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Book: Encyclopedia of VIRO Article No.: 00446

Dear Author, During the preparation of your manuscript for typesetting some questions have arisen. These are listed below. Please check your typeset proof carefully and mark any corrections in the margin of the proof or compile them as a separate list. Your responses to these questions should be returned within seven days, by email, to MRW Production, email: [email protected]

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AU1 Please check the long affiliations for accuracy. These are for Elsevier’s records and will not appear in the printed work. AU2 The reviewer has asked whether ‘‘pyknotic’’ should also be added in the glossary section. AU3 The reviewer has asked to consider using an abbreviation for ectromelia virus throughout the article, as it is used so often (say, ECTV or EV) (similarly for rabbitpox virus). AU4 The reviewer has added the word ‘‘virus’’ here; OK? AU5 The reviewer comments here that ‘‘A section on the genetics of ectromelia virus, especially the genome structure and gene content, seems in order. This need not be long, but it is a significant advance in the area, and to ignore it altogether seems strange.’’ Please check. AU6 The reviewer comments here that ‘‘Mention of the availability of the complete genome sequence of rabbitpox virus and a brief description of its relationship to that of vaccinia virus would seem appropriate at this point.’’ Please check. AU7 We have also received a permission letter for Figure 1, according to which the source is Fenner F (1982) Mousepox. In: Foster HL, Small JD, and Fox JG (eds.) The Mouse in Biomedical Research, vol. II, pp. 209-230. New York: Academic Press. However, the credit line is not inserted in the figure caption as Zentralinstitut fu¨r Versuchstiere is mentioned as the source already. Please confirm as to which is the source to be credited for Figure 1. VIRO: 00446

a0005 Mousepox and Rabbitpox Viruses M Regner, F Fenner, and A Mu¨ llbacher, Australian National University, Canberra, ACT, Australia

This article is a revision of the previous edition article by Frank Fenner, volume 2, pp 973 – 980 ã 1999, Elsevier Ltd.

virus. During experimental epidemics carried out in Burnet’s Au2 Glossary laboratory, F. Fenner found that in animals that did not g0005 Caspases A group of proteases with unusual die of acute hepatitis there was a rash, and he named the cleavage specificity; essential for apoptosis. disease mousepox. Subsequent studies led to the develop- g0010 Cytokines Proteins that are secreted by certain cells ment of a classical model explaining the spread of virus of the immune system and have an effect on other around the body in generalized viral infections with rash. cells. In laboratories in Europe and the USA, the virus was p0020 g0015 Enzootic Disease of animals regularly occurring in a regarded as a major menace to colonies of laboratory particular area or season. mice, and stringent steps were taken to prevent its entry g0020 Epizootic Temporary outbreak of an animal disease. to the USA. Only after extensive outbreaks in several g0025 Granzymes Enzymes secreted by cytolytic cities of that country in 1979 were studies of the virus lymphocytes to induce apoptosis in other (e.g., undertaken in the USA, in high-security laboratories. virus-infected) cells. g0030 Inclusion bodies Cytoplasmic structures that PROOF sometimes form where viral replication occurs. Classification s0020

g0035 Perforin A membrane pore-forming protein, Ectromelia virus is a species within the genus Orthopoxvirus p0025 Au4 secreted by cytolytic lymphocytes to permit of the family Poxviridae, as evidenced by the morphology granzyme entry into virus-infected cells. of the virion, cross-protection tests, and restriction endo- g0040 Phagocytes Cells capable of engulfing foreign nuclease mapping. Most strains of Ectromelia virus (e.g., matter or other cells, e.g. macrophages. Moscow, Hampstead) recovered from naturally infected mouse colonies are highly virulent. However, a substrain of Marchal’s original strain was attenuated by serial passage on the chorioallantoic membrane of chicken eggs s0005 Introduction (Hampstead egg).

p0005 Ectromelia (mousepox) virus and rabbitpox virus share

two features; they are both orthopoxviruses and both are Host Range and Virus Propagation s0025 known only as infections of laboratory animals, the mouse Mus musculus and rabbit, respectively. Ectromelia virus produces disease in and p0030 several other species of mice, and is considered a natural mouse pathogen. The rabbit, guinea pig, and rat can be infected by intradermal or intranasal inoculation, with the s0010 Ectromelia Virus production of small skin lesions or an inapparent infec- s0015 History tion. Ectromelia virus will grow on the chorioallantoic membrane of the developing chick embryo, and also in p0010 Ectromelia virus was discovered in 1930 by J. Marchal, as a spontaneous infection of laboratory mice at the National cell cultures derived from a variety of species. Quantita- Institute ofELSEVIER Medical Research in London. It was called FIRSTtion of virus stocks is determined by growth of ectromelia infectious ectromelia because of the frequent occurrence virus on cell culture monolayers (plaque assay). of amputation of a foot in animals that had recovered from infection. Soon after, J. E. Barnard showed by ultraviolet Geographic Range and Seasonal Distribution s0030 (UV) microscopy that it had oval virions about the same size as those of vaccinia virus. The only other experiments Ectromelia virus has been spread around the world inad- p0035 done with the virus at that time involved studies of exper- vertently by scientists working with laboratory mice, and imental epidemics by W. W. C. Topley and his colleagues. has been repeatedly reported from laboratories in several p0015 In 1946, F. M. Burnet, in Melbourne, showed that countries of Europe and from Japan and China. Mousepox ectromelia virus was serologically related to vaccinia has never been enzootic for prolonged periods in mouse

1 VIRO: 00446

2 Mousepox and Rabbitpox Viruses

colonies in the USA, but accidental importations some- infections. Mu¨llbacher has more recently used the mou- times occurred with mice or mouse tissues from European sepox model for the analysis of immune effector molecules laboratories, with devastating consequences. In contrast, required for resistance to ectromelia virus infections, using there are extremely limited data regarding the occurrence specific gene knockout mutant mouse strains. Mousepox is of ectromelia in wild animals. generally considered an excellent mouse model of human smallpox and is now used increasingly by the bioterrorism s0035 Epidemiology defense research community. p0040 In laboratory mice, ectromelia virus is infectious by all Mice are usually infected in the footpad and, after p0065 routes of inoculation. It always produces a generalized an incubation period of c. 7 days (as found in natural infection but there are local lesions in the lungs after infections), a local (‘primary’) lesion develops at the inoc- intranasal inoculation and in the peritoneal cavity after ulation site. A few days later some mice die, with no other intraperitoneal injection. The response of mice is strongly visible skin lesions but with acute necrosis of the liver conditioned by mouse genotype (see below). and spleen, and in those that survive a rash develops p0045 The usual source of natural infection is via minor which goes through macular and pustular stages before abrasions of the skin, which may occur from contaminated it scabs. bedding or during manipulations by animal handlers. During the incubation period the virus passes through p0070 Infection may also occur by the respiratory route, but the mouse body in a stepwise fashion: infection, multipli- probably only between mice in close proximity to each cation and liberation, usually accompanied by cell necro- other. A primary lesion usually develops at the site of sis, first in the skin and then the regional and possibly the infection. Since mice are readily infected by inoculation, deeper lymph nodes, until it reaches the bloodstream virus-contaminated mouse serum, ascites fluid or mouse (primary viremia). cells, tumors or tissues constitute a risk to laboratory C. A. Mims showedPROOF in the 1960s that, during the p0075 colonies previously free of infection. primary viremia, virus is ingested by the phagocytic littoral cells of the liver and spleen. After a day or so, much s0040 Enzootic mousepox larger amounts of virus are liberated into the circulation p0050 Until the introduction of rigorous screening techniques (secondary viremia). Next follows an interval during in the 1960s, mousepox was enzootic in many mouse- which the virus multiplies to high titer before visible breeding establishments in Europe and Japan. A variety changes are produced, so that 2 or 3 days usually elapse of mechanisms probably operated to maintain the virus, between the appearance of the primary lesion and the without disrupting the mouse-breeding program as to secondary rash. Some animals die before skin lesions make control mandatory. One important factor was prob- appear, but titration experiments and histological exami- ably the high level of genetic resistance and trivial symp- nation showed that early skin lesions are present. tomatology exhibited by many mouse genotypes. Another may have been maternal antibody. Another possible mechan- Clinical Features of Infection s0055 ism for maintaining enzootic infection is chronic, clini- cally inapparent infection, which sometimes occurs after Early workers described two forms of the disease, a rap- p0080 oral administration, when some mice show infection of idly fatal form in which apparently healthy mice die Peyer’s patches, excretion of virus in the feces, and lesions within a few hours of the first signs of illness and show in tail skin. extensive necrosis of the liver and spleen at autopsy, and a chronic form characterized by ulcerating lesions of the feet, tail, and snout. Fenner found that in natural infec- s0045 Susceptibility of Different Strains of Mice tions most mice develop a primary lesion, usually on the p0055 Analysis of spontaneous epizootics and deliberate experi- snout, feet, or belly. Subsequently, virus multiplies to high ments in the 1980s showed that C57BL/6, 129J, and AKR titer in the liver and spleen. Some mice die at this stage, mice wereELSEVIER highly resistant to mouse pox, CBA/J FIRST and but if they survive they almost invariably developed a SJL/J intermediate, and BALB/c and A/J mice were generalized rash (Figure 1). highly susceptible. Strain differences are best demon- Age affects the response of genetically susceptible p0085 strated after footpad inoculation or in natural epizootics, mice. Both virulent and attenuated strains produce higher since C57BL/6 mice are relatively susceptible by intrana- mortalities in suckling mice and in mice about a year old sal, intracerebral, or intraperitoneal infection. than in the 8-week-old mice.

Pathology and histopathology s0060 s0050 Pathogenesis The pathological changes in naturally occurring mouse- p0090 p0060 Fenner’s work in the 1930s to 1940s established mousepox in susceptible mice are quite characteristic. Addi- pox as a model system for the study of generalized viral tional lesions in the peritoneal cavity or lung occur after VIRO: 00446

Mousepox and Rabbitpox Viruses 3

intraperitoneal or intranasal inoculation, respectively; viral multiplication; more characteristic of mousepox are these are important because mousepox sometimes occurs the prominent acidophilic inclusion bodies (A-type), after unwitting passage of ectromelia virus by these which are always found in infected epithelial cells but routes. rarely in liver cells (Figure 2).

s0065 Intracytoplasmic inclusion bodies Skin lesions s0070 p0095 Ectromelia virus produces two types of intracytoplasmic The earliest primary lesions that can be recognized mac- p0100 inclusion body in infected cells, A-type and B-type. The roscopically are the seat of advanced histological changes, latter occur in all poxvirus infections and are the sites of for viral multiplication has then been in progress for several days. There is no macroscopic breach of the skin surface, but the dermis and subcutaneous tissue are edematous and there is widespread lymphocytic infiltration of the dermis. Inclusion bodies can be seen in the epidermal cells at the summit of the lesion. Necrosis of these epidermal cells is followed by ulceration of the surface. The exudate forms a scab beneath which healing occurrs. Histologically, the changes of the rash are similar to those in the primary lesion.

Lesions of the liver s0075 The liver and spleenPROOF are invariably invaded during the p0105 incubation period and virus multiplies to high titer here. The liver remains macroscopically normal until within 24 h of death, when it appears enlarged and studded with f0005 Figure 1 The rash of mousepox as it appears 14 days after minute white foci. The necrotic process extends rapidly Au7 infection, in a naturally infected genetically hairless mouse (not and at the time of death the liver is enlarged with many athymic). Similar lesions occur beneath the hair of other strains of susceptible mice and can be clearly demonstrated by epilation. large semiconfluent necrotic foci. In animals that sur- Courtesy of the Zentralinstitut fu¨ r Versuchstiere, Hanover, vive, the liver usually returns to its normal macroscopic Federal Republic of Germany. appearance, but occasionally numerous white foci occur.

ELSEVIER FIRST

f0010 Figure 2 Section of the skin of the food of a mouse injected with ectromelia virus in the footpad six days earlier. (a) Low power. (b) High power, Mann’s stain. Almost every epithelial cell contains an eosinophilic A-type inclusion body. With most strains of ectromelia virus, these A-type inclusion bodies contain large numbers of mature virions. Reprinted from The Mouse in Biomedical Research, Vol. II, Fenner F, Mousepox, pp. 209–230, Copyright (1982), with permission from Elsevier. VIRO: 00446

4 Mousepox and Rabbitpox Viruses

p0110 Histologically, little change is apparent until macro- congestion; the changes in the liver and spleen are those scopic changes have appeared, although immunofluores- characteristic of naturally acquired mousepox. With cence techniques have shown that infection always occurs larger doses of virus, congestion of the lungs is more first in the littoral cells of the hepatic ducts, from which pronounced and consolidation may occur, and when the virus spreads to contiguous parenchymal cells. very large doses are given death occurs with patchy or Numerous scattered foci of necrosis then appear through- complete consolidation of the lungs and little change in out the liver parenchyma and in fatal cases these rapidly the liver and spleen. The apparent pneumotropism is due extend until they became semiconfluent. The portal tracts to the fact that the local reaction, which occurs after show slight infiltration with lymphoid cells. Liver regen- the intranasal inoculation of very large doses of virus, eration commences early and is active, especially in non- kills the animal before there is time for the characteristic fatal cases, and fibrosis does not occur. changes in the liver and spleen to occur. s0080 Lesions of the spleen p0115 The spleen shows macroscopic changes at least a day Immune Response s0100

earlier than the liver and higher titers of virus are found Two weeks after infection mice are solidly immune to p0140 in the spleen. Virus reaches the spleen in infected lym- re-infection by footpad inoculation of the virus. This immu- phocytes, which initiate infection in the substance of the nity declines slowly but even a year after recovery multipli- follicles. While infected follicles are destroyed by the cation of the virus after footpad challenge is confined to the spreading infection, neighboring follicles show the pro- local skin lesion. liferative response characteristic of antibody production. p0120 In surviving mice, lesions of the spleen vary from small Humoral immunity s0105 raised plaques about a millimeter in diameter to areas of Antibodies generatedPROOF by a primary infection protect from p0145 fibrous tissue that, after severe attacks, almost completely subsequent challenge. Newborn mice receive maternal replace the normal splenic tissue. These changes consti- antibody via the placenta and in the milk during the tute reliable autopsy evidence that a mouse has recovered first 7 days after birth. Until titers decline to undetectable from an attack of mousepox. levels by the seventh week after birth, this maternal antibody confers protection against death, but not against s0085 Lesions of other organs infection, with moderate doses of ectromelia virus. Fur- p0125 The regional lymph nodes draining the site of the primary thermore, in the absence of functional B-cells, clearance lesion are enlarged from the time the primary lesions can of primary infection with ectromelia may be deficient, be detected, and they usually show localized areas of leading to viral persistence and eventual death. necrosis, with pyknotic nuclear debris in a featureless background. In fatal cases, the gut is often engorged and Cell-mediated immunity s0110 the lymphoid follicles enlarged. Small necrotic foci with p0150 Work by Blanden in the early 1970s showed that T-cells typical inclusion bodies occur in the intestines in most are critical in recovery from primary infection with ectro- acutely fatal cases of mousepox. Occasionally, especially melia virus, and mice pretreated with anti-thymocyte in very young mice, there are hemorrhagic foci in the serum die from otherwise sublethal doses of virus due to kidneys. uncontrolled viral growth in target organs. These mice have impaired cell-mediated responses but normal neu- s0090 Lesions after intraperitoneal inoculation p0130 There is no primary skin lesion, but in acutely fatal cases tralizing antibody responses, elevated interferon levels in the necrosis of the liver and spleen resembles that found the spleen, and unchanged innate resistance in target after natural infection. In addition, there is usually some organs. The active cells in the immune population are increase in intraperitoneal fluid and a considerable cytotoxic T-cells, although natural killer cells probably amount of pleural fluid, and the pancreas is often grossly also play an important role early in the infection. edematous.ELSEVIER In animals that survive the acute infection FIRSTVirus-specific cytotoxic T-cells are detectable 4 days p0155 there is a great excess of peritoneal and pleural fluid, the after infection and reach peak levels in the spleen 1–2 days peritoneal surfaces of the liver and spleen are covered later, while delayed hypersensitivity is detectable by the with a white exudate, the walls of the gut are thickened footpad test 5–6 days after inoculation. In contrast, signifi- and rigid, and there is often fat necrosis in the intraperi- cant neutralizing antibody is not detectable in the circula- toneal fat. Extensive adhesions between the abdominal tion until the eighth day. viscera develop later. Cytotoxic T-cells employ two different mechanisms to p0160 destroy virus-infected cells before the release of viral s0095 Lesions after intranasal inoculation progeny: one, the granule exocytosis pathway, is mediated p0135 When small doses of virus are inoculated intranasally, by perforin and granzymes that are stored in their cyto- there is usually little change in the lungs except patchy lytic granules and secreted toward, and enter, the infected VIRO: 00446

Mousepox and Rabbitpox Viruses 5

cell, inducing apoptosis; the other one via triggering of Rabbitpox Virus s0125 death receptors (e.g., Fas) on the surface on infected cells, History and Classification s0130 inducing a cascade of caspase activation that also leads to

apoptosis. However, poxviruses encode inhibitors of the Rabbitpox is a laboratory artifact, due to the infection of p0180 death receptor pathway of killing (e.g., SPI-2, see below), laboratory rabbits with vaccinia virus, usually with neu- rendering the granule pathway indispensable for recovery. rovaccinia variants; hence this account of rabbitpox virus Consequently, mice genetically deficient in perforin or will omit reference to those aspects that are covered in the both principal granzymes (A and B) are highly susceptible entry on vaccinia virus. to ectromelia infection. The name rabbitpox was originally given to devastat- p0185 p0165 T-cell-secreted cytokines are also important factors ing outbreaks of a generalized disease likened to smallpox determining the outcome of infection. Whereas inter- in man, in a colony of laboratory rabbits at the Rockefeller feron-gamma (IFN-g critically contributes to viral clear- Institute of Medical Research in New York in 1932–34, ance, an imbalanced cytokine response of the so-called when other scientists had been working with neurovacci- Th2 type, characterized by lack of IFN-g and excess of nia virus in rabbits in an adjacent room prior to the interleukin-4 (IL-4), predisposes to greater susceptibility. outbreak. The virus recovered from the outbreak was A recombinant ectromelia virus expressing IL-4 was called rabbitpox virus and was shown to be very similar found to be highly virulent even in resistant strains of to neurovaccinia virus in its biological properties. Subse- mice, and those vaccinated with attenuated virus, prompt- quently, the restriction map of the Utrecht strain (see ing concerns about the possible creation of recombinant below) was found to be almost identical with that of poxviruses with increased virulence in humans for the vaccinia virus. purpose of bioterrorism. Another outbreak occurred in the Netherlands in 1941. p0190 It began among rabbitsPROOF bought from a dealer a few days s0115 Host response modulation after they were introduced into the laboratory colony, and p0170 As do other poxviruses, ectromelia encodes numerous spread among the stock rabbits. The disease was usually host-response modifiers, in order to evade or suppress lethal, death occurring before there was time for the the immune response to allow for maximal viral replica- development of a rash. The virus that caused this out- tion. Broadly, these can be divided into inhibitors of break, designated rabbitpox-Utrecht, caused similar the inflammatory response, and anti-apoptotic proteins. highly lethal epizootics when it ‘escaped’ in the Institut Several ectromelia-encoded proteins have been shown to Pasteur in Paris in 1947; other outbreaks have been neutralize or inhibit key inflammatory cytokine pathways, described in laboratory rabbits in the USA in the 1960s. for example, an IL-18-binding protein and homologs of the IL-1b, tumor necrosis factor (TNF) and IFN receptors. On the other hand, virally encoded inhibitors of components of Epidemiology s0135 the caspase cascade inhibit apoptotic pathways. Examples In all outbreaks spread appeared to occur by the respira- p0195 are the ectromelia protein p28, a RING finger-domain tory route, and experiments confirmed that infection protein, which is a potent ectromelia virulence factor that occurs readily by this route. Rabbits infected by contact inhibits UV-induced, but not Fas- or TNF-induced apopto- are not infectious for other rabbits until the second day of sis; and SPI-2, a serine proteinase inhibitor, which blocks illness, which is usually 5 days after infection. Actual TNF-a-mediated apoptosis via caspase 1/8 inhibition. contact is not necessary; transmission can occur across the width of a room, and air sampling revealed the pres- s0120 Future ence of rabbitpox virus in the air of rooms housing infected rabbits. p0175 Mousepox is now very rare as a natural infection in laboratory colonies of mice but it is likely that, despite the strict controls necessary to protect mouse colonies, mousepox ELSEVIER FIRSTGenetics s0140 will be investigated more extensively in the future. Work- ers in Australia, the USA, and the UK are now using it as a Since 1960, the Utrecht strain of rabbitpox virus has been p0200 model for studies of problems such as immunocontracep- used for genetic studies on poxviruses, since it was found tion, the role of the many homologs of mammalian host to give rise to white pock mutants on the chorioallantoic response modifier genes that are found in all poxviruses. In membrane of chicken eggs and host range mutants in a pig addition, the recognition of mousepox as a good mouse kidney cell line, both of which entail deletions and trans- model for human smallpox has, in the light of increased positions of DNA. Recombination experiments with the interest in poxvirus immunobiology, seen a resurgence of white pock mutants were used to construct the first crude research into its pathologies, immune evasion strategies, ‘genetic map’ produced for an animal virus. Au6 Au5 and the mechanisms of recovery from this disease. VIRO: 00446

6 Mousepox and Rabbitpox Viruses

s0145 Pathogenesis p0205 A good deal of experimental work has been carried out on the pathogenesis of rabbitpox as an animal model of smallpox, with results that were largely confirmatory of those obtained with mousepox. In rabbits infected by the intranasal instillation of a small dose of virus, by aerosol, or after intradermal infection or contact infection, there is a stepwise spread of virus through the organs, although the incubation period is shorter than in mousepox and there seems to be little delay at the regional lymph nodes. Viremia is leukocyte associated.

s0150 Clinical Features of Infection p0210 Rabbitpox causes an acute generalized disease in which a rash appears in animals that survive long enough, pre- senting as pocks on the skin and mucous membranes (Figure 3). Rabbits dying of hyperacute infection show no obvious skin lesions, the so-called ‘pockless’ rabbitpox. Such infections are analogous to acutely lethal cases of mousepox and perhaps to early hemorrhagic-type small- PROOF pox, in which death occurs before there is time for pustular skin lesions to develop.

s0155 Pathology and Histopathology p0215 The most distinctive lesions are the pocks on the skin and mucous membranes and occasionally small areas of focal necrosis are found in the internal organs (liver, spleen, lung, testes, ovaries, uterus, adrenals, and lymph nodes). In the so-called ‘pockless’ form, a few pocks may occur Figure 3 Rabbitpox. (a) and (b) Littermates with different types f0015 around the mouth and they may be visible on the shaved of disease. The course of infection was mild in the rabbit shown in skin. The most prominent gross lesions are pleuritis, focal (a) and external lesions were limited in the skin; the animal in necrosis of the liver, enlarged spleen, and edema and (b) was seriously ill and its posture is a manifestation of acute hemorrhage of the testes. respiratory distress resulting from extensive mouth lesions. (c) Cutaneous lesions on the trunk. The coat in this area was p0220 Rabbitpox virus, being a strain of vaccinia virus, pro- loose and easily plucked by hand. (d ) Skin of a pregnant doe duces B-type inclusions (Guarnieri bodies) in infected self-plucked for nest fur, showing both dry crusted pustules and cells, but not the prominent A-type inclusions found in others in earlier stages of development. Reproduced from The cells infected with ectromelia virus. Journal of Experimental Medicine, 1934, 60: 427–440. Copyright 1934 The Rockefeller University Press. s0160 Immune Response p0225 Rabbits that have recovered from rabbitpox are immune This work helped to explain the failure of inactivated to infectionELSEVIER with vaccinia virus, but in very severe infec- FIRSTvaccinia to provide protection against infection with tions rabbits die before there is time for an effective orthopoxviruses. immune response. The importance of enveloped virions in the pathogenesis and immunology of orthopoxvirus Prevention and Control s0165 infections was fist demonstrated in experiments with rabbitpox virus. Passive immunization with sera that did not Since rabbitpox appears to be a laboratory artifact, due to p0230 contain antibody to the viral envelope failed to protect the introduction of strains of vaccinia virus that can rabbits against challenge infection, even though the neu- spread from one rabbit to another in rabbit colonies, tralization titer of the ineffective antiserum (produced by prophylaxis appears to be a matter of preventing such immunization with inactivated vaccinia virus) was much events. They were rare even when vaccinia and especially higher, as judged by conventional neutralization tests. neurovaccinia viruses were extensively used in animal VIRO: 00446

Mousepox and Rabbitpox Viruses 7 experiments, several decades ago, and it is unlikely that Fenner F and Buller RML (1996) Mousepox. In: Nathanson N (ed.) Viral Pathogenesis, pp. 535. Philadelphia: Lippincot-Raven. further episodes will occur now that most research with Fenner F, Wittek R, and Dumbell KR (1989) The Orthopoxviruses. San vaccinia virus utilizes cultured cells rather than intact Diego: Academic Press. animals. Nevertheless, laboratory managers who use Greene HSN (1934) Rabbit pox. I: Clinical manifestations and course of disease. The Journal of Experimental Medicine 60(4): 427–440. rabbits should be aware of the possibility that some strains Mu¨ llbacher A (2003) Cell-mediated cytotoxicity in recovery from of vaccinia virus can spread naturally from one rabbit to poxvirus infections. Reviews in Medical Virology 13: 223–232. another. Mu¨ llbacher A and Lobigs M (2001) Creation of killer poxvirus could have been predicted. The Journal of Virology 75: 8353–8355. See also: Vaccinia virus (Poxviridae) (00525); Poxviridae (00691); Smallpox and monkeypox viruses (Poxviridae) (00506).