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C
Animal Models for the Study of Whooping Cough and the Testing of
Vaccine Materials
ANIMAL MODELS FOR THE STUDY OF
WHOOPING COUGH
Bordetella pertussis does not naturally cause disease in
animals. Nevertheless, experiments in animals have made important
contributions to the present, although incomplete, understanding of
pertussis. Mice, rats, rabbits, dogs, ferrets, and primates have
been used. The respiratory colonization of mice by B.
pertussis mimics that of humans, but mice do not cough, and so
the infection is not spread from mouse to mouse (Pittman et al.,
1980). Among experimental animals, only primates have been found to
develop a paroxysmal cough and mucus production; they do transmit
the infection from one animal to another (Weiss and Hewlett, 1986).
However, adult primates can become resistant to pertussis, so that
newborn animals are needed for use in experiments, and this is
impractical. Rats are very hard to infect with B. pertussis,
and rabbits carry the organism for months without showing signs of
disease (Ashworth et al., 1982; Weiss and Hewlett, 1986).
Most of the information about pertussis gained from animal
models has come from the study of mice. Three sites of infection
have been used: intraperitoneal, respiratory, and intracerebral.
Mice can rapidly kill B. pertussis when the organism is
injected intraperitoneally. But, given enough bacteria by this
route, they will die of apparent toxemia in 1 to 3 days (Pittman,
1970; Proom, 1947). These responses do not represent a model of
whooping cough. Unlike the situation in humans, virulence by the
intraperitoneal route in mice is inversely related to intracerebral
virulence (Pittman, 1970),
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an observation that illustrates the difficulties of using animal
models to represent human disease.
Older mice are relatively resistant to respiratory infection;
infant or suckling mice have reproducible symptoms and mortality
from pertussis pneumonia, and the disease resembles the disease in
humans (Pittman et al., 1980; Sato and Sato, 1988; Sato et al.,
1981). Infection induced by intranasal inoculation (Pittman et al.,
1980) has been reported to be less reproducible than that induced
by aerosol inhalation (Sato and Sato, 1988). The strain of mice
used can affect the results (Pittman et al., 1980). Survivors
of a sublethal dose of organisms can develop a chronic infection
that lasts for weeks or months (Dolby et al., 1961; Sato et al.,
1981; Weiss et al., 1984).
Using intranasal inoculation of infant mice, Weiss and
colleagues (1983, 1984) showed that mutant strains of B.
pertussis lacking pertussis toxin (PT) or extracytoplasmic
adenylate cyclase were much less virulent than the wild-type
(naturally occurring) organism. A mutant deficient in filamentous
hemagglutinin was nearly as virulent as the wild-type strain. The
results obtained with these carefully engineered strains raise a
question about the contribution of filamentous hemagglutinin to
virulence. Such a contribution had been suggested by data from
other models. These and other considerations warrant reservations
about the general applicability of the results obtained with this
or the other models to the disease in humans.
Mice infected intracerebrally have been the most widely used
animal model for pertussis. To achieve this model, anesthetized
mice are injected with various numbers of organisms, in some cases
after immunization with bacteria or bacterial products (usually
given intraperitoneally). Only one strain of B. pertussis,
strain 18-323, works well in the model, which raises further
questions regarding the applicability of this model to the natural
disease in humans. In fact, analysis of isoenzyme patterns suggests
that this bacterial strain is genetically more closely related to
Bordetella bronchiseptica than it is to other strains of
B. pertussis (Musser et al., 1986). In mice, the bacteria
attach to the ciliated cells of the ependymal lining of the
ventricles (Berenbaum et al., 1960), which simulates attachment to
the respiratory cilia in humans with whooping cough. However, this
infection within the skull otherwise deviates rather markedly from
the presentation of the disease in humans. Despite these obvious
differences from the infection in humans, protection in this model
has correlated with vaccine efficacy in humans (Medical Research
Council, 1959; Standfast, 1958).
STANDARDIZED ANIMAL TESTS OF VACCINE
MATERIALS
The intracerebral mouse protection test (Kendrick et al., 1947,
1949) has served importantly in the progress in vaccine development
that has been made to date. The test uses a standardized strain of
bacteria (strain 18-323)
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stored in liquid nitrogen (Cameron, 1988), standardized mice
(strain HSFS/ N) (Manclark et al., 1976), a freeze-dried reference
vaccine (Armitage and Perry, 1957), and an interval between
immunization and injection of 14 to 17 days (Cameron, 1988).
The intranasal mouse protection test has been improved by use of
a standardized system for delivery of bacteria by aerosol (Sato and
Sato, 1988). This test has been used for the study of the role in
pathogenesis of bacterial adherence proteins, for example, the
69-kilodalton outer membrane protein (Shahin et al., 1990).
The toxicities of vaccines have been studied by the mouse weight
gain test. This test depends on the observation that
intraperitoneal injection of vaccine into young mice leads to a
weight loss within hours, followed by total recovery of weight
within the next 7 days (Cameron, 1988). The causes of
toxicity (manifested as poor weight gain) in the test are not well
understood; the test is not very sensitive to endotoxin (Cameron,
1977). Results of the test have been shown to vary with the
adjuvant or absorbent used with the vaccine, mouse strain, diet,
size of cage, ambient temperature, and duration of exposure to
light (Cameron, 1988). These vagaries further illustrate the
difficulty of generalizing to humans the results obtained from
studies in animals.
A sensitive assay for the particularly important toxin PT and
for anti-PT has been developed by using Chinese hamster ovary (CHO)
cells (Gillenius et al., 1985; Hewlett et al., 1983). In the
presence of PT, CHO cells undergo a characteristic clumping, which
can be blocked with antibody to PT. The test can detect PT at
levels one-fiftieth those of the next most sensitive assay
(Cameron, 1988).
In summary, B. pertussis is a complex organism, multiple
factors having been proposed as possible contributors to its
virulence. Their role in whooping cough has not been clearly
established. Without better understanding of the organism and the
human disease, it cannot be concluded with confidence that data
from animal models relate to findings in humans.
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Representative terms from entire chapter:
whooping cough