions which are essentially pustular, proliferative (pseudocowpox) or tumor-like (myxomatosis). Several, such as sheeppox, cause generalized disease with visceral lesions and significant morbidity. Immunity is prolonged if the virus undergoes a viremic stage; however with parapoxviruses in which lesions are localized only, immunity is short-lived. {3764} The preferred method of laboratory diagnosis is electron microscopy, since the viruses are large and distinctive. Most grow readily in cell culture, except for the parapoxviruses. They also produce pocks on the chorioallantoic membrane of embryonated hen’s eggs.{3764} OrthopoxvirusVaccinia and variola (smallpox), and cowpox belong in this group. The confirmatory histologic lesion is intracytoplasmic inclusion bodies. MousepoxMousepox (the disease) is caused by ectromelia virus. It is rarely encountered now and was first described in the UK. There are several strains which vary in virulence; Hampstead is a low-virulence strain and Moscow has high virulence. Disease development is highly strain-dependent in mice. DBA/1, DBA/2, BALB/c, A, and C3H mice are very susceptible, usually dying acutely; whereas C57BL/6 and AKR mice are resistant, perhaps because they can mount rapid immune responses to the virus (see below for recent reference). Resistant strains are very dangerous, because they can act as carriers.{3551, 3763} There are three clinical courses: acute with high mortality, chronic, and carrier. In acute infection, genetically susceptible mice develop disseminated disease with multifocal necrosis of several organs such as liver, lymphoid tissue, intestine, spleen and skin. Acute death with necrosis of lymphoid tissue and intestinal hemorrhage occurs within hours. Differential diagnosis includes other causes of acute death, such as MHV, Tyzzer’s disease, and reovirus 3. Those mice that survive develop a pox rash of variable intensity, depending on their level of secondary viremia. The rash lasts for several weeks. Infection of the feet and tail can lead to amputation. Differential diagnosis includes skin lesions caused by bacteria, acariasis, or bite wounds. Semi-susceptible mice develop disseminated disease with rash and ectromelia (shortening of limbs due to dry gangrene), and act as carriers. Mice that are experimentally inoculated via oral exposure develop chronic infection in Peyer’s patches, with prolonged fecal excretion and sometimes tail lesions. These mice can infect cell cultures. {3763}  At left are typical intracytoplasmic inclusion bodies in mouse skin (from RADIL, via Merck Manual).
Virus is excreted in respiratory, urinary, fecal fluids and from the skin. Classic poxviral inclusions (Cowdry types A and B) are seen in skin and mucosal epithelium. Type A inclusions are acidophilic, and are also called Marchal bodies. Type B inclusions are basophilic. If the animals survive, the spleen is characteristically scarred. Necrosis of red and white pulp gives the spleen a “mosaic” pattern of red and white/brown. {3763} A MLV vaccine is available, but should only be used to protect valuable stocks in imminent danger, as the mice will seroconvert and it protects against mortality but not morbidity. The vaccine is applied to a scarified area at the base of the tail. Positive vaccination response indicates the mouse was uninfected; if there is no response the mouse was previously positive and should be culled.{3763} Mousepox was diagnosed in a group of 20 CAF1 mice inoculated with killed murine cells in 1999. The source turned out to be mouse serum (treated at 56° C for 30 min) used inadvertently to feed the cell culture. Half of the affected mice died within a week of inoculation, showing hyperemia at injection sites, intraluminal small bowel hemorrhage, hepatic mottling {3551}and multiple 1mm white splenic foci. Histologically there was acute diffuse necrosis of liver, kidney and spleen; in the skin there was ballooning degeneration of epithelial cells and intracytoplasmic eosinophilic inclusions.{3975} Mousepox is a model for human smallpox infections and so has been the subject of renewed interest in recent years. C57BL/6 mice are resistant because their NK cells exert both a direct antiviral effect and increase the secretion of immune modulators such as interferon gamma. Similar mechanisms are probably involved the C57BL/6 resistance to herpesviruses such as MCMV. Another factor appears to be that MHC expression is inhibited during herpes and poxvirus infections, downregulating MHC control and resulting in increased NK cell activity.{4754}
Rabbit poxRabbit pox caused a highly fatal disease in labs in the US and the Netherlands between 1932-1967. In Holland the disease was not exanthematous, and was called “pockless rabbitpox.” The virus is a strain of vaccinia and may have originated in vaccinia-inoculated rabbits. After direct contact with nasal discharges there is respiratory tract infection (fever and profuse nasal discharge) followed by viremia. Lesions then occur in the skin as confluent papules rather than pustules, and may be seen in the oropharynx, spleen and liver. Edema occurs in the face, scrotum (with orchitis) or vulva, and eyelids. Gross lesions consist mainly of small gray or white nodules on almost all organs except the CNS and kidneys. Seldom are cytoplasmic inclusions seen, in contrast to the usual poxvirus infection. Diagnosis is by VI or FA.{3768}{3773} It can be propagated either in hens’ eggs or cell culture{3773}. Monkeypox
In 2003 a shipment of African rodents to the US resulted ultimately in the first human cases of monkeypox in the Western hemisphere. Gambian pouched rats (Cricetomys sp.) and dormice (Graphiuris sp.) in the shipment infected prairie dogs also being sold as exotic pets; these two species showed conjunctivitis (the most common presenting sign is "swollen eyes"), skin lesions and lymphadenopathy. Subsequently, there were 37 confirmed human cases of monkeypox in this outbreak; most had minor flu-like clinical signs and there were no fatalities.{4771} ParapoxvirusThese viruses cause contagious pustular dermatitis, pseudopox (milker’s nodule), and bovine papular stomatitis AvipoxvirusCapripoxvirusThese viruses infect sheep, goats, and cattle (lumpy skin disease). Presumably orf (contagious ecthyma) belongs in this group. In cattle, sheep, goats and wild ungulates, the virus causes papules on the skin and face (eyelids, lips, ears, nostrils). In humans, there is usually a solitary lesion that is macropapular or pustular at the site of inoculation. Lesions usually resolve by themselves in 10-14 days, conferring immunity.{4206} Yaba pox occurs in rhesus, baboons, and occasionally man. Unlike other poxviruses that infect epithelial cells, Yaba pox infects histiocytes; the lesions may be confused with benign histiocytoma. Infected cells contain eosinophilic intracytoplasmic inclusions. The disease is similar to lumpy skin disease in cattle.{3770} LeporipoxvirusMyxomatosis is common in wild rabbits (Sylvilagus spp.). It was used to control overpopulation of European Oryctolagus rabbits in Australia and Europe in the 1950s, as Oryctolagus are more likely to develop acute fatal disease. Transmission is through direct contact and also by arthropod vectors such as mosquitoes, fleas, and fur mites. Following inoculation of Sylvilagus, a small subcutaneous mass forms. A few days later, the rabbit develops mucopurulent conjunctivitis, subcutaneous edema and multiple subcutaneous masses. Oryctolagus rabbits die peracutely with only conjunctivitis and edema around body orifices (where fleas and mites often bite), and sometimes skin hemorrhage and convulsions. Histologically the masses contain stellate mesenchymal cells in a mucinous, homogeneous matrix. There are few inflammatory cells. Endothelial cell proliferation occurs in the masses. The overlying epidermis may be hypertrophied or degenerative, and epithelial cells contain intracytoplasmic inclusion bodies. Diagnosis is confirmed by VI, either in embryonated hens’ eggs (on which the virus produces distinctive pocks) or by cutaneous inoculation of neonatal rabbits. In areas such as the western US where the virus is endemic in wild rabbits, vector control is very important.{3768}{3773} Shope fibroma occurs commonly in the US in wild rabbits in which it causes a mild, self-limiting condition. The causative leporipoxvirus is closely related to myxoma virus{3773}. It is spread by arthropod vectors. Firm, flat lesions consisting of fibroblasts develop mostly on the feet and legs, but also on the muzzle, periorbital and perineal areas. The masses may grow to 7 cm in diameter. Fibroblasts contain eosinophilic intracytoplasmic inclusion bodies. Differential diagnoses are myxomatosis{3768} and papillomavirus{3773}. Virus is propagated in cell culture or on hens’ eggs. It can be a threat to commercial rabbitries with outdoor husbandry and the potential for exposure to insect vectors.{3773} Rabbit pox is caused by an orthopoxvirus and is covered there. SuipoxvirusMolluscipoxvirusMolluscum contagiosum is a disease of humans and chimpanzees. Lesions are smooth-surfaced, waxy, umbilicated epithelial papules 3-8mm in diameter especially on the eyelids and groin. There are large basophilic cytoplasmic inclusions.{3770} YatapoxvirusThis occurs in African wildlife and humans. Tanapox, benign epidermal monkey pox, or OrTeCa pox occurred in macaques in Oregon, Texas and California in 1967. It is zoonotic. Lesions included multiple crusty macules on the face and arms which healed in 3-4 weeks. Epithelial cells were swollen and contained eosinophilic cytoplasmic inclusion bodies.{3770} Circoviruses{4778}Circoviruses are non-enveloped icosahedral viruses with tiny (<1800 nucleotides) circular, single-stranded DNA. The DNA encodes only two proteins: viral replication proteins (Rep) and the capsid protein (Cap). Most have been found in birds, although there are human ones (not thought to cause disease), and there are 2 genera of porcine circoviruses. PCV1 was originally discovered in 1974 as a contaminant of a porcine kidney cell line (ATCC CCL-33), and is widespread in swine, but does not cause disease. PCV2 was discovered in association with postweaning multisystemic wasting syndrom (PMWS) in Canada in 1991. In 2006 the American Association of Swine Veterinarians renamed this syndrome porcine circovirus-associated disease (PCVAD) because of the large number of syndromes with which it is now associated. PCVAD is present in every major swine-producing country and costs producers plenty. PCVAD includes:
The hallmark lesion in PCV2 infection is lymphoid depletion with histiocytic replacement. The means by which lymphocytes are depleted are unknown; it might be apoptosis, decreased production in the bone marrow, or decreased proliferation in secondary lymphoid tissue. Pathogenesis is apparently due to immunomodulatory effects. The B cell growth fact IL-4 and CTL and macrophage-activating cytokine IL-2 are decreased in expression, resulting in decreased lymphocyte proliferation and antiviral response. Pro-inflammatory cytokines, IL-1b and IL-8, are increased. Transmission method is via fecal-oral contact, contact with infected urine, by direct contact with infected pigs, or (rarely) via the placenta. PCV2 first infects tonsils and lymph nodes of the head, and then is disseminated in B cells via the lymphatics. Maternal antibodies apparently protect piglets, because they show no signs of disease until 4 weeks of age. There are four factors involved in disease development:
Diagnosis is based on clinical signs and demonstration of PCV2 antigen in lymphoid tissues and another organ system such as the lungs, liver, kidney or intestine. PCR, in situ hybridization, and immunohistochemistry are used to confirm diagnosis. Serology is available for herd diagnosis; however, many clinically healthy pigs are seropositive. Iowa State University has a disinfection protocol involving degreasing detergent, then Virkon S, then fogging with Clidox. ©1999, Janet Becker Rodgers, DVM, MS, DipACLAM, MRCVS All rights reserved. Comments? Send an email to janet.rodgers@vet.ox.ac.uk |
Monkeypox is a zoonotic disease of
monkeys in Africa that occurs sporadically.