Laboratory Animals Ltd. Laboratory Animals (2002) 36, 357â372 .... Systems and transferred to Harlan Inc. in ...... reference library (in Filemaker format) may.
REVIEW ARTICLE
Diversifying animal models: the use of hispid cotton rats ( Sigmodon hispidus ) in infectious diseases Stefan Niewiesk1 & Gregory Prince2 1 2
Institut fu¨r Virologie und Immunbiologie, Versbacher Str. 7, 97078 Wu¨rzburg, Germany and Virion Systems, 9610 Medical Center Drive, Suite 100, Rockville MD 20850, USA
Summary T he hispid cotton rat (Sigm o d o n h ispid us) has been a longstanding laboratory anim al model of infectious diseases. In this review, the most common usage of hispid cotton rats as models of infectious diseases is discussed in detail and all organisms, which have been shown to infect cotton rats, are listed. A state of the art overview is given on handling and maintenance of hispid cotton rats as well as experimental techniques such as narcosis and blood withdrawal. Most im portantly, through the development of new reagents, the hispid cotton rat can be used to study im mune responses against the respective pathogen. Hispid cotton rat cytokine and chemokine genes have been sequenced and cotton rat speci®c antibodies and cell lines have been produced which in connection with the establishment of immunological methods should facilitate the use of hispid cotton rats as anim al models in the pathogenesis of infectious diseases. Keywords therapy
Hispid cotton rats; vaccine; RSV; measles; herpes simplex; adenovirus; gene
Infectious diseases are still a major public health concern, claiming 13 million lives every year (WHO Report 1999). In order to study the pathogenesis of infectious diseases and to develop vaccines and therapeutics, monkeys have been used because of their close relationship to humans and their susceptibility to many human pathogens. However, the use of monkeys is limited for ethical, economic and technical reasons, and the development of small rodent models has greatly faci litated research in infectious diseases. Mice and, to a lesser extent, rats have been used extensively as animal models because the mouse and rat are immunologically and genetically well de®ned. T he main disadvantage of these species is that, quite C o rre spond e nc e to : Stefa n Niew ie sk E-m a il: nie w ie sk @vim .uni-wue rzb urg.de Accepted 9 January 2002
often after inoculation with a human pathogen, infection is barely detectable or depends on the cumbersome adaptation of a virus =bac terium =parasit e to the murine host or immunosuppression of the host. T his means that quite often an im mune response, but not the replicati on and spread of the pathogen, can be analysed in mice or rats. Attempts have been made to improve the insuf®ciency of the models by introducing transgenes encoding the receptor molecule, e.g. polio virus, human immunode®ciency virus and measles virus. So far these attem pts to produce rodents in which the pathogenesis observed in the natural host is reproduced in the anim al model have failed. T his is not surprising, as it is known that fact ors other than receptor molecules play an important role in the propagat ion and spread of pathogens (e.g. Niewiesk e t a l. 1997b).
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In recent years, much effort has been made to analyse the host±pathogen relat ionship, and the emphasis of research is shifting from the study of im munology using pathogens
Table 1
towards the analysis of the infectious disease, including both the immune response and the pathogen in a suitable animal model. A particularly promising approach has been the
Cotton rat models of infectious diseases
Pathogen Viral infections Adenovirus (genetic therapy) Human Bovine Model of keratitis Black Creek Canal virus Bovine herpesvirus Human immunode ciency virus In uenza virus Keystone virus Measles virus Respiratory syncytial virus Human Bovine Parain uenza virus Human Bovine Pirital virus Poliovirus Tamiami virus Vacciniavirus Venezuelan equine encephalomyelitis virus
Reference
Comment
Pacini et al. 1984 Mittal et al. 1995 Tsai et al. 1992 Hutchinson et al. 1998, Rollin et al. 1995 Papp et al. 1997 Rytik et al. 1995, Langley et al. 1998 Prince 1994 McLean 1982 Wyde et al. 1992
2
1, 2 2 2 2 2 2 2
Dreizin et al. 1971 Murphy et al. 1990 2 Murphy et al. 1981 Mittal et al. 1995 Fulhorst et al. 1997 Armstrong 1939 Murphy et al. 1976 Rytik et al. 1976 Zarate & Scherer 1968, Howard 1974
1 2 1 2 1, 2
Bacterial infections Borrelia burgdorferi Francisella tularensis Haemophilus in uenzae Leptospira Mycobacterium bovis Rickettsia prowazeki Rickettsia rickettsi Rickettsia orientalis
Burgdorfer & Gage 1987, Oliver et al. 1995 Lowery 1981 Patel et al. 1992 Clark 1984 Steinbach & Duca 1940 Ignatovich et al. 1983 Shirai et al. 1967 Fox 1948, Fulton & Joyner 1945
1, 2 1 2 1 2 1, 2
Fungal infections Microsporum gypseum Trichophyton mentagrophytes
Clark 1984 Clark 1984
1 1
Parasitic infections Brugia pahangi Coccidia Dipetalonema vitae Echinococcus multilocularis Fasciola hepatica Leishmania donovani Litomosoides carinii (natu¨rlicher Wirt) Naegleria fowleri Paragonimus uterobilateralis Sarcocystis sigmodontis n. sp. Toxoplasma gondii
Ramachandran & Pacheco 1965 Sundermann & Lindsay 1989, Elangbam et al. 1993 Bayer & Wenk 1988 Kroeze & Tanner 1985 McKown et al. 2000 Azazy et al. 1994 Kershaw & Storey 1976 John & Hoppe 1990 Weber et al. 1988 Dubey & Shef eld 1988 Clark 1984
1 1 2 2 2
1 ˆ natural infection; 2 ˆ experimental infection Laboratory Animals (2002) 36
1, lariasis 2 2 1 1
Use of hispid cotton rats in infectious diseases
development of genetically manipulated pathogens. To study these organisms in vi vo , a cost-effective small anim al model is required in which genetically manipulated, wild-t ype and laboratory =vaccine strains of pathogens replicate and spread. Despite this, there is still a need for a suitable animal species susceptible to a wide range of human pathogens. T he hispid cotton rat (Sigm o d o n h ispid us) may have the potential to ®ll the gap. Armstrong (1939 ) described their use for paralytic poliovirus infection. Since then, numerous groups have dem onstrat ed that the hispid cotton rat is susceptible to a wide range of infectious diseases (Tabl e 1). Because of this feature, hispid cotton rat s have been used successfully (mainly by companies) in the search for vaccines and antiviral drugs. In academic research, the cotton rat has been under-represented because many reagents available for the mouse system were not available for the cotton rat. As academ ic interests are usually focused on the dissection of mechanisms, a model system without reagents is of little value. However, over the last few years this has changed fundam entally due to the increasing interest in the hispid cotton rat as an animal model for infectious diseases. In this review we will demonstrate the usefulness of hispid cotton rats exempli®ed by their use as models for respiratory syncytial virus (RSV), measles virus, herpes simplex virus (HSV) and adenoviral gene therapy. We also review the development of new reagents and methods in the cotton rat system.
Taxonomy and physical characteristics of hispid cotton rats (Sigmodon hispidus) T he hispid cotton rat (Si gm o d o n h ispid us) is one of the most abundant rodents throughout the southeastern United States, Mexico and Central America: Distribution map for Sigm o d o n h ispid us (Smithsonian Institution 1993a). Cott on rats belong to the order Rodentia, fam ily Muridae, subfam ily Sigmodontinae. T here are 10 Sigm o d o n species: (Sm ithsonian Institution 1993b), S. h ispid us being the one most commonly used in the laboratory set-
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ting. Hispid cotton rats have a length of 125 to 200 mm, weight of 70 to 200 g and a grayish brown fur (Cam eron & McClure 1988 ). T he nam e is derived from the sigmoid enamel loops on the grinding surface of the molar. In the wild, hispid cotton rats are solitary animals with the only prolonged contact occurring between males and females. In captivity, it is not uncommon for animals to ®ght sometim es until death. T herefore husbandry practices have to take that into account (see below). T he lifespan of hispid cotton rats in the wild is less than 6 months, which is thought to be due to diseases and predators (Cameron & McClure 1988, Faith e t a l. 1997 ). In captivity, colonybred animals have been reported to have a lifespan of 23 months (Fai th e t a l. 1997). For the inbred strain COT T ON =NIco the lifeexpectancy 50% is around 14 months (Iffa Credo, Lyon, France, unpublished inform at ion).
Inbred strains of hispid cotton rats One prerequisite for studying infectious diseases is the use of inbred animals. At present, two inbred strains are commercially available from Iffa Credo (Lyon, France; http: ==www.criver.com =) subsidiary, and Harlan Inc. (Indianapolis, Indiana, USA; http: ==www.harlan.com =). Originally, wild hispid cotton rats were captured to set up an outbred colony at the National Institute of Health (NIH), Bethesda, USA, Veterinary Resources Program. By Caesarean section and weaning onto rat (Ra ttu s no rve gic us) foster mothers, a speci®c pathogen free colony was rederived. By serial brother±sister mating an inbred strain was established (SIG =N ). In 1991 anim als were obtained by Iffa Credo, Lyon, France in their G27 generation. Animals from this inbred strain are marketed under the strain designation COT T ON =NIco. In 1989 breeding anim als from the NIH colony were obtained by Virion Systems and transferred to Harlan Inc. in 1998. Although the strain history suggests that both strains are closely related the degree of genetic diversity or identity has not been de®ned and no appropriate genetic markers have been developed. In addition to Laboratory Animals (2002) 36
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these commercial sources, other breeding colonies exist at university institutes. Most of them seem to have small colonies with a high degree of inbreeding without an actual inbreeding program me. In mouse and rat breeding colonies a number of mutants have been found over time. Similarly, between our anim al facilities, we have observed three different mutant s of hispid cotton rats. A white cotton rat with dark eyes was found in a litter derived from COTT ON =NIco breeders. T his animal died 16 days after birth with an extended abdom en. In another instance animals were seen which were 30±40% white and which would breed only heterozygously. Because homozygous breeding was lethal, the line was discontinued. A more recent development is of a white-footed cotton rat which can be bred homozygously. However, strain characteristics of these anim als need to be de®ned.
Handling, maintenance and breeding In comparison to rats and mice, cotton rats are dif®cult to handle. Although often thought of as being aggressive this is not true. Cotton rats will not attac k. However, if held they try to twist free and, unless successful, they turn around and bite. If held at the tail, cotton rats free themselves in a spinning motion, thereby degloving the tail. It has been recommended wearing garden leather gloves when handling cotton rat s. Although for an experienced and quick handler maintenance is no problem , we have found this technique not to be applicable with inexperienced students. We therefore developed a cotton rat handling device which enables even individuals with little training in anim al handling to securely transfer cotton rats from cage to cage or into an anaesthetic chamber (Niewiesk e t a l. 1997c ). As a precaution the cage can be put into a plastic box used for bedding in order to impair an escape into the room. For the maintenance of cotton rats, standard polycarbonate cages with wire mesh tops are used. Breeding pairs are kept in type IV cages with a nest box (Niewiesk e t a l. 1997c ). For maintenance, animals are kept in type III cages (3±5 anim als =cage depending on Laboratory Animals (2002) 36
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age and size). Animals are fed standard rodent chow a d lib it um . In comparison to rat s, cotton rats drink a lot and this has to be taken into account. Paper bedding or chipwood bedding can be used as bedding. Animals are kept at 22 2 C with a 12 h light =12 h dark cycle. In order to avoid boredom and ®ghting, environmental stim uli can be used. Helpful items include hazel wood sticks, petite Nylabones, nest boxes and PVC tubing (Ward 2001). Hard objects to chew on are also useful because hispid cotton rats have ever growing incisors and teeth can be overly long. Under laboratory conditions animals are diurnal. At the age of 6 weeks cotton rats reach sexual maturity. It might be necessary to separate males after the age of 8 weeks, as during ®ghts extended wounds on the bac k are in¯icted. It is recommended to pair breeding pairs monogamously before this time. We have obtained best breeding by segregat ing animals by sex at the tim e of weaning (2±3 weeks old), then establishing breeding pairs at 5±6 weeks of age. It seems to be advantageous to introduce the female into the male’s cage. In our experience it is also easier to pair animals coming from the same breeding colony rather than to pair animals obtai ned from outside. It is possible to pair one male with two fem ales but this may result in increased ®ghting. Cotton rat s produce litt ers of 2±9 animals with an average of ®ve. Gestation is about 27 days. Pups are born haired and are often hidden in the bedding. T hey open their eyes at 36 h aft er birth, incisors erupt at day 5±6 after birt h and solid food is consumed. Pups may be weaned off between 2±5 weeks after birt h. It is recommended never to separate a breeding pair as re-introduction of the partner usually results in ®ghts. If cotton rats start to breed, a litter every month can be expected.
Anaesthesia and euthanasia As volatil e anaesthetics we use ether for short-term anaesthesia and iso¯urane for both short and long-term anaesthesia. When using ether it is important to take appropriate safety precautions (e.g. ventilat ion using a hood) and to air the ether cham ber well in order to avoid the generation of peroxides
Use of hispid cotton rats in infectious diseases
which will kill the animals. Iso¯urane has to be administered by vaporizer as a mixture of 3±5% iso¯urane and 95% oxygen. As injectable combinations of anaesthetics, ketam ine (25 mg=kg) and acepromazine (2.5 mg=kg)= diazepam (10 mg=kg) or ketam ine (22 mg=kg), xylazi ne (10 mg=kg) and acepromazine (5 mg=kg) have been recommended (Prince 1994). Any standard method of euthanasia may be used, although we routinely use CO 2 inhalation.
Blood withdrawal and drug administration Our experience is that blood sam pling is best done from the retro-orbital plexus. T his method requires training in order to avoid ocular damage. Other peripheral veins such as the tail vein are not suitable for blood withdrawal because the tail is fragile and the tail vein is dif® cult to see and to target. Cardiac puncture has been described, however it requires a trai ned person to avoid haemorrhaging from the heart. For administrat ion of substances intravenously, no peripheral vein is suitabl e. Also here application into the heart has been used with the same caveat s as above. We have had best results using needles 22 gauge or smaller. Intranasal administrati on of substances works well in cotton rats. Inoculation is done on lightly anaesthetized animals by carefully placing droplets of ¯uid on the nostril with a pipette, while holding the animal upright using one’s thumb to close the anim al’s mouth so that the inoculum is aspirated directly into the lungs. T he whole volume should not exceed 100 ml in anim als aged up to 6 weeks, or 200 ml in older animals. Administrat ion via the mouth cannot be done by feeding cotton rats like mice. Alternati vely, gastric administrati on by gavage on sedated animals may be used, as has been described for rat s (Waynforth & Flecknell 1992). Intraperitoneal and intramuscular administrat ion is done as in mice or rats.
De ning humane endpoints To de®ne humane endpoints we have used weight measurements using the cotton rat
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handling device, temperature measurements by transponder and testing of the ¯ight re¯ex. Our experience was that the weighing of animals proved to be the most sensitive indicator of infection, by demonstrating weight loss or the lack of weight gain in young animals. No changes in temperature or in the ¯ight re¯ex were observed aft er measles virus infection. However, measles virus does not cause a serious infection in cotton rats, and more useful inform ation might be obtained with a more severe disease.
Microbiological standardization T he microbiological monitoring of cotton rats for bact eria or for parasites is done according to standard procedures. However, serological testing of cotton rats is more dif®cult. T his is due to the fact that diagnostic laboratori es do not possess antisera speci®c for cotton rat immunoglobulins. In our experience the use of cross-reactive sera leads to a 2- to 3-fold loss in assay sensitivity (e.g. ELISA). We have also found that cotton rat sera haemagglutinate primat e erythrocytes spontaneously, which therefore interfere with haemagglutin ati on inhibition assays. As this acti vity was heat-stabl e, naturally occurring cross-reactive antibodies might be involved. In contrast , a spontaneous lytic act ivity against heterologous erythrocytes was found in cotton rats. T his activity was heat-labil e, indicating the activity of complement (Vestey & Lochmiller 1994 ). In order to avoid these problems it is recommended to use sentinel rats or mice for serological testing. It is not clear for which pathogens cotton rat colonies should be monitored. In wild cotton rats infection with hantavirus (Black Creek Canal virus) (Rollin e t a l. 1995), Venezuelan equine encephalomyelitis virus (Zarate & Scherer 1968 ), Tam iami virus (Murphy e t a l. 1976 ), Bo rre lia b urgd o rfe ri (Oliver e t a l. 1995 ), Fra nc ise lla tula re nsis (Lowery 1981 ), Le pto spira sp. (Clark 1984 ), Tric h o ph yto n m e nta gro ph yte s (Clark 1984 ), Mi cro spo rum gyps e um (Cl ark 1984 ), and To xo pla sm a go nd ii (Clark 1984) have been detected. In barrier-reared anim als it is probably reasonable to subject sentinel aniLaboratory Animals (2002) 36
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mals to the same program me as is recommended for rat s or mice by FELASA (1996 ).
Cotton rats as animal model for infectious diseases Cotton rats were introduced into research of infectious diseases by Dr Charles Armstrong who was in search of a small animal model for polio virus infection as an alt ernat ive to non-human primates (Arm strong 1939). T he use of cotton rats from 1939±1979 for polio virus research ®rmly established cotton rats as an laboratory animal. During World War II British troops in Southeast Asia were threatened by endemic (`scrub’) typhus (caused by Ric k e ttsi a tsut sum a gus h i (now orientalis)). T his led to a major initiative in Great Britain to develop a scrub typhus vaccine using the cotton rat. T he classi®ed project, code-nam ed `Operation Tyburn’ involved the airlift ing of cotton rats and a large breeding programme. T he end of the war also ended this project. Near the end of World War II it was reported that ®lariasis could be induced in cotton rats through infection with Lito m o so id e s ca rin ii via bites by the natural vector, O rni th o nyssus b a co ti. Up to the present time, ®lariasis research has been the major use of cotton rats in a laboratory setting. However, over the years cotton rats have been found to be susceptible towards many parasiti c, bac terial and viral pathogens (see Table 1). More recently, cotton rats have gained importance in the study of the pathogenesis and vaccine development for respirat ory syncytial virus (RSV), measles virus, herpes simplex virus and the development of adenovirus vectors in genetic therapy.
Respiratory syncytial virus T he susceptibility of the cotton rat to RSV was ®rst described by a Soviet laboratory in 1971 (Dreizin e t a l. 1971 ). Inexplicably, these investigators never followed up this important discovery. After con®rming and extending their ®ndings (Prince e t a l. 1978 ) Prince ®rst reported RSV infection in inbred mice (Prince e t a l. 1979 ). However, the cotton rat was found to be at least 50-fold, and as much Laboratory Animals (2002) 36
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as 1000-fold, more permissive than the mouse strains we examined, and for this reason we elected to carry out our subsequent RSV work in cotton rats. Respiratory syncytial virus infection in S. h ispid us lasts for about 6 days in the lungs and slightly longer in the nose. T he magnitude of viral replication and histopathology are directly proportional to the infectious dose. Increasing doses will cause mild-t omoderate peribronchiolitis (in¯ammat ory cells, primarily lymphocytes, around the small airways), while doses of above 10 6 plaque-form ing units will also cause interstitial pneumonitis (thickening of alveolar walls accompanied by in¯am matory cells) and alveoliti s (in¯ammatory cells within air spaces), and compromise of pulmonary function. T he primary applicat ion of the cotton rat RSV model has been the development of two antibody form ulations for preventing severe RSV disease in high-risk infants. RSVIg (RespiGam 1 , MedImmune, Inc., Gait hersburg, MD, USA) is puri®ed human IgG derived from plasma donors, while palivizumab (Synagis 1 , MedImmune, Inc.) is a humanized anti-R SV monoclonal antibody. Both drugs advanc ed to clinical trial s on the strength of data from cotton rat studies, without the need of intermediat e studies in non-human primat es. While RSVIg and palivizumab have been highly effective in preventing RSV disease in high-risk infants, neither is an economically viabl e option for normal risk infants and children, whose numbers far exceed those of the high-risk population. T hus there remains a great need for an RSV vaccine, and the cotton rat has been the primary model for assessing the ef®cacy and safety of candidate vaccines. T he question of vaccine safet y is particularly important in the light of failed vaccine trials in the 1960s, wherein a formalin-inact ivated RSV vaccine led to enhanced, sometim es fatal, RSV disease (Chin e t a l. 1969, Fulginiti e t a l. 1969 ). Ongoing efforts to charact erize the histopathology and cytokine pro®les of vaccineenhanced RSV disease will establish the param eters agai nst which the safety of candidat e vaccines may be assessed.
Use of hispid cotton rats in infectious diseases
Measles virus Measles is still one of the 10 most common and deadly infectious disease worldwide, causing one million deaths each year. Acute measles induces a temporary im mune suppression which leaves children vulnerable to secondary infections. Infection can be prevented by im munization with a liveattenuated vaccine virus. However, the vaccine does not induce lifelong immunity in all immunized individuals, and in the presence of mat ernal antibodies it is not effective. In consequence, one has to wait with vaccinat ion until maternal antibodies have been removed from the circulation (at between 3 and 12 months of age). However, in countries with high levels of infection, children with non-protective levels of mat ernal antibodies become infected with wild-t ype virus early in life. T he study of measles virus pathogenesis and the development of vaccines has been ham pered by the lack of a suitable anim al model. Monkeys are the only animal that develops a disease similar to that seen in humans, with immune suppression after natural and experimental infection (van Binnendijk e t a l. 1995 ). However, the high costs, the lack of an inbred population, their limited availabilit y and ethical factors restrict the use of monkeys. In rodents, such as hamsters (Burnstein e t a l. 1963 ), mice (Grif®n e t a l. 1974 ) and rat s (Liebert & ter Meulen 1987 ), encephalitis can be induced with a rodent-adapted neurotropic strain of measles virus, after intracerebral infection, but the infection does not spread to the periphery (McFarland 1974 ). Recently, the SCIDhu mouse, replaced with foetal human thymic tissue (Tishon e t a l. 1996 ), and CD46 transgenic mice (Horvat e t a l. 1996 ) have also been explored as model systems. None of these rodent models accurately mimic acute measles, nor is it possible to obtain a systemic infection or even infection of the respiratory tract. In 1992 Philip Wyde reported that cotton rat s can be infected intranasally via the natural route (Wyde e t a l. 1992 ). Both vaccine and wild-type strains infect cotton rats without adaptation and grow in the respiratory tract and lym phoid organs
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like the spleen and lymph nodes (Wyde e t a l. 1992, 1999). Measles induces a strong im mune suppression in cotton rats, which is dependent on the viral glycoproteins (haemagglutini n and fusion protein) (Niewiesk e t a l. 1997a). T hese proteins induce a retardation of the cell cycle (Niewiesk e t a l. 1999 ). Interestingly, the T cell response against third party antigens is strongly im paired, whereas the B cell response is nearly not affect ed (Niewiesk e t a l. 2000 ). T he inhibition of the T cell response is due to a proliferation inhibition, whereas T cell functions like B cell help, cytoki ne secretion or cytotoxic ity remain unaffected. In cotton rats, clearance of measles virus infection correlates with the development of neutralizing antibodies, and cotton rat s have been used to test putative vaccine vectors (Fook s e t a l. 1998, Schlereth e t a l. 2000a, Spreng e t a l. 2000, Wyde e t a l. 2000b, Weidinger e t a l. 2001) and antivirals (Wyde e t a l. 2000a) again st measles. By transferring a human measles virus speci®c serum into cotton rats it has been possible to mimic maternal antibodies which inhibit immunizat ion and the subsequent protection against challenge. T he advantage of this model is that passively transferred human antibodies can be distinguished from cotton rat antibodies by ELISA. Using this system it has been shown that a recombinant vesicular stomatitis virus expressing the measles virus haemagglutinin is able to overcome maternal antibodies when administered intranasally (Schlereth e t a l. 2000b).
Herpes simplex virus Besides mice and guineapigs, the cotton rat provides another model system to exam ine HSV latency. Recently published studies with cotton rats (Lewandowski e t a l. 2002 ) describe HSV-1 pathogenesis in a labi alis model, with a histological appearance and tim e course quite similar to herpes labial is in humans. Of even greater interest is the observation that virus reactivation with recurrent lesion formation may be effected with relati vely mild doses of cyclophospham ide, corticosteroids or ultraviolet irradiat ion. T hus it appears that the cotton Laboratory Animals (2002) 36
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rat will become a valuable model for studying recurrent herpetic disease, including the testing of prophylactic and therapeutic HSV vaccines, and other form s of therapy.
Adenovirus-based genetic therapy In 1984, Pacini and co-workers described the pathogenesis of human adenoviruses in the cotton rat (Pacini e t a l. 1984 ). Subsequent studies have laid the groundwork for the understanding of adenovirus pathogenesis and the genetic basis of viral disease. To date, human adenovirus is one of the most promising vectors for genetic therapy due to its ef®ciency of infection, high viral yields, ability to accommodate a reasonably sized DNA insert, and stability in blood (for a review see Haddada e t a l. 1995 ). Because the cotton rat is unique among laboratory animals in being permissive for human adenovirus (Prince e t a l. 1993) it has been used early on to test the safety of putat ive adenovirus vectors for gene therapy (Oualik ene e t a l. 1995). Studies using an adenovirus vector containing the human cystic ®brosis transmembrane conductance regulator (CFT R ) gene resulted in in vivo expression of human CFRT protein in cotton rat pulmonary epithelium (Rosenfeld e t a l. 1992 ). T he vector, however, was engineered by deleting Table 2
the E3 region of the adenovirus genome to create space for the CFRT gene, a deletion which studies in cotton rats had suggested would accentuate the host in¯ammatory response to infection (Ginsberg e t a l. 1989, Ginsberg & Prince 1994 ). Subsequent Phase I clinical trials demonstrated pulmonary disease caused by the vector in some of the recipients (Cryst al e t a l. 1994 ). T he recent death of a patient after gene therapy with an adenovirus vector has underlined the importance of testing and developing vectors in the cotton rat model.
Reagents and methods T he main obstac le to working with the cotton rat is the relative lack of reagents. However, the situation has changed over the last few years and the cell lines, antibodies, cytok ine genes and other gene sequences currently available are summarized below.
Cell lines For cotton rats one osteoblast cell line (CCRT ) and two lymphoid cell lines (CR-T 1 and CR-T 2) are avai lable (Niewiesk, unpublished). CCRT was obtained from a cotton rat osteogenic sarcoma (Prince, unpublished). In vivo , it induces tum ours after inoculat ion
Cotton rat cell lines and hybridomas secreting antibodies speci c for cotton rats
Name
Cell type
Comment
CCRT CR.T1
Osteogenic sarcoma T cell
CR.T2
T cell
Induces tumours in vivo, expresses MHC I Fusion product between BW 5147 and cotton rat T cell, expresses MHC I, no CD4 Fusion product between BW 5147 and cotton rat T cell, expresses MHC I, no CD4
Name
Speci city
Hybridoma CR-IgA CR-IgM CR-IgG CR-CD4 B19 W6=32
13=4
IgA IgM IgG CD4 Rat CD59 Human b2-microglobulin (Barnstable et al. 1978, Shields & Ribaudo 1998) Mouse MHC II (Ha¨mmerling et al. 1979)
Laboratory Animals (2002) 36
Comment
Cross-reacts with cotton rat macrophages Cross-reacts with cotton rat MHC I
Cross-reacts with cotton rat MHC II
Use of hispid cotton rats in infectious diseases
of 10 6 cells. CCRT cells express MHC I and no MHC II. CR-T 1 and CR-T 2 were derived from a fusion of mitogen stim ulated cotton rat spleen cells and the mouse thym oma BW 5147. Both are grown in IL-2 containing medium and are stained strongly with a cotton rat T cell speci®c antiserum, indicating expression of cotton rat T cell markers (see Tabl e 2).
Monoclonal antibody In order to ®nd monoclonal antibodies reactive with cotton rat lymphocytes, monoclonal antibodies speci®c for human, mouse and rat cell surface molecules were tested for cross-reactivity with cell surface molecules on cotton rat lym phocytes. T he monoclonal antibody W6 =32 (Barnstabl e e t a l. 1978 ) which recognizes human b2-microglobulin was found to recognize also cotton rat MHC I, and can be used for immuno¯uorescence and im munoprecipitat ion. Monoclonal antibody 13 =4 (HaÈmmerling e t a l. 1979 ) which recognizes mouse MHC II also recognizes cotton rat MHC II and can be used for immuno¯uorescence. To produce monoclonal antibody speci®c for cotton rat lymphocytes, BALB =c mice were immunized with Concanavalin A stimulated spleen cells. From the collection of hybridomas obtained, a monoclonal antibody speci®c for cotton rat CD4 (clone CR-CD4) has been identi®ed (Niewiesk, unpublished). For other monoclonal antibodies we have only a putat ive identi®cati on and interested parties should inquire into our progress. To establ ish assay systems for the detection of cotton rat immunoglobulins, we have produced monoclonal antibodies speci®c for cotton rat IgM (Niewiesk, unpublished), IgA and IgG and a polyclonal rabbi t serum speci®c for cotton rat IgG (Prince, unpublished) (see Table 2).
Cytokine and chemokine assays Historically, a number of assays have been used in im munology to identify cytokines. For cotton rats a number of bioassays have been successfully adapted from the mouse system (for interleukin 1 and tum our necrosis factor (Dabbert e t a l. 1994), for interleukin
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2 and interferon gam ma (Niewiesk e t a l. 2000 )). In addition, we have established a RT-PC R assay for interferon gamma (IFN-g) and interleukin 5 (IL-5 ) and 4 (IL-4 ) and RNase protection assays for a variety of cytok ines (Niewiesk & Prince, unpublished). Monoclonal antibodies speci®c for cotton rat cytok ines and chemokines, as well as the gene products against which the antibodies are directed, are commercially available from R& D Systems, Minneapolis, MN, USA (http: ==www.rndsystems.com =). Apart from some cytoki ne genes only a few gene sequences have been published for cotton rat genes. T he genes and their accession numbers are summarized in Table 3. In addition, genes cloned by Virion Systems (which are freely available upon request) are summarized in Tabl e 4.
Haematological, histological and pathological data T he haematological values in cotton rat s have been studied extensively ((Dotson e t a l. 1987, Katahi ra & Ohwada 1993, McMurry e t a l. 1995, Robel e t a l. 1996), summarized in (Faith e t a l. 1997)) and are similar to those of other rodents. Also similar to other species the lym phocyte to neutrophil rat io is inverted in juveniles compared to adults. Reference values for blood chemistry were determ ined by Ohwada e t a l. (1994 ) and for differential blood counts by McMurry e t a l. (1995 ). T he lymphoid system of cotton rats does not differ very much from that of mice or rats. T he number of lymphocytes in the spleen (5±10610 7) is closer to that found in mice than in rats. Cotton rat lymph nodes are quite small and not as prominent as in rat s. In a very detailed description of cotton rat lymph nodes Wenk found a lack of the sacral lymph nodes (Wenk 1964 ). In the small intestine of wild cotton rats 4±13 Peyer’s patches were found that increase in size over tim e (Lochmiller e t a l. 1992 ). Histologically, cotton rat Peyer’s patches are similar to those of the rat and mouse and start to decrease in senescent animals (Niewiesk, unpublished). T he respiratory tract of cotton rats has been thoroughly investigated by histology in Laboratory Animals (2002) 36
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Table 3
Niewiesk & Prince
Gene sequences from cotton rats
Gene
EMBL accession No.
Interferon (IFN) alpha IFN-gamma mRNA Tumour necrosis factor alpha Interleukin (IL)-1 alpha IL-1 beta IL-2 IL-4 IL-5 IL-6 IL-10 IL-12 p35 IL-12 p40 IL-18 Macrophage in ammatory protein 1 alpha Macrophage in ammatory protein 1 beta Macrophage in ammatory protein 2 Rantes IFN gamma inducible protein 10 Growth-regulated protein Beta actin
AF421386 AF167349 AF421388 AF398548 AF421387 AF398549 AF421390 AF148211 AF421389 AF398550 AF421396 AF421395 AY059406 AY059407 AF421392 AY059408 AF421391 AF421394 AF421393 AF421789
Various alleles of MHC class II antigen (Sihi-DQA) gene, Sihi-DQA* 23 allele, exon 2 MHC class II antigen (Sihi-DQA) gene, Sihi-DQA* 11 allele, partial cds Prion protein Cytochrome B (cytB) gene
AF279850-62
NADH dehydrogenase subunit 3 (ND3) and NADH dehydrogenase subunit 4L (ND4L) genes Mitochondrial DNA for SSU ribosomal RNA gene p53 gene, partial cds Surfactant protein C mRNA
experimentally-infected and non-infected anim als and is similar to that of rat s. T he cotton rat lung consists of two left and three right lobes. Pathologically, adenocarcinomas occurring in a cotton rat strain in Japan have been observed (Kawase & Ishikura 1995 ) and investigated (Waldum e t a l. 1999, Cui e t a l. 2000). In a different study, systematic histopathological analysis of 18 cotton rats from the Bail or College of Medicine in Texas
Reference Houard et al. 1999
Houard et al. 2000
AF155914-24
Pfau et al. 1999
AF117325 AF108702
Wopfner et al. 1999 Smith & Patton 1999
U83823
Engel et al. 1998
X89788 U66066 AF339911
Sullivan et al. 1995
revealed in six animals signs of chronic nephropathy and in 10 animals signs of degenerative cardiomyopathy. Cardiom yopathy was also found by Sorden and colleagues who investigated cotton rats with exophthalmus which had died spontaneously or had been killed (Sorden & Wat ts 1996 ). It is not clear if that is a general ®nding in cotton rats, but it might explain their relatively short lifespan compared to mice and rats.
Table 4 Cotton rat genes cloned by Virion Systems Fully cloned genes: MCP-5, MHC class I, KC (IL-8 homolog) Partially cloned genes: TNF-b, TGF-b1, CD4, CD8-a, CD11b, IRF-1, IRF-2, ICSBP, Cox-1, Cox-2, surfactant protein C The cloning and sequencing of these genes was done as part of an ongoing sequencing project by Virion Systems. Enquires into the progress, please contact Dr Gregory Prince. The availability of gene products and antibodies against them are listed at http:==www.rndsystems.com Laboratory Animals (2002) 36
Use of hispid cotton rats in infectious diseases
Immunological methods In a wild cotton rat populati on the humoral and cell-mediated im mune response was observed to vary over time (Lochmiller e t a l. 1994). T here appeared to be no seasonal in¯uence, and other factors like populat ion density and genetic variability might play a role. In a laboratory setting with a controlled environment, we have found no temporal variation in immune responses. What in¯uenced immunological assays most was ®ghting between males. T his results often in an enlarged spleen which yields very few lym phocytes. It is therefore advisable to separate mature males before use in experiments. A number of immunological methods have been adapted from mice or rats to the cotton rat system:
Ma cro ph a ge s Macrophages can be isolated from the peritoneal cavity 2±3 days after injection of bac teria or bac terial lysat es according to standard procedures (Hudson & Frank 1989). Macrophages can be de®ned by adherence and non-speci®c esterase staining (Wyde e t a l. 1999). T he function of macrophages can be investigated using phagocytosis of erythrocytes, a macrophage migrati on inhibition test (Nogam i e t a l. 1985 ) and assays for the Table 5
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secretion of interleukin 1 and tumour necrosis factor. Recently, a method to induce formation of granulocyte-macrophage progenitor cells from bone marrow has been described (Kim e t a l. 2001), and this might be a starting point for the development of dendritic cells from blood precursors in vitro .
T c e ll re spo nse s For the analysis of T cell responses most methods described for the mouse work in cotton rats. One caveat has to be taken into account: the puri®cation of cotton rat T cells via nylon wool columns does not work, because more than 90% of spleen or lymph node cells stick to the column (Niewiesk, unpublished). For testing of T cell proliferation a standard 3H-t hymidine incorporation assay works well. To stimulate antigen unspeci®c T cell proliferation a variety of mitogens and superantigens has been tested (see Table 5). For testing antigen-speci®c T cell proliferation, it is useful to couple the antigen to the surface of a 96-well plate with Na2CO 3 buffer (pH 9.6 ) overnight (Schlereth e t a l. 2000a). To test the cytolytic capabilit y of T cells, primary ®broblasts and macrophages as target cells have been used (Niewiesk e t a l. 2000 ). In comparison to standard target cells in the mouse system (L929 or P815 ) the chromium uptake of ®broblasts and macrophages is low and the
Superantigens and lectins
Lectin=superantigen T cells (Niewiesk et al. 1997a) Concanavalin A Succinyl-concanavalin A Vicia sativa Phytohaemagglutinin SEB SEC-1 SEC-3 TSST-1 T- and B-cells (Niewiesk et al. 1997a) Phytolacca americana (pokeweed mitogen) B cells (Niewiesk et al. 2000) Cross-reactive antiserum speci c for rat immunoglobulins, cross-link with e.g. donkey anti rat serum and lipopolysaccharides
Optimal concentration (mg=ml)
Relative proliferation in % (Concanavalin A as 100%)
2.5 10 5 5
100 60 100 10 20 20 30 20
0.5
100
10
20–30
Laboratory Animals (2002) 36
368
spontaneous release (leakiness) high. To measure the activity of natural killer cells the mouse lym phoma YAC-1 has been used (Niewiesk e t a l. 2000 ).
B ce ll re spo nse s To assay B cell responses, Elispot assays for the demonstration of single antigen-speci®c B cells and ELISA assays to demonstrate the secreted antibody have been used (Niewiesk e t a l. 2000). For both Elispot and ELISA we have used the above-nam ed monoclonal antibodies and antisera speci®c for cotton rat IgA, IgM and IgG. It is important to incubat e cotton rat sera at 4 C in order to avoid unspeci®c binding. It has been reported that S. h ispid us generates a good antibody response preferentially consisting of IgG1 (Coe & Prince 1996 ). In contrast to mouse B cells, cotton rat B cells do not proliferat e well aft er in vitro stim ulation with lipopolysacchrides alone. However, after crosslinking membranebound im munoglobulins on the surface of cotton rat B cells with an antiserum in addition to lipopolysaccharides a reasonable proliferation can be seen (Niewiesk e t a l. 2000).
Outlook T he emphasis in the research of infectious diseases is shifting towards the analysis of host±pathogen interactions. For many pathogens where the mouse =rat model is insuf®cient, cotton rats have proven to be a good alternative. In practical terms, the cotton rat model is developing. Cotton rat s are commercially avai lable in speci®c pathogen free (SPF) quality and some reagents are commercially available. In addition, a variety of methods necessary to investigat e infectious diseases have been established and the development of reagents has gained pace. Because of this it is a good time for everyone who has not a satisfactory anim al model at her=his disposal to try the cotton rat model. To facilitat e the literature research into cotton rats as models of infections diseases a reference library (in Filemaker format ) may be downloaded from Virion Systems, Laboratory Animals (2002) 36
Niewiesk & Prince
(http: ==www.radix.net = virion =). In addition, a great selection of PhD theses and other documentation is available from Dr Gregory Prince at Virion Systems. It might be a good start to obtain either the cell lines mentioned or a small number of animals to test their susceptibility towards the respective pathogen. In Europe advice and reagents can be obtained from the Institute of Virology and Immunobiology, Wuerzburg, Germany; in the Americas from Virion System s, Rockville, USA and in other continents from either source. No te : Tables found in this manuscript will be updat ed continuously and are accessible at: http: ==www.uni-wuerzburg.de =virologie = cottonrat =. Ac k no w le d gm e nts Stefan Niewiesk was supported by a grant from Deutsche Forschungsgemeinschaft and Gregory Prince by a grant from NIH.
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Houard S, Jacquet A, Haumont M, Glineur F, Daminet V, Milican F, Bollen A (1999) Cloning, expression and puri® cation of recombinant cotton rat interferon-gamma. G e ne 240, 107±13 Howard AT (1974) Experimental and intracage transmission or Venezuelan equine encephalitis virus (subtype IB) among cotton rats, Sim o d o n h ispid us. Am e ric a n Jo urna l o f Tro pica l Me d ic ine 23, 1178±84 Hudson L, Frank CH (1989) Pra c ti ca l Im m uno lo gy. Oxford: Blackwell Scienti®c Hutchinson KL, Rollin PE, Peters CJ (1998) Pathogenesis of North American hantavirus, Black Creek Canal virus, in experimentally infected Sigm o d o n h ispid us. Am eric a n Jo urna l o f Tro pica l Me d icine a nd Hygie ne 59, 58±65 Ignatovich VP, Barkhatova OI, Rydkina EB (1983) Persistence of Ric k e ttsia pro w a ze ck ii with different initial biological properties in infected cotton rats. Ac ta Viro lo gica 27, 528±32 John DT, Hoppe KL (1990) Susceptibility of wild mammals to infection with Na egle ria fo w le ri. Jo urna l o f Pa ra sito lo gy 76, 865±8 Katahira K, Ohwada K (1993) Hematological standard values in the cotton rat (Sigm o d o n h ispid us). Experim enta l Anim a ls 42, 653±5 Kawase S, Ishikura H (1995) Female-predominant occurrence of spontaneous gastric adenocarcinoma in cotton rats. La b o ra to ry Anim a l Sc ie nc e 45, 244±8 Kershaw WE, Storey DM (1976) Host±parasite relations in cotton rat ®liariasis. Anna ls o f Tro pica l Me d ic ine a nd Pa ra sito lo gy 70, 303±12 Kim S, Stair EL, Lochmiller RL, Lish JW, Qualls CWJ (2001) Evaluation of myelotoxicity in cotton rats (Sigm o d o n h ispid us) exposed to environm ental contaminants. I. In vitro bone-marrow progenitor culture. Jo urna l o f To xico lo gy a nd Enviro nm enta l He a lth A 62, 83±96 Kroeze WK, Tanner CE (1985) Ech ino co c cus m ultilo c ula ris: responses to infection in cotton rats (Sigm o d o n h ispid us). Inte rna tio na l Jo urna l o f Pa ra sito lo gy 15, 233±8 Langley RJ, Prince GA, Ginsberg HS (1998) HIV type-1 infection of the cotton rat (Sigm o d o n fulvive nte r and S. h ispid us). Pro ce e d ings o f th e Na tio na l Aca d em y o f Scie nc e 95, 14355±60 Lewandowski G, Zimmerman MN, Denk LL, Porter DD, Prince GA (2002) Herpes simplex type 1 infects and establishes latency in the brain and trigeminal ganglia during prim ary infection of the lip in cotton rats and mice. Arc h ives o f Viro lo gy 147, 167±79 Liebert UG, ter Meulen V (1987) Virological aspects of measles virus-induc ed encephalomyelitis in Lewis and BN rats. Jo urna l o f G e ne ra l Vi ro lo gy 68, 1715±22 Lochmiller RL, Vestey MR, McMurry ST (1994) Temporal variation in humoral and cell-mediated Laboratory Animals (2002) 36
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immune response in a Sigm o d o n h ispid us population. Eco lo gy 75, 236±45 Lochmiller RL, Vestey MR, Nash D (1992) Gut associated lymphoid tissue in the cotton rat (Sigm o d o n h ispid us) and its response to protein restriction. Jo urna l o f Wild life Dise a se s 28, 1±9 Lowery GH (1981) Th e Ma m m a ls o f Lo usia na a nd its Ad ja c ent Wa te rs. Baton Rouge: Louisiana State University Press McFarland HF (1974) T he effect of measles virus infection on T and B lymphocytes in the mouse. Jo urna l o f Im m uno lo gy 113, 1978±83 McKown RD, Ridley RK, Kennedy GA (2000) T he hispid cotton rat (Sigm o d o n h ispid us) as an experimental host for the bovine liver ¯uke (Fa sc io la h epa tic a ). Ve te rina ry Pa ra sito lo gy 87, 125±32 McLean RG (1982) Potentiation of keystone virus infection in cotton rats by glucocorticoid-induced stress. Jo urna l o f Wild life Dise a se s 18, 141±8 McMurry ST, Lochmiller RL, Chandra SAM, Qualls CW (1995) Sensitivity of selected immunological, hematological, and reproduc tive parameters in the cotton rat (Sigm o d o n h ispid us) to subchronic lead exposure. Jo urna l o f Wild lif e Dise a se s 31, 193±204 Mittal SK, Middelton DM, Tikoo SK, Babiuk LA (1995) Pathogenesis of bovine adenovirus type 3 in cotton rats (Sigm o d o n h ispid us). Viro lo gy 213, 131±9 Murphy BR, Sotnikov AV, Lawrence LA, Banks SM, Prince GA (1990) Enhanced pul monary histopathology is observed in cotton rats immunized with formalin-inactivated respiratory syncitial virus (RSV) or puri®ed F glacoprotein and challenged with RSV 3±6 months after immunization. Va cc ine 8, 497±502 Murphy FA, Winn WCJ, Walker DH, Flemister MR, Whit®eld SG (1976) Early lymphoreticular viral tropism and antigen persistence. Tamiami virus infection in the cotton rat. La b o ra to ry Inve stiga tio ns 34, 125±40 Murphy T F, Dubovi EJ, Clyde WA (1981) T he common cotton rat as an experimental model of hum an parain¯uenzy virus type 3 disease. Expe rim e nta l Lung Re se a rc h 2, 97±109 Niewiesk S, GoÈtzelmann M, ter Meulen V (2000) Selective in vivo suppression of T lymphocyte responses in experimental measles virus infection. Pro c ee d ings o f th e Na ti o na l Ac a d em y o f Scie nc e 74, 4652±7 Niewiesk S, Ohnimus H, Schnorr J-J, GoÈtzelmann M, Schneider-Schaulies S, Jassoy C, ter Meulen V (1999) Measles virus-induced immunosuppression in cotton rats is associated with cell cycle retardation in uninfected lymphocytes. Jo urna l o f G e ne ra l Viro lo gy 80, 2023±9 Niewiesk S, Eisenhuth I, Fooks A, Clegg JCS, Schnorr J-J, Schneider-Schaulies S, ter Meulen V (1997a) Measles virus-induc ed immune suppres-
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sion in the cotton rat (Sigm o d o n h ispid us) model depends on viral glycoproteins. Jo urna l o f Viro lo gy 71, 7214±19 Niewiesk S, Schneider-Schaulies J, Ohnim us H, Jassoy C, Schneider-Schaulies S, Diamond L, Logan JS, ter Meulen V (1997b) CD46 expression does not overcome the intracellular block of measles virus replication in transgenic rats. Jo urna l o f Viro lo gy 71, 7969±73 Niewiesk S, VoÈ lp F, ter Meulen V (1997c) A maintenance and handling device for cotton rats (Sigm o d o n h ispid us). La b Anim a l 26, 32±3 Nogami S, Shibusawa M, Sekiguchi M, Tanaka H (1985) Macrophage migration inhibition test of peritoneal exudate cells of Lito m o so id es c a riniiinfected cotton rats by direct method in agar plate. Bio m ed icine & Ph a rm a c o th era py 39, 140±5 Ohwada K, Ito T, Katahira K (1994) Reference values for blood chemistry in the cotton rat (Sigm o d o n h ispid us). Sca nd ina via n Jo urna l o f La b o ra to ry Anim a l Sc ie nce 21, 29±31 Oliver JH, Chandler FW, James AM, Sanders FH, Hutcheson HJ, Huey LO, McGuire BS, Lane RS (1995) Natural occurrenc e and characterization of the Lym e spiro ch ete , Bo rre lia b urgdo rfe ri, in cotton rats (Sigm o d o n h ispid us) from Georgia and Florida. Jo urna l o f Pa ra sito lo gy 81, 30±6 Oualikene W, Gonin P, Eloit M (1995) Lack of evidence of phenotypic complementation of E1A=E1B-deleted adenovirus type 5 upon superinfection by wild-type virus in the cotton rat. Jo urna l o f Viro lo gy 69, 6518±24 Pacini DL, Dubovi EJ, Clyde WA (1984) A new animal model for human respiratory tract disease due to adenovirus. Jo urna l o f Infe ctio us Dise a se s 150, 92±7 Papp Z, Middleton DM, Mittal SK, Babiuk LA, BacaEstrada ME (1997) Mucosal immunization with recombinant adenoviruses: induction of immunity and protection of cotton rats against respiratory bovine herpesvirus type 1 infection. Jo urna l o f G e ne ra l Viro lo gy 78, 2933±43 Patel J, Faden H, Sharma S, Ogra PL (1992) Effect of respiratory syncytial virus on adherence, colonization and immunity of non-typable Ha e m o philus in¯uenza e: implications for otitis media. Inte rna tio na l Jo urna l o f Pe d ia tric O to rh ino la ryngolo gy 23, 15±23 Pfau R, Van Den Bussche R, McBee K, Lochmiller R (1999) Allelic diversity at the Mhc-DQA locus in cotton rats (Sigm o d o n h ispid us) and a comparison of DQA sequences within the family Muridae (Mammalia: Rodentia). Im m uno gene tics 49, 886±93 Prince GA (1994) T he cotton rat in biomedical research. AWIC New sle tte r 5, 3±5 Prince GA, Horswood RL, Berndt J, Suf®n SC, Chanock RM (1979) Respiratory syncytial virus infection in inbred mice. Infe c tio n a nd Im m ununity 26, 764±6
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