The Cat in Biomedical Research
Research Animal Methods
Paula D. Johnson, DVM
The cat, like the dog, was one of the first domestic animals that scientists observed. Early studies involved the falling reflex and integration of the mechanisms of balance. Researchers commonly used the cat in psychological, socialization, and learning studies. The occurrence of blood cancers and solid tumors such as lymphomas, leukemia, and adenocarcinoma and endocrine tumors comparable to those of humans makes the cat valuable to cancer research. Cats are useful models for studies into the AIDS virus, and as models for research involving the brain, genetics, head-eye-ears, pharmacology, nutrition, virology, and surgical technique development. While cats provide an important and necessary animal model, they only comprise less than 1% of the total animals used in research, and this number has dropped dramatically over the years.
Cats and humans have several similar infectious diseases: hemolytic anemia of the cat is similar to Oroya fever of man; toxoplasmosis occurs among both species; Chlamydia, cholera, sporotrichosis, and filariasis infect both cats and humans. Cats are, therefore, noteworthy models for the development of effective treatments and preventative measures of infectious diseases. Selective models in which cats are currently used are given in sections VII through XV.
There are also many benefits to animal diseases/disorders/and preventive measures that have occurred as a result of using the cat as a model in biomedical research. This includes improved animal surgical procedures and new vaccines to prevent animal diseases. As stated by the Foundation for Biomedical Research, “Thanks to research, the life expectancy of house cats has been expanded more than eight years. In fact, some pets can live up to more than 20 years.”
Scientists who are planning experiments evaluate both animal and non-animal approaches. If there are no suitable alternatives to the use of live animals, the appropriate species is selected on the basis of various scientific and practical factors, including the following:
For some scientific experiments, the answer to those questions will be the domestic cat. The size, biologic features, and cooperative, docile nature of the well-socialized cat make it the model of choice for a variety of scientific inquiries. The contributions of the cat to human health and well-being are numerous.Although research with cats is often primarily to benefit humans, it has also greatly benefited cats that are kept as companion animals. Examples of the benefits to cats are improvements in diagnostic techniques; treatments for diabetes and arthritis; surgical procedures for correcting or treating cardiovascular, orthopedic, and neurologic disorders; and therapies for bacterial, neoplastic, and autoimmune diseases. Moreover, cats have been necessary for the development of vaccines that protect companion animals against viral diseases (e.g. feline panleukopenia, feline viral rhinotracheitis, feline calicivirus, and feline leukemia) and drugs that prevent parasitic diseases.
Genetic, biological, and behavioral factors are also important factors to consider when determining the model of choice. There are numerous references available that discuss these factors at length.
Unvaccinated cats may harbor rabies virus, and pre-exposure immunization should be made available to personnel who are at substantial risk of infection. Cats also have internal and external parasites that can be shared with humans. Table 2 lists selected zoonoses. Personnel can develop allergies to feline dander and saliva, and can be bitten or scratched. To deal with these and other animal-related health problems, institutions must provide occupational health programs for personnel who work in animal facilities or have substantial animal contact.
(Bartonella henselae Infection)
Rabies is caused by a virus that enters the body through a wound, usually from a bite of an infected animal, and eventually affects the brain. Animals that can carry rabies include: Cat, Dog, Ferret, Raccoons. Bats, Cattle, Rabbits, Skunks, Foxes. If an animal is suspected of rabies, it must be quarantined for ten days or euthanized and the brain submitted for testing. Animals infected with rabies exhibit unusual behavior, cats that are usually shy, could suddenly become aggressive; dogs which are usually friendly, may suddenly become shy. Signs may include: drooling or foaming at the mouth, the appearance of being injured or are having trouble walking.
If an animal is suspected of rabies it must be quarantined, or the brain submitted for testing – State laws will determine the regulations and guidelines that must be followed.
If a person is bitten, immediately seek emergency medical care. A preventive vaccine may be administered to prevent the disease. Once symptoms develop, however, it may be too late to treat the disease. Early signs and symptoms of rabies in people include: restlessness, fatigue, loss of appetite, headache, fever, itching at the site of the animal bite. As the virus replicates, the disease progresses and infected people can become aggressive and alternate between periods of wild excitement and seemingly normal behavior, eventually becoming unconscious and paralyzed. Rabies is nearly always fatal.
Because of the seriousness of the disease, all cats in research must be vaccinated for rabies. This is also a good reminder to have pets vaccinated and the reason it is recommended to not leave your pets loose outside unsupervised where they can encounter other animals that may carry rabies.
The criteria for
housing are specifically given in the Guide for the Care and
Use of Laboratory Animals. The design and management of
feline facilities are discussed in this reference and may also
be found in “Laboratory Animal Management – Cats”
ILAE, 1978d, and in “Laboratory Animal Housing”
Environmental Enrichment is critical to the well being of cats. The specifics will depend on the research project the animals are involved in, as well as the number of other cats in the housing environment. Enrichment should include toys, scratching post/boxes, and food treats if possible.
Due to the potential of disease, random source cats should be individually housed for the first few weeks. Panleukopenia will usually show clinical signs during the first week, however, respiratory viruses may take 2 weeks or more to manifest symptoms of disease. Fleas, ear mites, and intestinal parasites must all be identified and treated at arrival. Ideally, random source cats should be vaccinated and isolated until immunity develops. It is critical for animal care staff to be aware of the potential disease signs and notify the Veterinary staff as soon as signs are noticed. Once the cats have successfully completed the conditioning period they can be placed in community groups.
Below is an example outline of a Conditioning program:Arrival Procedures
As discussed previously in Housing, the environment must be kept clean and dry, the humidity and temperature must be controlled and monitored regularly. Due to fecal-oral transmission of disease and parasites, cleanliness is a necessity. The arrangement of cages will depend on the type of cats involved (males, females, nursery, kittens). It will vary depending on the age and sex of the animals. Proper social environment is extremely important, this includes human contact. For an animal to be useful in a research project it must be socialized to humans.
The Animal Welfare Act requires that animals be fed clean, wholesome palatable food at least once daily from food containers that minimize contamination by excreta. A good quality commercially available balanced cat food should be fed. Nutrient requirements are outlined in the national Research Council document “Nutrient Requirements of Cats” (NAS-NRC, 1978), as well as a variety of other resources. It will depend on the age of the cat as to the amount and timing of the feedings. Most research facilities feed cats ad libitum, unless obesity or research requirements dictate otherwise. Depending on the type of research and/or the condition of the animal, the requirements will vary, i.e. gestational requirements are significantly different than for an older male cat.
Clean fresh water should be available at all times, unless less is necessary for surgical preparation or for specific research projects. The Animal Welfare Act requires that water must be offered for a 1-hour period twice daily.
A routine vaccination program should be instituted for long-term cats. Short-term cats should be dealt with on an individual basis. As stated previously, FVR, FCV should be given to all cats. FPN and Chlamydia may be given depending on the presence in the colony or in incoming animals. Vaccination against rabies is not generally warranted unless it is required for shipping regulations.
Routine testing is important to detect parasites (internal and external). This is a very important part of the preventive medicine program in a cat colony. External parasites are easily controlled by sanitation and treatment with parasiticidal agents on a routine basis or after positive testing. The type of research may dictate the type of agent possible. Direct fecal smears and fecal flotations should routinely be surveyed for internal parasites. The appropriate treatment will be dictated by the results of the tests.
Parasite control depends on sanitation and appropriate therapies.
Thorough and accurate record keeping is key to a successful management program. All physical information, such as: size, conformation, abnormalities, growth rate, litter-mate information, behavioral disposition, maternal instinct, mating behavior, libido, gestational parameters, parturition information, lactation, kitten growth and health, medical history should be recorded to assist in future colony and medical management.
Incoming cats should be tested for Feline Leukemia Virus (FeLV). This is extremely important if a breeding colony is in place or to be established, as FeLV may cause thymic atrophy and immunologic incompetence in the kittens. This results in increased susceptibility to other diseases. Once tested negative the cats may be vaccinated if the protocols for the research facility warrant.
Cats should also be tested for Feline Infectious Peritonitis (FIP) as this disease will have detrimental effects on breeding colonies and long-term research projects. FIP is a coronaviral disease that may be asymptomatic, or cause upper respiratory disease, chronic weight loss, depression, and fever that is nonresponsive to antibiotic therapy. The clinical syndrome varies widely depending on the organs affected.
Feline pneumonitis, which is caused by Chlamydia psittaci, causes a small percentage of the upper respiratory infections. Many respiratory infections are caused by a combination of viral and bacterial agents, thus clinical differentiation is not easy. Direct contact, fomites or aerosol droplets spread these diseases, thus the importance of quarantine for new animals. A quarantine period for a minimum of 30 days and animals that are disease free for 2 weeks helps to decrease the potential for disease spread. Diagnoses of disease potential and appropriate vaccination are important elements in keeping a facility free of disease.
Many cats also serve as a reservoir of Salmonella infections for other animals and the animal caretakers. Newly arriving cats should also be screened for enteric salmonella, as this may result in a serious zoonotic problem. Ringworm (Microsporum sp.) is also commonly found in random source cats. These may be transmitted from cat to cat and cat to human. Diagnosis and treatment are effective, but animals should be held in quarantine until cleared of the disease. Only personnel with the proper protective clothing should handle positive animals. All surfaces in the animal room should be treated, as the dermatophytes can persist in a dry environment for up to 13 months.
While in quarantine, cats should be screened and examined for internal and external parasites. Appropriate therapies should be instituted.
The cat Sartorius muscle is especially appropriate for the study of microcirculation because it is thin, accessible, and the circulation can be well visualized. The cat Sartorius muscle permits alteration of arterial pressure to muscle by localized occlusion of the supply artery. The processes of vasodilation, hemorrhage, hyperemia, and stimulation as it relates to blood flow can be studied.
Since cardiomyopathy in cats closely resembles that in humans, the cat has been used as a model to evaluate new therapeutic approaches
Diabetic cats have proven extremely useful models for the study of Diabetes Mellitus. Diabetes Mellitus with amyloidosis of pancreatic islets occurs with significant frequency only in the cat and in man. Type 2 (non-insulin-dependent) diabetes mellitus constitutes up to 90% of all cases of diabetes mellitus in humans. In contrast to Type 1 (insulin-dependent) diabetes mellitus, where evidence supports an absolute insulin deficiency related to insulitis and islet cell destruction by a combination of viral and immunologic mechanisms, the intra-islet deposition of amyloid is a common islet alteration in human Type 2 diabetes. The diabetes mellitus-islet amyloid complex which occurs spontaneously in adult cats has many documented similarities to Type 2 diabetes mellitus in humans, and provides a model for further investigation into the sequential morphologic and biochemical alterations that occur in islets of individuals with this form of diabetes mellitus associated with aging. Through the use of the feline model, more has been learned about the protein that decreases insulin production, thus the research may someday lead to a cure for diabetes. Information about Cats with Diabetes (www.felinediabetes.com).
This disease has been described in Aleutian mink, Hereford cattle, mice, killer whales, and cats. It is a disease characterized by inheritance as an autosomal recessive trait, dilution of the color of the hair and eyes caused by enlargement of the melanin granules in the hair and ciliary processes of the eye, and includes an increased susceptibility to disease as a prominent feature, probably related to the increased size of the granules in the leukocytes. Sufferers also tend to have hemorrhagic tendencies due to a platelet storage pool deficiency. In the cat, it is present in Blue-smoke Persians with yellow rather than the more typical copper-colored irises. The genetic, clinical, and pathological manifestations of CHS in cats is remarkably similar to the syndrome in humans. In addition, CHS cats make an appropriate animal model to evaluate hemostatic capabilities of transfused platelets.
Feline AIDS is a virus similar to the human AIDS disease, and both have similar symptoms. These include: swollen lymph nodes, extreme weight loss and respiratory infections. Because of the research using cats as a model, scientists have been able to develop a vaccine for feline leukemia. The hope and further study is that this breakthrough can provide a model for the development of a vaccine against human AIDS. Severe progressive immunodeficiency syndrome can be induced experimentally with a molecularly cloned isolate of feline leukemia virus (FeLV-FAIDS). Persistent viremia, lymphopenia, progressive weight loss, persistent diarrhea, enteropathy, and opportunistic infections characterize the resultant disease syndrome. The onset of clinical immunodeficiency disease is prefigured by the replication of the FeLV-FAIDS variant virus in bone marrow and other tissues.
The FeLV-FAIDS system can be used to evaluate antiviral agents which act on steps in the replication cycle which are conserved among retroviruses (e.g., reverse transcriptase, protease, assembly). The persistence and magnitude of viremia serves as a useful parameter in antiviral studies because it can be easily measured, presages the eventual development of immunodeficiency, and provides a convenient indicator of therapeutic efficacy either in preventing de novo FeLV infection or in reversing or ameliorating established infection. The FeLV model, therefore, can be used to assess rapidly experimental single agent or combined antiviral therapies for persistent retrovirus infection and disease.
Feline immunodeficiency virus infects the CNS and results in predictable pathophysiology strikingly similar to that seen with HIV-1 infection of humans. The observed pathophysiology is mimicked in several physiologically assessed modalities, further supporting the validity of the feline model. Peripheral and control evoked potential findings and the occurrence of the sleep architecture changes in both cat and human disease provide an intriguing focus for further investigation. Although structurally diverse in an absolute sense, FIVand HIV-1 share basic structural features and commonalties of their life cycle. It is likely that by understanding the common mechanisms by which these lentiviruses influence CNS function, a more complete understanding of the neurological deficits seen in HIV-1 infected patients will be obtained. The cat model is particularly valuable for study of CNS disease, since it allows detailed analyses of events during the acute phase of infection, under circumstances in which the nature and timing of the infection are carefully controlled. The availability of molecular clones for mutational analysis will facilitate mapping of genomic regions critical to the perturbation of CNS function. It is suggested that development of intervention strategies in the cat model will yield treatment modalities directly applicable to HIV-1 infection of humans.
In man, patients with monoclonal gammopathies such as multiple myeloma or Waldenström’s macroglobulinemia frequently have large quantities of homogenous immunoglobulins in their sera. Spontaneous, functional plasma cell dyscrasias have also been encountered with in the dog and in the cat. Studies of the pure proteins isolated from such animals led to a clearer understanding of the classes of canine and feline immunoglobulins and to a fuller appreciation of the structural relationships between theses proteins and their counterparts in man.
In the April 1987 issue of Lab Animal, there is an article describing the formation of a National Referral Center for Animal Models of Human Genetic Disease. In the article, there is a description of this feline model. This model has been shown to be a counterpart of MPS VI (Maroteaux-Lamy syndrome) in humans. In the classic form of MPS VI in humans, affected individuals exhibit growth retardation, facial abnormalities, corneal clouding, skeletal abnormalities, and heart valve defects. The most severely affected human patients do not survive past their twenties. The clinical and pathologic findings in Siamese Cats are rather similar and include growth retardation, broad faces with short ears, and skeletal abnormalities. Mentation is difficult to assess in animals; however, there have been no indications in any of the affected cats of deficits comparable to those defining mental retardation in man. The pathogenesis in cats and humans is essentially similar: it is a single gene mutation, inherited as an autosomal recessive disorder, which results in an activity deficiency of a lysosomal enzyme called arylsulfatase B. Without this enzyme, a specific compound, dermatan sulfate, cannot be broken down, so it accumulates in cells and overflows into the blood and urine. As the condition progresses, different organs are affected, which results in the clinical signs. One of the advantages of this model is its suitability for testing new modes of therapy for MPS. Such methods include enzyme manipulation/replacement, bone marrow transplantation, and gene therapy. Other animal models of MPS currently under investigation are domestic shorthair cats (MPS-1) and mixed breed dogs (MPS VII).Hearing Loss
As a result of exposure to high level noise, humans and cats may have resulting. Because of this similarity, researchers have been able to study the effects of noise on cats and apply it to humans.
Studies examining the causes and treatments for dental caries and destructive periodontitis have successfully been conducted using the cat as a model.
Feline GM1 Gangliosidosis
Cats with this disorder seem to be the best model yet discovered for the human condition of the same name. In both humans and cats, the CNS degeneration and deficiency of ß-galactosidase, with associated neuronal accumulation of GM1 gangliosides and visceral accumulation of proteoglycans, appear to be related to an autosomal recessive gene. The cat has much to recommend it as the model of choice in this case: 1) availability of established research colonies; 2) extensive characterization of the feline disease; 3) remarkably close analogy with the diseases in children; 4) high reproductive capacity in cats; 5) ease of maintenance and handling of cats; 6) body size which facilitates clinical observations, surgical manipulations, testing and treatment procedures, and availability of reasonable volumes of tissues and body fluids; and 7) unrivaled position of cats as the favorite species for neurological research, which leads to a vast repository of data on the feline nervous system.
Sphingomyelin Lipidosis (Niemann-Pick Disease)
Spinal Cord Injuries
The responses of cats to Brugia parangi, which parasitizes them in nature, mimic those of humans to Brugia malayi and Wuchereria bancrofti, the causative agents for Elephantiasis, in many important respects. In both host-parasite relationships, the adult worms are found in the lymphatics and microfilariae circulate in the blood. Infections are often very long lasting in both human and feline filariasis. Some people who have lived in an endemic area for some years eventually become amicrofilaremic, as do some cats if repeatedly infected with larvae. It is likely that many of the features of the relationship between host and parasite that can be studied in cats infected with B. parangi also apply to humans, but for a variety of practical reasons cannot be demonstrated in humans.
Toxocariasis is a parasitic infection caused by roundworms and while roundworms are most common in dogs, they may also be found in cats. Although the infection usually doesn't cause symptoms in adults, it can cause a variety of problems in children, including allergy-like signs and symptoms such as, hives, muscle pain, fever, abdominal pain, respiratory problems (coughing, wheezing). In rare cases it can lead to swelling of organs, central nervous system and partial blindness. Again, prevention is key. Checking feces for eggs and treating appropriately, washing hands, and not allowing feces to remain (in sand, soil, lawns) will effectively eliminate roundworm populations.
Since methylmercury is an extremely toxic compound and lesions often are irreversible, early detection of disease when methylmercury poisoning is suspected and satisfactory methods of treatment must be developed in animal studies. Since the cat is more susceptible to methylmercury than man, this species can be useful as a sentinel animal to avert possible impending disasters. Cats becoming ill in northwestern Ontario, Canada in 1975 alerted authorities to look for a methylmercury toxicity problem, which they promptly found before any human illness had occurred. Cats became ill prior to the outbreak in Minamata, Japan, in the 1950s, but it went unrecognized until after-the-fact.
Approximately 4500 infants are born with congenital Toxoplasmosis annually in the United States. This disease is carried by cats and spread through infective stools and ground. Virtually all research on this infection has been done using the cat as a research model, and the goal is to develop treatments and protective measures.
Toxoplasmosis (TOX-o-plaz-MO-sis) is a disease that can come from cats, but people are more likely to get it from eating raw meat or from gardening (areas where infected cats have defecated). Toxoplasmosis is sometimes called litter box disease and results from contact with a parasite present in cat feces, soil or undercooked meat. Most cats do not exhibit signs or symptoms of infection, rather family members will have symptoms resembling the flu (swollen lymph glands, fatigue, fever, headache), although there may be no signs.
Prevention is key, thus don’t feed cats undercooked meat or to allow potential exposure to infected animals (for pets this means keeping them indoors). Pregnant women should allow others to clean litter box due to the severe cost if infected (miscarriage, premature births and mental retardation in newborns). Fortunately, Toxoplasmosis can be treated, even during pregnancy.Carcinogenesis
Cats have been used to evaluate potential therapeutic techniques in the treatment of lymphosarcoma, adenocarcinoma, malignant lymphoma, multiple myeloma, squamous cell carcinoma, acute lymphoblastic leukemia, aplastic anemia, and hypercalcemia of malignancy.
Because of its similarity to human breast cancer, feline mammary carcinoma continues to be an important model for the evaluation of new forms of therapy for breast cancer.Investigative Models
Because dietary-induced atherosclerosis also occurs in cats, this species has been used as a model of atherosclerosis in humans.Cats are extensively used as investigative models in neuroanatomy, neurosurgery, neurology, neurophysiology, toxicology, and reproductive physiology. The fact that adult cats are fairly uniform in size with regard to the head, skull, and brain makes the placement of neurologic probes a more precise procedure, thus making cats a better model for this type of research than other species.
Bacterial Infections:TABLE 2 - Selected Feline Zoonotic Diseases
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