laboratory animal models for experimental cryptosporidiosis

Transcription

Research and Reviews in Parasitology.
©
1994 Asociaci6n
de
54 (I): 13-28 (1994)
Editorial
Parasitologos Espanoles
Fornalba,
S.A.
Printed in Spain
LABORATORY ANIMAL MODELS FOR EXPERIMENTAL
CRYPTOSPORIDIOSIS: A MINIREVIEW
C.W.
KIM
Division of Infectious Diseases, Department of Medicine and Department of Microbiology,
School of Medicine, State University of New York, Stony Brook, New York, US.A.
Received
REFERENCE: KIM (C.W.),
1994.-
Laboratory
animal
15 March
models
1994; accepted
for experimental
28 March
1994'
Cryptosporidiosis:
a minireview.
Research and Reviews in
Parasitology, 54 (I): 13-28.
SUMMARY: Mice, rats, guinea
pigs and hamsters are suitable hosts for experimental cryptosporidiosis.
Experimental
studies in these hosts
in the immunocompetent
as
provide data that are helpful in understanding
the pathogenesis
and immune response to Cryptospiridium
well as the immunocompromised
state. These animal models are valuable in the assessment of effective chemotherapeutic
agents against
cryptosporidiosis.
Essentially all the experimental data in mice are based on infections with Cryptospidium parvum obtained from calves or humans. C.
parvum is infectious for many strains of mice. Neonates are more susceptible to the infection than adult mice. In the BALBIc nude mice,
the infection is accompanied
by diarrhea, which is not present in normal mice. T cells appear to be important for recovery from infection
in mice. The antibody response in infected mice is valuable in characterizing
the antigenic composition
of the parasite. The significance
of antibody in controlling the infection is still unresolved, although there are now data to support its use for pasive immunotherapy.
Several
chemotherapeutic
agents have been tested in mice, but only a very few compounds exhibit limited prophylactic or therapeutic activity.
\ Suckling rats are susceptible to Cryptosporidium and shed oocysts for a longer period than do other laboratory animals. However, immunosuppressed
adult rats can serve as a convenient rat model with very high perecentages showing infection as long as the immunosuppressive drug is administered.
The availability of athymic (mu/mu)
rats offers an ideal rat model to study the pathophysiological
changes
and immune response to the infection without the need for chemical immunosuppression.
The immunosuppressed
rat model is useful in
the evaluation of the efficacy of anti-Cryptosporidium agents.
The guinea pig shows the same lack of host specificity as other laboratory animal hosts to Cryptosporidium, but there is an additional
species, C. wrairi, that is found in the guinea pig. Diarrhea is observed in some guinea pigs, not a consistent finding in other normal laboratory
animals. Adult guinea pigs are infective like the neonates, although adults show some innate resistance as with other animals. One of the
more interesting findings in guinea pigs is the demonstration
of Cryptosporidium within the cytoplasm of M cells overlying Peyer's patches,
suggesting that this may be the path for the Cryptosporidium antigens to provide the antigenic stimulus to the intestinal lymphoid cells.
It may also explain the difficulty encountered
in eradicating this parasite in the immunocompromised
host.
The hamster is the most recent of laboratory animal hosts to be reported to be susceptible to experimental cryptosporidiosis.
As with
other small laboratory animals, the neonates seem to be more susceptible, although adults are also susceptible when immunosuppressed
with chemical agents. The aged hamsters also appear to be more susceptible to the infection than young adults. The hamster appears to
be a suitable host for studying the efficacy of chemotherapeutic
agents against cryptosporidiosis.
KEY
WORDS:
Cryptospiridium,
experimental
cryptosporidiosis,
mice, rats, guinea
pigs, hamsters.
CONTENlS
Introduction
Animal models
Mice
Cryptosporidium species
Endogenous
development
Infection in neonates vs adults
Immune response
Treatment
and control
Rats
Infection in neonates and immunosuppressed
Immune response
Treatment
Guinea pigs
Pathogenicity
Immune response
Hamsters
Experimental
in fections
Treatment
References
14
15
15
15
16
16
17
adult
rats
18
18
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18
19
20
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21
21
22
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22
22
14
CW. KI\I
INTRODUCTION
Cryptosporidium is a coccidian parasite that has been
known since 1907 when TYZZER (1907) first described it
in the gastric epithelium of laboratory mice and named
it Cryptosporidium muris. In 1912, he (TYZZER, 1912)
identified and named a new species, C. parVUI11, which
was smaller than C. muris and, when transmitted
to
laboratory mice, developed only in the small intestine.
Cryptosporidium infects more than 40 host species, including fishes, reptiles, birds and mammals, including
humans (CURRENT, 1986). It was not until 1971, when
the infection
was reported
in a calf (PA Cl ERA,
THOMASSE & GARNER, 1971) that interest in the parasite
and infection was rekindled among veterinarians. The first
human cases were reported from the United States in a
immunologically competent child (NIME er al., 1976) and
in an immunosuppressed
adult (MEISEL et al., 1976).
Since then there has been an overwhelming number of
reponed cases in immunologically competent individuals
(TZIPORI et al., 1980 b; ANDERSON et al., 1982; BABB,
DIFFERDING & TROLLOPE, 1982; FLETCHER, SIMS &
TALBOT, 1982; CURRENT et al., 1983; TZIPORI et al., 1983
a; JOKIPll, POHJOLA & JOPIKll, 1983; BLAGBUR & CURRE T, 1984; Mc COLL & MOONEY, 1984; KOCH et al.,
1985; SOAVE & MA, 1985; VANDEPITTE, ROBRECHTS &
VANNESTE, 1985; WOLFSON et al., 1985; SOAVE & ARM·
STRONG, 1986; HOLLEY & DOVER, 1986; LEVINE et al.,
1988). The infection in immunocompetent
individuals is
self-limiting and the diarrhea is resolved without therapy,
although it can be severe (DELMAN & OLDFIELD, 1988).
In contrast,
individuals
with
impaired
immunocompetence develop a chronic, life-threatening diarrhea. Conditions of immunodeficiency have included congenital immunodeficiency
(LASSER, LE\VIN & Rv I G,
1979; BIRD, SMITH & BRYCESON, 1980; SLOPER et al.,
1982; CURRENT et al., 1983), those receiving immunosuppressive drugs (MEISEL et al., 1976; WEISBURGER et al.,
1979; MILLER, HOLMBERG & CLAUSEN, 1983; LEWIS,
HART & BAXBY, 1985), concurrent infections (STEMMER.
MAN et al., 1980; WEI STEIN et al., 1981; FORGACS et
al., 1983; WITTNER et al., 1984; NG et al., 1984), and
especially acquired immunodeficiency
syndrome (AIDS)
(CURRENT et al., 1983; KOCH et al., 1983; PETRAS, CAREY
& ALANIS, 1983; PITLlK et al., 1983 b; MALABRA CHE
et al., 1983; PAPE et al., 1983; GOTTLlEB et al., 1983;
COOPER et al., 1984; SOAVE et al., 1984; WHITESIDE et
al., 1984 a; DOBBINS & WEINSTEIN, 1985; MODIGLlANI
et al., 1985; ZAR, GEISELLER & BROWN, 1985). In AIDS
patients, Cryptosporidiurn has involved other sites in addition to the intestinal tract, such as the respiratory tract
(FORGACS et al., 1983; BRADY, MARGOLlS &
KORZENIOWSKI, 1984; MA et al., 1984; MILLER et al.,
1984), gall bladder (GUARDA et al., 1983; PITLIK et al.,
1983 a; BLUMBERT, KELSEY & PERRONE, 1984), as well
as the biliary tree and pancreas (GROSS et al., 1986), suggesting dissemination.
One of the important aspects of cryptosporidiosis
is
wi t h
the higher
prevalence
in young
children
gastrointestinal
symptoms in both rural and urban environments throughout
the world, including Australia
(CURRE T et al., 1983), Wales (CASHIORE & JACKSO:--:,
1983), Denmark
(HOLTEN-ANDERSON, GERSTOFT &
HENRIKSEN, 1983), England (HUNT et al .. 1984; WYLLlE,
1984; ISAAcs et al., 1985), New Zealand (CARTER, 198.+),
Bangladesh (SHAHID et al., 1985), India (DAS et al., 1987),
Chile (WEITZ et al., 1987), and Israel (S-\LLOi': et al.,
1988). The infection is also present in the African continent, including Liberia (HOJLYNG, MOLl:lAK & JEPSEi\,
1984) and Rwanda (DE MOL et al., 1984; BOGAERTS et
al., 1984). In the United States, the incidence has been
high in day-care centers (ALPERT er al., 1984, 1986; DIERS
& Mc CALLlSTER, 1989). Routine microbiological
examination in Newfoundland
and Labrador has revealed
Cryptosporidiurn oocysts in 1,4070of the faecal samples
from infants and children under 10 years of age (RATNA\I
et al., 1985). The rate was much higher (10,8%) in
Venezuelan children with acute diarrhea (PEREZ-SCHAEL
et al., 1985) and still higher in Haitian children, 16,3%
in an urban hospital and 17,5% at a rural dispensary
(PAPE et al., 1987). In Costa Rica, oocysts were detected
in faeces of 4,2% of rural and 4,4% of urban children
with diarrhea, although there was no infection in infants
who where wholly breast-fed (MATA et al., 1984). OOCYSIS
were rarely found in stools of infants receiving only breast
milk in Haiti as well (PAPE et al., 1987). The infection
has been observed in the United States in chil-dren who
travelled through endemic centers, such as the African
continent
(SOAVE & MA, 1985), and in England in
children from Pakistan (FLEGG, 1987).
The mode of transmission is assumed to be the faecaloral route, which may explain the higher incidence in
young children. A person-to-person
transmission
or a
hospital cross infection was suggested when an attending
nurse was presumed to have contracted the infection from
a 13-month-old baby (BAXBY, HART & TAYLOR, 1983).
Since then person-to-person
transmission among hospital
personnel has been suggested to be common (KOCH et
al., 1985). Waterborne outbreaks have been attributed to
contaminated
water supply (D'ANTONIO et al., 1985;
ISAAc-RENTON et al., 1987; HAYES et al., 1989).
Natural infections in calves, lambs, goats, monkeys,
birds and other domestic animals have been reviewed
(A GUS, 1983; TZIPORI, 1983, 1988; CURRE 'T, 1986;
FAYER & U GAR, 1986; FERNANDEZ et al., 1988; CLR·
RE T & BICK, 1989; DUBEY, SPEER & FAYER, 1990).
Natural infection has also been reported in a pup
(WILSON, HOLSCHER & L YLE, 1983), gazella (FENWICK,
1983), piglet (ARES et al., 1988), and C-57 brown mouse
(HAi\IPTON & ROSARIO, 1966), as well as wild mouse
(KLESIUS, HAYNES & MALO, 1986). Cryptosporidiutn has
been reported to be one of the most common infectious
agents associated with diarrhea of newborn calves in
Canada (MORIN, LARIVIERE & COLLIER, 1976), United
Kingdom (PEARSON & LOGAN, 1983; S ODGRASS et al.,
1980), and the United States (MOON et al., 1978;
Animal
models for experimental
Cryptosporidiosis
POHLENZ et al., 1978 b) in the absence or presence of
other enteropathogens.
It was often difficult to draw a
firm conclusion
as to whether the parasite was solely or
partially responsible
for the diarrhea in neonatal calves
(POHLENZ et al., 1978 b). It is even more difficult when
there is concomitant
infection.
A more causal relationship of Cryptosporidium and clinical diarrhea was shown
in artificially
reared lambs (TZIPORI er al., 1981 a) and
artificially
reared deer (TZIPORI er al., 1981 b). Cryptosporidium may well be an opportunistic
agent that appears when abnormal
conditions
in the host permit it to
thrive. Although
Cryptosporidium is generally found in
the epithelium
of the intestinal tract, it is found in the
respiratory
epithelium
of turkeys (HOERR, RANCK &
HASTINGS, 1978) and chickens (DHILLON er al., 1981), and
in other sites, such as the epithelium of the common bile,
intrahepatic
and pancreatic ducts and the gall bladder of
rhesus monkey (KOVATCH & WHITE, 1972), and the
epithelium of kidney tubules of the black-throated
finch
(GARDINER & IMES, 1984).
The real pathogenic
nature of Cryptosporidium is not
known,
i.e., whether
the damage
to the mucosa
is
mechanical, mediated by destruction of cells by the liberation of parasite metabolites,
or even a hypersensitivity
reaction of the mucosa to the parasite antigens.
The
parasite appears to enhance epithelial cell ageing and extrusion rate (MATOVELO, LANDSVERK & POSADA, 1984)
and may actually destroy the cell (HEINE er al., 1984). The
mechanism of diarrhea is also not fully understood,
since
the degree of mucosal injury is insufficient to account for
the diarrhea. It is thought to be secondary to profuse fluid
secretion in the duodenum and proximal jejunum in AIDS
patients (ANDREANI et al., 1983). A recent report has indicated that enterotoxic activity was present in stools of
Cryptosporidium-uiiecica
calves, and this activity may
be responsible
for secretory
diarrhea
in humans
(GUARINO et al., 1994).
Although
the mechanism
of the immune response in
cryptosporidiosis
is unknown, control of the infection by
the immune system has been observed. Oral administration of immune anti-Cryptosporidium
sp. bovine colostrum to a hypogammaglobulinemic
child with a persistent infection resulted in remission of diarrhea
and
termination
of oocyst shedding (TZlPORI, ROBERTON &
CHAPMAN, 1986). On the other hand, oral administration
of
bovine
colostrum
containing
antiCryptosporidium antibody failed to alter the course of
the infection in others (SAXON & WEINSTEIN, 1987). The
role of cell-mediated
immune responses in C. parvum infection in any host species has not been clarified until
recently.
Cryptosporidium had not been cultivated outside the
animal host until its life cycle was reported to be completed from the sporozoite
to the infective oocyst in 8to lO-day-old chicken embryos via the allantoic
route
(CURRENT & LONG, 1983) and in human fetal lung,
primary chicken kidney and porcine kidney cell cultures
(CURRENT & HAYNES, 1984). Recently, in monolayers of
15
mouse fibroblast cell line L929 asexual multiplication
was
observed, including small numbers of garnetocytes (Mc
DONALD er al., 1990).
Screening
for an antiCryptosporidium drug in this cell line was not altogether
successful since greater concentrations
of the drug, e.g.,
monensin,
which inhibited the parasite, also had a toxic
effect on the monolayer
cells.
Nearly 80 therapeutic
agents, including coccidiostats
and other anti protozoa compounds,
broad-spectrum
antibiotics, and anthelmintics
had been tested against Cryptosporidium in the course of treatment ot in fections in
humans and animals (CURRENT, 1986; FAYER & UNGAR,
1986). Most of the drugs were ineffective against Cryprosporidium. Preliminary
reports suggested that a few
AIDS patients may have responded
to treatment
with
spiramycin (WHITESIDE er al., 1984 a, b; PORTNOY er al.,
1984) or the combination
of quinine and clindamycin
(WHITESIDE er al., 1984 b). Amprolium
was shown to
although
the
reduce the number of Cryptosporidiurn,
parasite
was not eradicated
in an AI DS patient
(VELDHUYZEN VANZANTEN er al., 1984). Presumably the
diarrhea due to Cryptosporidiurn in two AIDS cases ceased under treatment with highly purified, culture-derived
recombinant
interleukin-2
(KERN, Toy & DIETRICH,
1985). However, clinical data are lacking with regard to
the immunomodulating
ability of IL-2. Hence, to date.,
effective treatment for cryptosporidiosis
in both animals
and humans
has yet to be identified.
Much of the
therapeutic
study has been limit-ed by the lack of a simple in vitro cultivation
system, as well as a good small
animal model susceptible
to the infection.
ANIMAL
MODELS
Experimental
cryptosporidiosis
has been studied in
many types of mammals,
including
calves (MOON &
BEMRICK, 1981; POHLENZ er al., 1978 a, b; TZlPORI er al.,
1980 a, 1983 b; FAYER et al., 1985), lambs (ANGLJS,
TZIPORI & GRAY, 1982; TZIPORI et al., 1980 a, 1981 c, e,
1982 a), fetal lambs (KIM er al., 1988), piglets (MOON &
BEMRICK, 1981; TZIPORI et al., 1980 a, 1981 d, 1982 b),
and others. The disadvantages
of using large animals for
experimental
infections are the high cost and the requirement of large quarters for maintenance.
Therefore, the
development of a reliable laboratory animal model is ideal
for studies of pathogenesis,
mechanism
of immune
response and the evaluation of various therapeutic agents
for either prophylaxis or therapy. Several laboratory small
animal models have been developed and proven to be
suitable hosts for Cryptosporidium .
Mice
Cryptosporidium
species
C. muris and C. parvum were both originally observed
in mice and identified
as separate species by TYZZER
(1907, 1912). C. muris, which is larger than C. parVUI11,
16
developed in the gastric glands of the stomach, while the
smaller form was found in the intestinal
tract. Two
separate species were distinguished
morphologically
by
light microscopy
(UPTON & CURRE T, 1985) and later
confirmed by ultrastructural
studies (UNI et al., 1987). C
muris was infectious for other hosts, including guinea
pigs, rabbits, dogs, and cats (lSEKI et al., 1989). Mice and
cats were found to be highly susceptible, whereas guinea
pigs, rabbits, and dogs showed low susceptibility.
The entire endogenous
development
of this parasite occurred in
the stomach and not in the small and large intestines of
these experimental
animals. The more common form, C
parvum, has been shown to be infectious for numerous
mammals,
including
humans.
Thus, based on morphology and the site of infection, there are two species,
C parvum and C muris, that infect mammals.
Endogenous development
umerous endogenous
stages of Cryptosporidium sp.
were observed in l-day-old white mice 6 days following
an oral inoculation
of oocysts of human and calf origin
study in suckl(REESE et al., 1982). A more quantitative
ing Swiss Webster mice revealed that following an oral
administration
of 1 x 105 to 1 X 106 oocysts,
the
sporozoites excysted within the lumen of the duodenum
"and ileum, penetrated
into the microvillous
region of
villous enterocytes, and developed into type I meronts with
six or eight merozoites
and type II meronts with four
merozoites
(CURRE T & REESE, 1986). The sequential
stages of the life cycle of C parvum was recently confirmed by Nomarski interference-contrast
microscopy of
gut specimens of 4- to 5-day-old suckling BALB/c mice
(SCAGLIA et al., 1991).
Infection in neonates vs adults
Essentially all the experimental
data in mice are based
on infections with C parvum oocysts obtained from calves
or humans, although the earlier papers refer to it as Cryptosporidium sp. One of the early experimental infections
in mice showed
that sporulated
oocysts
of Cryptosporidium sp. of human and calf origin orally inoculated into l-day-old white mice produced heavy infections, primarily in the brush border of the ileum, when
examined 6 days later (REESE et aI., 1982). The ID50 for
5-day-old Swiss Webster mice was determined to be under
(ER EST et al., 1986). If
1000 C parvum oocysts
Cryptosporidium-Iaden calf faeces were dried, infectivity for 3- to 7-day-old
mice was found to be reduced
(ANDERSON, 1986).
Cryptosporidium sp. has been shown to be infectious
for at least eight laboratory
strains of mice, including
random-bred
Swiss White and Porton and the inbred
strains of CBA, CBA Nude, C57 Black, BALB/c, Porton, and Hairless (HR/HR-ADR)
(SHERWOOD et al.,
1982). One- to four-day-old
mice were susceptible, while
the infection was only transient in those of 21 days of age
or older,
even when immunosuppressed
with cy-
CW.
KI~I
c1ophosphamide.
The infected mice did not manifest
clinical illness, but parasites were detected in the faeces
and confirmed
in histological
preparations
even after
faecal shedding had ceased. In BALB/c nude (athymic,
nu/nu) mice of 6 days, the infection was accompanied
by dial' rh ea (HEINE, MOON & WOODMANSEE, 1984), not
present in normal mice. In addition to villous atrophy and
crypt hyperplasia
of the small intestine, diffuse cystic
mucosal hyperplasia
and crypt abscess were observed in
the large intestine at 56 days of age. These findings suggested that T cells were required for recovery from the
infection. Adult mice, which had normal T-cell function
but had a deficit in erythrocyte and granulocyte lineages,
including intestinal mast cells (W/W\\), were inoculated
with 106 oocysts (HARP & MOO, 1991). These mice were
much more heavily infected 1 week later than were adult
normal mice, although the recovery rate was similar. These
findings suggested that, while the recovery of adult mice
from the infection also required functional T cells, other
factors were involved in the initial resistance of adult mice
to the infection.
Even nude mice were reported to be relatively more
resistant to the infection at 42 days of age than at 6 days
of age (HE! E, MOON & WOODMANSEE, 1984). To determine the factor(s) responsible
for the relative resistance
of adult laboratory mice to C parvum, COl and BALB/c
germfree, conventional,
and antibiotic-treated
adult mice
of 6-8 weeks of age were inoculated
with 1 x 105 or
1 X 106 oocysts (HARP et al., 1988). Germfree mice of.
both COl and BALBIc strains were colonized at day 7
following infection,
whereas untreated
and antibiotictreated (500 fAg/ml vancomycin,
I mg/ml ampicillin and
100 fAg/m I gentamicin) conventional
mice remained resistant to colonization.
These results suggested that the
micro flora in the intestine was not the sole determinant
of resistance or susceptibility to colonization.
The number
of parasites seen in the intestinal tissues of adult germfree mice never equaled that seen in the neonate control
mice. Interestingly, attemps to infect adult mice were successful only when adult BALB/c mice were inoculated via
an unusual route, such as into the uterine horn (LIEBLER,
POHLE Z & WOODMA SEE, 1986).
There is evidence in adult mice that the mechanism of
recovery from existing C parvum infection and resistance
to initial infection are different (CURRENT & BICK, 1989).
The innate resistance of adult mice to challenge may be
more
dependent
upon
physiologic,
age-related
mechanisms.
When severe combined
immune
deficient
(SClO)
neonatal and adult mice which have no functional
T or
B cells and nude mice (NIH-IlI)
which have defective T
cell-independent
B lyrnphocytes were infected with C parVUI11 oocysts, they developed
chronic infections that persisted over 12 weeks (MEAD et al., 1991). Infections
in
neonatal mice were rapidly established
while infections
in adult mice were initially light but steadily increased to
a comparable
level of infection. The role of T or B cells
in eradicating the infection was again evident when SCIO
Animal models for experimental Cryptosporidiosis
suckling mice developed progressively severe cryptosporidiosis that killed all animals within 7 weeks, while
BALBIc mice were able to eradicate the infection (KUHLS
et al., 1992). The mortality was 720/0 in adult SCID mice
at 5 months and 0% in BALB/c adult mice. On the other
hand, SCID mice have been reported to be initially resistant to C. parvum, which was attributed not to specific
immune response but to nonspecific mechanisms
associated with the presence of intestinal flora that
stimulates gamma interferon (HARP, CHEN & HARMSEN,
1992).
Adult mice of strains C57BL/6N, DBA/2N, CBA,
C3H/HeN, and BLAB/cAnN were immunosuppressed
with dexamethasone (DEX) and infected with C. parvum
oocysts. Of these only C57BL/6N given 125 f..Ig/day
developed chronic infections that persisted over 10 weeks,
suggesting that the genetic background of the mouse
played a role in determining susceptibility to cryptosporidiosis (RASMUSSE & HEALEY, 1992 c).
Immune response
The results in 6-day-old BALBIc nude mice had suggested that T cells were required for recovery from infection with Cryptosporidium (HEI E, Moo
& WOODMA SEE, 1984). Recovery of adult mice from infection
also appeared to require T cell-mediated immunity
(UNGARet al., 1990). In adult athymic nude mice, a lack
of T cells was crucial to the establishment of persistent
Cryptosporidium infection, and reconstitution with a Tcell population
that included CD4 + T cells was
necessary for successful recovery from the infection. Lymphoid cells from histocompatible, Cryptosporidium sp.immune mice cured infected nude mice. When adult
BALBIc mice were treated with mAb directed against
CD4 + or CD8 + T lymphocytes or with neutralizing antiIFN-y or IL-2 mAb, chronic infection as evidenced by
shedding of oocysts occurred with anti-CD4 + anti CD8
mAb treatment (UNGAR et al., 1991). Anti-CD8 mAb
treatment alone did not allow infection. Treatment with
anti-IF -y mAb greatly enhanced oocyst shedding but infection was self-limited. Treatment with anti-IL-2 mAb
did not permit infection. These findings suggested that
both CD4 + cells and IFN-y are required to prevent initiation of infection, whereas either alone can limit the
extent (lFN-Y) or duration (CD4 + cells) of infection.
The importance of CD4 + cells and IFN-y in the
resolution of an established C. parvum infection was
observed in SCID mice. When C. parvum-infected SCID
mice were reconstituted with splenic cells from immunocompetent donors, the recipients were able to resolve
the infection by 17 days postreconstitution (CHE , HARP
& HARMSEN, 1993). Treatment of reconstituted SCID
mice with either anti-CD4 mAb to deplete them of
CD4 + cells or with IFN-y to neutralize IFN-y activity
reduced or eliminated their ability to resolve the infection. These findings again indicated that the resolution
of established cryptosporidiosis
in immunologically
17
reconstituted SCID mice was dependent on both CD4 ~
cells and IFN-y.
The role of cell-mediated immune response has been
substantiated by in vitro studies in which spleen lymphocytes from multioral-infected
mice demonstrated
significant Ag-specific blastogenesis, while mesenteric
Iymphocytes did not respond (WHITMIRE& HARP, 1990).
Lymphocytes from lymph nodes of inbred SWR/JH-2Q
mice exposed to C. parvum oocysts proliferated when
cultured in vitro with soluble or particulate antigens
prepared from oocysts (Moss & LAMMIE, 1993). Unlike
the findings of WHITMIRE & HARP (1990), the lyrnphocytes from spleens had no proliferative response. Attempts to transfer C. parvum resistance by means of
spleen or mesenteric lymph node (MLN) cells to susceptible infant mice was unsuccessful (HARP & WHITMIRE,
1991).
The antibody response of mice infected with C. parvum oocysts has been valuable in characterizing the antigenic composition of the parasite (LuFT et al., 1987).
Our data suggested that carbohydrate moieties with
molecular weights greater than 60000 were important immunogens in C. parvum infection. Antioocyst mAb-based
immunofluorescence assay has been utilized to detect
oocysts in faecal smears as well as those in tissue sections
(ARROWOOD& STERLI G, 1989).
Bovine immune serum was shown to neutralize the infectivity of sporozoites in neonatal mice (RIGGS & PERRYMA , 1987; FAYER,PERRYMAN& RIGGS, 1989). The
greatest reduction in parasite number was found in mice
treated with IgGI, IgA, or whey (FAYER, GUIDRY &
BLAGBURN, 1990). Immune bovine serum and two
surface-reactive antisporozoite mAb with neutralizing activity were used to identify sporozoite surface Ag by
radioimmunoprecipitation/SDS-PAGE
and immunoblotting (RIGGS et al., 1989). The results indicated that two
different molecules capable of inducing neutralizing antibody were exposed on the surface of C. parvum
sporozoites. Hence, it was suggested that neutralizing antibodies may be useful for pasive immunotherapy against
cryptosporidiosis in neonatal animals and imrnunocompromised humans. C. parvum merozoites have been
shown to share the neutralization-sensitive epitopes with
the sporozoites (BJORNEBY,RIGGS& PERRYMAN,1990).
As in human infections, bovine colostrum has been
reported to have no protective effect in mice (Moo et
al., 1988). Therefore, it was concluded that passive lacteal
immunity was not an efficient means of protection against
cryptosporidiosis in mice. Also, BALB/c neonates suckled by dams that recovered from C. parvum infection were
susceptible to infection as were the neonates receiving
orally administered antisporozoite monoclonal antibodies
(ARROWOODet al., 1989).
Monoclonal antibody (MAb5C3) was developed against
15-kDa surface glycoprotein of C. parvum sporozoites
(TILLEYet al., 1991). When hybridoma supernatants containing the MAb5C3 were administered orally to suckling mice infected with C. parvum, a 75% reduction in
CW.
18
developmental stages was observed at 72 h postinfection
and a 67,5070 reduction in oocyst shedding at 6 days
postinfection. These data indicated that the parasite might
depend upon rapid elimination by the immune system,
suggesting that passive immunotherapy may be effective.
In congenitally athymic nude mice, a significant reduction in intestinal Cryptosporidium
infection was
demonstrated when oral passive immunotherapy with
neutralizing MAb 17Al was administered rather than
isotype control MAb 7.3A or no treatment. These findings again give support to the use of passive immunotherapy with neutralizing anti-Cryptosporidium antibodies as a treatment approach (BJOR EBYet al., 1991).
A study using B cell-deficient (anti-u-treated) neonatal
BALB/c mice has shown that even abrogation of
Cryptosporidium-specific
antibody responses had no
detectable impact on the infection, suggesting that the role
of specific in vivo antibody in the resolution of the infection was minor (TAGHl-KlLANl, SEKLA& HAYGLASS,
1990). More recent data have shown that when 3- or
4-week-old female C57BI/6 mice were first infected with
LP-BMS murine leukemia retrovirus for 4 months and
then inoculated with C. parvum oocysts, parasite colonization of intestinal villi and oocyst shedding were
significantly reduced in immunosuppressed animals that
received pooled bovine colostrum compared to those that
did not receive colostrum (W ATZL et al., 1993). The
passively transferred antibodies alone were unlikely to
have provided the improved resistance, since nonimmune
bovine colostrum contained no anti-Cryptosporidium antibodies. Hence, the findings suggested the therapeutic
potency of normal colostrum in controlling cryptosporidiosis.
To determine
the impact of anticryptosporidial
immune rat bile on the infection,
microscopic analysis were done of intestinal sections of
nu/nu BALBIc mice infected with C. parvum oocysts and
treated with immune bile. The results showed less villus
atrophy, crypt hyperplasia and fewer organisms per crypt
than in untreated mice (ALBERT et al., 1994). The
amelioration of the infection was believed to be due to
C. parvum-specific IgA in the rat bile, giving support to
the role for humoral immunity in controlling the infection.
Treatment and control
Many drugs have been tested, both prophylactically and
therapeutically, against Cryptosporidium in mice. Sixteen
antimicrobial agents were administered 4 days after inoculation with Cryptosporidium in day-old C57 mice, but
none of the drugs arrested or modified the course of the
infection as assessed by oocyst excretion and mucosal infection of the small and large intestines (TZlPORl, CAMPBELL& ANGUS, 1982). Several anticoccidial compounds
were administered prophylactically to 1- to 3-day-old Porton or randomly-bred Swiss white mice two days before
infection with Cryptosporidium and continued on the
average for 7 days (A GUSet al., 1984). Based on excretion of oocysts in faeces and histological examination of
KI~I
the small and large intestines, nearly all of more than 20
drugs tested proved to be ineffective. The only drugs of
any prophylactic
promise
were arprinocin
and
salinomycin.
Studies in neonatal HSd:(lCR)BR Swiss mice that were
treated with polyether ionophores (maduramicin and
alborixin), a fluorinated 4-quinoline (enrofloxacin), and
three analogs of pentamidine, all compounds, except for
enrofloxacin and one of the pentamidine analogs
[1,3-(4-imidazolinophenoxy) propane], resulted in significant reduction in oocyst shedding (BLAGBURNet al.,
1991). These compounds had a prophylactic effect, since
they were administered prior to infection with C. parvutn.
When 7-week-old ICR mice were immunosuppressed
with prednisolone acetate and then infected with C. parvum oocysts and 13 h later treated with azithromycin or
lasalocid, the oocyst shedding was markedly reduced in
medicated mice. In fact, some treated mice did not
discharge oocysts (KlMATA, UNl & ISEKl, 1991), suggesting that both azithromycin and lasalocid had prophylactic or therapeutic activity.
One of the measures in the control of cryptosporidiosis
would be to identify disinfectants that would effectively
inactivate the oocysts in the environment. Several disinfectants have been assessed for their effect on destroying
Cryptosporidium oocysts by infecting mice following incubation of oocysts in the disinfectants (CAMPBELLet al.,
1982). Only two common disinfectants, formaldehyde
(10%) and ammonia (5%), proved to be effective in
destroying the viability of the oocysts. In order to identify less toxic and more aesthetically suitable preparations
for hospital use, Tegodor (Th. Goldschmidt) and FormulaH (Hoechst) were tested against Cryptosporidium oocysts
using inbred Porton mice (ANGUSet al., 1982). either
disinfectant destroyed the oocysts, even when exposure
time to faecal homogenates containing the oocysts was
increased to 6 hours. There was no improvement in efficacy at higher concentrations.
Rats
Cryptosporidium
species
The house rat, Rattus norvegicus, has been shown to
be naturally infected with C. parvum (lSEKl, 1986). In
earlier experimental work in rats, although the species of
Cryptosporidium was not identified, it is probably safe
to assume that it was C. parvum (TZlPORl et al., 1980 a;
REESE et al., 1982).
Natural infection with C. muris in the house rat, Rattus norvegicus, has been documented (lSEKI, 1986). Rats
have also been experimentally infected with C. muris
(lSEKl et al., 1989).
Infection in neonates and immunosuppressed
adult rats
Suckling rats inoculated with bovine ileal hornogenates
containing Cryptosporidium began to shed oocysts 5 days
later and continued for 16 days (TZlPORl et al., 1980 a).
Animal
models
for experimental
Cryptosporidiosis
However, the rats did not develop diarrhea or any other
obvious illness, and the histological changes varied from
no apparent
lesions to moderate villous atrophy of the
intestine and infiltration
of mononuclear
cells.
Cryptosporidium sp. oocysts of calf and human origin
administered
orally into I-day-old rats produced heavy
infections
when necropsied
6 days later (REESE et al.,
1982). As in mouse neonates,
numerous
endogenous
were observed in the brush
stages of Cryptosporidium
border of the ileum and moderate numbers in the caecum
and colon.
Since normal adult animals were known to be refractive to infection with Cryptosporidium, a convenient adult
rat model was developed by treating the animals with an
immunosuppressive
drug, cyclophosphamide
(REHG,
HANCOCK & WOODMANSEE, 1987). Female SpragueDawley rats weighing 200 to 250 grams were administered
cyclosphosphamide
at a concentration
equivalent
to 50
mg/kg/day
in the drinking water for 14 days before inoculation
with 1 X J04 or more oocysts. Eighteen days
following inoculation,
800/0 or more of the animals showed infection of the ileum. The infection cleared the small
intestine approximately
7 days after withdrawal of the immunosuppressant,
but oocysts continued to be shed in the
faeces for an additional 5 to 7 days after the parasites were
no longer attached to the enterocytes of the small intestine.
The histologic findings correlated with the faecal smear
results, although
the percentage
of animals infected as
detected by histologic examinations
was higher during the
prepatent period.
Although
cyclosphosphamide-treated
adult rats were
susceptible to Cryptosporidium,
because of the delayed
toxicity induced by cyclophosphamide
in rodents, it was
not possible to investigate
latent infection.
Therefore,
female Sprague-Dawley
rats were treated with another immunosuppressant,
dexamethasone,
specifically
to study
active and latent cryptosporidiosis
(REHG, HANCOCK &
WOODMANSEE, 1988). Dexamethasone
was administered
for 14 days or for 3, 7, and 14 days prior to inoculation
with 1 X J05 C. parvum oocysts of bovine origin. Dexamethasone
in dosages of 0,0625, 0,125, and 0,25 mg/kg
was well tolerated, whereas higher dosages produced toxicity. The optimal
drug dosage
was 0,25 mg/kg.
Withdrawal of dexamethasone
resulted in clearance of the
infection.
In contrast
to cyclophosphamide,
it was
necessary to administer
dexamethasone
for only 7 days
before oocyst inoculation
and 1 X J03 oocysts were sufficient for infection. The infection peaked at 7 days compared with 14 days in the cyclophosphamide
model, but
the infection was most severe in the terminal ileum as in
cyclophosphamide-treated
rats. The results indicated that
the infection can remain latent for as long as JO weeks
after withdrawal of the immunosuppressant
and an overt
infection could become reactivated if immunosuppression
was reinduced during that period.
Since immunosuppressed
patients easily develop cryptosporidiosis
when treated with corticosteroids
(MEISEL
et al., 1976; MILLER, HOLMBERG & CLAUSE , 1983;
19
MEAD et al., 1976; HOLLEY & THIERS, 1986), rats were
rendered more susceptible to Cryptosporidium by treating
them with hydrocortisone
acetate (BRASSEUR, LEMETEIL
& BALLET, 1988). Male Sprague-Dawley
rats, weighing
200 to 250 grams, received subcutaneous
injections of 25
mg of hydrocortisone
acetate twice weekly for 8 weeks,
each rat receiving a total dose of 400 mg. The rats were
on a low-protein
diet and infected with 1 X J05 Cryptosporidium oocysts. The rats shed oocysts from days 2
to 9 following infection and developed a persistent infection for more than 38 days. Excretion of oocysts decreased
subsequently,
suggesting that a progressive degree of protection was developing in these rats. Low-protein
diet
alone was found to be more effective in maintaining
the
infection than hydrocortisone
acetate alone, suggesting
that susceptibility
to Cryptosporidium infection could be
enhanced
by protein malnutrition.
Availability of athymic (rnu/rnu)
rats offered an ideal
rat model to study the pathophysiological
changes and
immune response to infection
with Cryptosporidium,
without
the need for chemical
immunosuppression
(GARDNER et al., 1991). NIH rnu/rnu male rats were orally inoculated with 2,5 X 106 to 6 X J07 Cryptosporidium
oocysts of calf origin within 24 h of birth. The infected
rats began to shed oocysts 5 days following infection with
diarrhea and failed to resolve the infection. In contrast,
the immunocompetent
rnu/ + (furred) littermates showed a self-limited disease and no diarrhea. These findings
indicated that homozygosity
for the rnu gene in the suckling rat was sufficient to permit persistent, symptomatic
cryptosporidial
infection without the need for chemical
immunosuppresion.
Active
infection
of both
immunocompetent
and immunocompromised
rats caused
functional derangement
of lactase and some derangement
of alkaline phosphatase
activities. The lactase deficiency
suggested that in addition to epithelial cell disruption, lactose intolerance
may sometimes contribute
to the diarrhea seen with cryptosporidiosis.
In order to develop a laboratory
animal that would
develop respiratory
cryptosporidiosis,
which occurs in
AIDS patients, Lewis rats were immunosuppressed
by subcutaneous
injection of methylprednisolone
acetate at 2
mg/JOO g body weight and inoculated intratracheally
with
J06 oocysts of C. parvum . The rats developed an infection consisting of all known developmental
stages in the
epithelium lining airways from the trachea to the terminal
bronchioles
(MUELBROEK,
OVILLA & CURRE T, 1991).
This
study
will undoubtedly
lead to studies
of
pathophysiology
of respiratory cryptosporidiosis
of which
very little is known at present.
Immune response
To determine whether the heterozygous
littermates of
rnu/rnu
rats were capable of mounting a cell-mediated
response to Cryptosporidium given orogastrically, the rats
were tested by the ear lobe assay (GARD ER et al., 1991).
NIH rnu/ + rats mounted
a cell-mediated
immune
c.w.
20
response to subcutaneous
3,5 Jig of Cryprosporidium antigen, as evidenced by an increment in the thickness of
the ear lobe. Similar testing in the mu/mu
rat showed
no response, which is consistent with the belief that these
animals lacked sufficient T-lymphocytes
to display a cellmediated immune response.
The role of humoral immunity
in the recovery from
cryptosporidiosis
is poorly understood,
but there is
humoral immune response to Cryptosporidium antigens
administered
orogastrically
in the rat. However,
the
development
of antibody
to specific macromolecules
associated with Cryptosporidium infection was restricted
to the immunocompetent
mu/ + rats, which exhibited
specific immunogobulin
binding in response to Cryptosporidium antigens administered orogastrically (GARDNER et al., 1991). Serum from infected mu/mu
rats, on
the other hand, did not show detectable binding to Crypantigen,
suggesting
that profound
Ttosporidium
lymphocyte defects impair humoral immune responses.
Whether exposure to the purified IgG components
of
hyperimmune
antiserum
could neutralize the ability of
C. parvum sporozoites to infect rats was tested by incubating the sporozoites
at 37° C for 30 minutes. When
the treated sporozoites were inoculated,
per rectum, into
5-day-old Lister rats, there was great reduction in infectivity and specific neutralization
was associated with the
IgG fraction (HILL, DAWSO & BLEWETT, 1993).
tosporidial
activity, azithromycin
consistently
prevented
ileal infection, whereas spiramycin was ineffective (REHG,
1991 b). The efficacy of azithromycin
was dose-related,
200 mg/kg/day
being the minimum dose that prevented
the infection. Azithromycin
also eliminated an established infection of the small intestine but the infection recurred when the drug was stopped,
suggesting
that
azithromycin
is a potentially
useful anticryptosporidial
agent but it requires long-term continuous administration.
When
dehydroepiandrosterone
(DHEA),
an immunomodulator
that up-regulates
the immune system,
was assessed
for its anticryptosporidial
activity
in
Sprague-Dawley
rats that were immunosuppressed
with
dexamethasone,
the oocyst shedding
was significantly
reduced (RASMUSSEN, ARROWOD & HEALEY, 1992). The
authors suggested that the therapeutic
effect of DHEA
may be in restoring the immune system of the host.
Anticryptosporidial
agents have also been assessed in
rats immunosuppressed
with a regimen of 25 mg of
hydrocortisone
acetate and challenged with 105 C. parvum oocysts. Of the 15 drugs tested, sinefungin
(10
mg/kgl24
h) and lasalocid A (10 mg/kgl24
h) exhibited
the highest anticryptosporidial
activity (LEMETEIL et al.,
1993). When sinefungin was administered
prior to or on
the day of oocyst challenge, it successfully prevented the
infection (BRASSEUR, LEMETEIL & BALLET, 1993).
Treatment
The dexamethasone-treated
rat model (REHG, HA COCK & WOODMANSEE, 1988) was used to assess the efficacy of arprinocid
(REHG & HANCOCK, 1990.). Arpronicid, an anti coccidial agent, has been reported to be
highly effective against Eimeria oocysts in broilers (RUFF,
ANDERSO & REID, 1978), but only relatively effective
against Cryptosporidium in mice (ANGUS et al., 1984) and
hamsters (KIM, 1987 b). Female Sprague-Dawley
rats
treated with dexamethasone
were inoculated with 1 x 105
C. parvum oocysts and dexamethasone
was administered
with the drinking water. The rats were given arprinocid
in their feed for 11 days. Arprinocid
had a substantial
parasitistatic
effect at 50 and 25 mg/kg/d
but not at 12,5
mg/kg/d.
Hence, it was concluded
that arprinocid
may
be a useful agent for treating cryprosporidiosis
(REHG &
HANCOCK, 1990).
Dexamethasone-immunosuppressed
rats infected with
C. parvum were used to assess 23 suflonamides.
Sulfadimethoxine
and sulfamethazine
exhibited both prophylactic
and therapeutic
activities
(REHG, 1991 a).
However, when sulfadimethoxine
was stopped after 10
continuous
days and immunosuppression
was continued
for another 11 days, the infection returned to the level seen
in the control rats that did not receive the sulfonamide.
Hence, success depends on continuous
administration
of
the sulfonamide.
When
dexamethasone-immunosuppressed rats infected with C. parvum were used to assess
the macrolides azithromycin and spiramycin for anticryp-
KI\I
Guinea pigs
Cryptosporidium
species
infection
of the guinea pig with Crypsp., the parasite measured
1,0-4,0 um in
tissue sections of the small intestine (JERvIS, MERRI L &
SPRINZ, 1966). Thus, both in its size and the site of infection, it resembled C. parvum originally described by
TYZZER (1912). Another species was designated C. wrairi,
based on its larger size (4,0-7,0 Jim in diameter)
and
longer duration of the endogenous
cycle (up to 15 days)
compared
to C. parvum, and on its different site of infection (posterior ileum) compared to C. muris (VETTERLING et al., 1971). Inoculation
of infected ileal scrapings
produced infection only in guinea pigs and not in mice,
rabbits, chickens, and turkeys. However, C. wrairi was
assumed to be synonymous with C. muris (LE VI E, 1984).
A strain of Cryptosporidium
that differed in certain
respects from C. wrairi was reported in guinea pigs in the
United
Kingdom
(ANGUS, HUTCH ISO & MUNROE,
1985). This finding indicated that more than one strain
can occur in the guinea pig. It resembled other isolates
of Cryptosporidium in its lack of host specificity. Cryptosporidium closely resembling the U.K. isolate has also
been observed in naturally infected guinea pigs (GIBSON
& WAGNER, 1986). It became apparent that both C. muris
and C. parvum can ·infect guinea pigs.
Recent host range and antigenicity studies have shown
that Cryptosporidium oocysts isolated from guinea pigs
In natural
tosporidium
Animal models for experimental Cryptosporidiosis
were not infectious for adult mice but were for suckling
mice. Oocysts isolated from mice infected with guinea pig
Cryptosporidium were not infective for guinea pigs. These
findings suggested that Cryptosporidium sp. from guinea
pigs and C. parvum were distinct species and, thus, the
authors felt that C. wrairi should be retained as a separate
species (CHRISP et al., 1992). However, the fact that
monoclonal
antibodies raised against oocysts and
sporozoites of C. parvum reacted with those of Cryptosporidium sp. from pigs indicated that they were
genetically related. Although Cryptosporidium sp. from
guinea pigs has been shown to be related to C. parvum,
electrophoretic profiles showed striking differences in the
outer oocyst wall proteins. Cryptosporidium sp. from
guinea pigs had a banding pattern clustered between 39
and 66 kDa with a smaller number of bands> 100 kDa,
whereas C. parvum had a wide molecular size range of
bands. Also, oocysts from guinea pigs inoculated into
suckling mice produced WO-fold fewer oocysts by day 7
postinoculation than did mice infected with oocysts of
C. parvum (TILLEY & UPTO , 1991). The authors
hypothesized that Cryptosporidium sp. from guinea pigs
was evolutionarily
derived from C. parvum and
represented an isolate in the process of being adapted to
guinea pigs or that the two were derived from a common
ancestor.
Pathogenicity
The initial report of Cryptosporidium infection in the
guinea pig revealed that the parasite was embedded in the
striated border of the epithelial cells covering the villi and
was most numerous toward the tips, and the infection was
greatly influenced by the nutritional status of the host
(JERVIS, MERRIL & SPRINZ, 1966). The pathologic
changes in the guinea pig consisted of necrosis and
sloughing of enterocytes at the villous tips of the small
intestine, inflammation, hyperemia and edema of the
lamina propria, and hyperplasia of crypt epithelium (GIBSON & WAGNER, 1986). The Cryptosporidium
in the
tissue sections was small, measuring 1- to 4- I'm. Diarrhea was observed in 36070and mortality was associated
with diarrhea in 11% of the animals.
Diarrhea was absent in guinea pigs that were naturally
infected with C. wrairi, although the posterior ileum was
heavily infected (VETIERLI G et al., 1971). Ultrastructural
studies revealed the intracellular nature of C. wrairi by
the way in which it penetrated the host cell (VETIERLING,
TAKEUCHI & MADDEN, 1971).
In experimental cryptosporidiosis,
when 5-day-old
guinea pigs were experimentally inoculated with pooled
caecal/colonic contents from an infected guinea pig, the
ileum was heavily infected with severe villous stunting and
fusion and infiltration of macrophages and eosinophils
into the lamina propria (ANGUS,HUTCHISON& MUNROE,
1985). The most interesting aspect of this study was that
older guinea pigs (24-day-old) became infected after exposure to contaminated environment. Even 16-week-old
21
guinea pigs were susceptible, as evidenced by organisms
in the ileum when necropsied at 8 and 12 days postinfection. The susceptibility of adult guinea pigs, in addition
to the neonates, was further substantiated in a study in
which 6-week-old guinea pigs became infected with doses
as low as 325 oocysts (CHRISP et al., 1990). The neonates
were still infected at 2 weeks postinfection, whereas the
older animals were all infected for only I week postinfection, suggesting that there may be some innate resistance
in the older animals. There were no significant differences
in morphometric measurements of the ileum between the
two age groups.
One of the most interesting and highly significant findings was the demonstration of Cryptosporidium within
the cytoplasm of M cells overlying Peyer's patches (MARCIAL & MADARA, 1986). This was the first observation
made of the real intracellular localization of Cryptosporidium. The significance of this observation is that
this may be the path for Cryptosporidium antigens to provide antigenic stimulus to the intestinal lymphoid cells.
It may also explain the difficulty encountered in
eradicating this parasite in the immunocompromised host.
Immune response
Evidence for specific immune response to Cryptosporidium was demonstrated in guinea pigs that were
completely refractory to reinfection when challenged by
reinoculation with Cryptosporidium oocysts (CHRISP et
al., 1990). No Cryptosporidium or morphological changes
were observed in the ileum at 1,2,3, or 4 weeks postinfection, despite challenge with five times the original inoculum. Since Cryptosporidium is attached to enterocytes
of the small intestine, the mucosal immune response can
be assumed to be important in resistance to reinfection
by Cryptosporidiurn as it is for other enteropathogens.
The essential component of mucosal immunity appears
to be not only the localization of Cryptosporidium in the
enterocytes, but its transport by the M cells to the intestinal immune system, as has been demonstrated by
MARCIAL & MADARA(1986).
Guinea pigs appear to be capable of mounting a
specific humoral antibody response to Cryptosporidium,
although IgG mayor may not be responsible for the protection of the animals from reinfection (CHRISP et al.,
1990). The anamnestic response in guinea pigs reinoculated at 10 weeks after the first inoculation was not marked, probably because antibody titers were still high.
The effects of hyperimmune bovine colostrum (HBC)
raised against C. parvum on oocyst shedding after infection with C. wrairi showed that incubation of sporozoites
with HBC markedly reduced shedding after intraintestinal
injection when compared to PBS and non-immune colostrum controls. However, per os administration of HBC
following oral inoculation of C. wrairi did not affect
oocyst shedding, and similarly, HBC had no effect when
administered simultaneously with inoculation of C. wriari
(HOSKINS et al., 1991).
cw. KI~I
22
Hamsters
A weaning male Golden hamster that was suffering
from proliferative ileitis was found to be naturally infected
with Cryptosporidium sp. (DAVIS& JENKI s, 1986). The
parasite, which measured only 1 to 3 /lm in diameter, was
visible along the enterocyte villous border of the intestine.
Transmission electron microscopic preparations revealed
various endogenous stages, including trophozoites, first
and second generation
schizonts,
macrogametes,
microgametes, and oocysts embedded in or lying above
the microvillous surface of enterocytes. There was loss of
microvilli that were displaced by the parasite.
Experimental
infections
The first account of experimental cryptosporidiosis in
Syrian golden hamsters was reported in neonates that were
inoculated with Cryptosporidium oocysts from calves
(KIM, 1987 a). Four- to five-day old hamster neonates
were inoculated with 1 x 103 or 3,45 X 103 oocysts and
necropsied starting at day 2 up to day 26 postinfection.
Oocyst shedding was observed as early as 2 days following inoculation, peaking at 6 days and declining thereafter.
Infection with various developmental stages in the ileum
paralleled oocyst shedding, starting at day 2 postinfection, peaking on day 8 and declining thereafter. A higher
percentage of infected animals was detected on
histological examination than on stool examination. The
histopathology consisted of displacement of microvilli by
the parasite, hypercellularity of the lamina propria, bridging of villi, and an acceleration of sloughing of senescent and presenescent epithelial cells from villous tips into
the lumen.
Oocyst shedding has been reported to be more intense
in aged (20-24 months) than in young (8- to 12-week-old)
Syrian golden hamsters following intragastric inoculation
with 106 C. parvum oocysts. Also, colonization of the
parasite was absent in the young hamsters. Moreover,
splenocytes from aged hamsters exhibited significantly
lower T, B, and natural killer cell activities than those from
young hamsters. These studies suggested that susceptibility to infection with Cryptosporidium may be greater in
the aged than had been previously realized (RASMUSSE
& HEALEY, 1992 a).
Cryptosporidiosis was established in adult female outbred white hamsters weighing 80 to 100 grams by immunosuppression with 8 to 10 mg of hydrocortisone
acetate subcutaneously (ROSSIet al., 1990). The hamsters
were then inoculated with either 0,5 x 105 or 1 X 105
oocysts. None of the hamsters manifested diarrhea but
oocyst shedding began 3 to 5 days postinfection, peaking on day 9 and decreasing thereafter followed by a lower
peak on day 13. The total number of shedding oocysts
were reported to be about a thousand times greater than
the infection dose.
Treatment
Arprinocid,
6-amino-9-(2-chloro-6-
fl uorobenzyl)
purine, an anticoccidial drug was first shown to be active against Eimeria (RUFF, ANDERSON& REID, 1978;
MILLER et al., 1977). Blockage of the hypoxantineguanine salvage pathway (WA G, SIMASHKEVICH&
STOTISH, 1979) and inhibition of the hypoxantine
transport (WA G et al., 1979) were suggested to be the
modes of action of arprinocid
in Eimeria. The
chemotherapeutic effect of arprinocid was evaluated in
5-day-old hamsters that were inoculated with 1 x 103
sporulated oocysts (KIM, 1987 b). In animals treated with
2 mg or 4 mg of arprinocid, there were significantly fewer
oocysts shed in the faeces as well as fewer developing
stages in the ileum than in the untreated animals. In
12-day-old hamsters inoculated with 2,3 x 10.1oocysts
immediately after weaning and each treated with a total
of 4 mg of arprinocid, very few oocysts were shed in the
faeces when examined 8 days postinfection, and the
developing stages in the ileum were fewer and peaked
earlier than in the untreated animals. These findings suggested that arprinocid had a parasitistatic, rather than a
parasiticidal,
effect on Cryptosporidium when administered therapeutically. Arpinocid also induced a
parasitistatic effect in adult hamsters that were immunosuppressed with dexamethasone and infected C. parVUI11 (unpublished).
When Syrian golden hamsters (20-24 months) were
treated with dehydroepiandrosterone
(DHEA), an immunomodulator
known to up-regulate
immune
parameters, there was significant reduction in oocyst shedding and colonization in the ileum than in the untreated
hamsters (RASMUSSEN& HEALEY, 1992 b). These results
suggested that DHEA may be considered an effective prophylactic agent for cryptosporidiosis, since aged hamsters
were less susceptible to cryptosporidiosis when treated
with it.
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