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Infect Immun, February 1998, p. 603-607, Vol. 66, No. 2
Departments of Pediatrics and Immunology,
University of Colorado School of Medicine, Denver,
Colorado1;
Department of Immunobiology,
Yale University, New Haven, Connecticut2; and
Department of Molecular Immunology, Research Institute for
Microbial Diseases, Osaka University, Osaka, Japan3
Mice with disrupted genes for CD40 and CD40 ligand (CD40L) are
unable to clear infection with Cryptosporidium parvum and
develop cholangitis. Parasites are present in the gut, gall bladder,
and biliary tree, and biliary epithelial cells express CD40 on the cell
surface. SCID mice infected with C. parvum for >1 month
can clear the infection after reconstitution with spleen cells from CD40, but not CD40L, knockout mice. In an in vitro model, C. parvum-infected HepG2 cells were triggered to apoptosis when
incubated with a CD40L-CD8 fusion protein. The requirement for
CD40-CD40L interactions for immunity to C. parvum indicated
by our results may entail the triggering of apoptosis in infected
cells, in addition to the known role of CD40L-CD40 interactions in
stimulating cytokine production and promoting T-cell responses.
Cryptosporidium parvum is
a highly infectious protozoan parasite responsible for
cryptosporidiosis in humans and many animals (6). C. parvum oocysts discharge sporozoites which then attach to and
replicate in the intestinal epithelium, causing changes in electrolyte
handling (8). Immunocompetent subjects experience a
transient diarrhea, while individuals with impaired immunity, such as
AIDS patients, are unable to clear the infection. The severity of the
diarrhea (14) and cholangitis (5), which C. parvum causes in immunodeficient patients, has focused increasing attention on mechanisms of cryptosporidial immunity. Immunocompetent hosts respond to infection with antibody production, and the secreted antibodies appear to reduce parasite numbers in the intestine. Nevertheless, antibodies to C. parvum do not seem to be able
to protect AIDS patients from heavy parasite burdens (6),
and it seems likely that cell-mediated immunity is important for
recovery from C. parvum infection. We recently identified
C. parvum as an important pathogen in boys with the
hyper-immunoglobulin M (hyper-IgM) syndrome (9), in which
mutations of the CD40 ligand (CD40L) gene prevent the expression of a
T-cell ligand important for T-cell immunity and for immunoglobulin
isotype switching (16).
Animal models provide the strongest evidence that cell-mediated
immunity plays a major role in recovery from C. parvum
infection. SCID and nude mice, for example, can be infected with
C. parvum with colonization of the ileum and gall bladder
(15, 20), and they are partially protected by cytokines such
as gamma interferon (IFN- Animals and infection.
The C57BL/6 CD40L knockout mice
(7) were supplied by R. Flavell, and the C57BL/6 CD40
knockout mice (12) were supplied by H. Kikutani. These and
the C57BL/6 SCID animals were bred in our specific-pathogen-free mouse
facility, were housed in microisolator cages, and received sterile
food, water, and bedding. Eight milliliters of
trimethoprim-sulfamethoxazole antibiotic solution was added to drinking
water in alternate weeks for P. carinii prophylaxis. Animals
(approximately equal numbers of males and females) were transferred to
a biohazard facility for infection with C. parvum at between
4 and 5 weeks of age, and stool specimens were collected weekly to
monitor infection status.
0019-9567/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.
Requirement for CD40-CD40 Ligand Interaction for
Elimination of Cryptosporidium parvum from Mice
ABSTRACT
Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References
INTRODUCTION
Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References
) (3) and interleukin-12 (IL-12)
(22). Although CD40L defects clearly predispose humans to
C. parvum infections and soluble CD40L can interfere with
C. parvum infection of hepatocellular cells (9),
the mechanisms for this increased susceptibility are not understood.
CD40L is a tumor necrosis factor-like molecule that is transiently
expressed on T cells after activation and which has recently been
implicated in the host defense against vaccinia virus (18),
herpes simplex virus, and Pneumocystis carinii
(26). CD40, the natural ligand of CD40L, is expressed on the
bile duct epithelial (BDE) cells, to which cryptosporidia can attach
(9). Exploration of the role of CD40-CD40L interactions in
the host defense against cryptosporidia requires an animal model, so we
tested mice with disrupted genes for CD40 and CD40L for their ability
to eliminate cryptosporidia.
MATERIALS AND METHODS
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Abstract
Introduction
Materials & Methods
Results
Discussion
References
Characterization of knockout animals. Offspring of the homozygous CD40L knockout and heterozygous CD40 knockout parents were bled once at 4 weeks. The serum was tested for IgG in a radial immunodiffusion assay (catalog no. RA272; Binding Site, Birmingham, United Kingdom) according to the manufacturer's instructions. Animals with serum IgG levels of below 15 mg/dl were verified as CD40L knockout mice on the basis of their inability to switch immunoglobulin subclasses from IgM to IgG.
Blood mononuclear cells were stained for CD40 with a fluorescein isothiocyanate (FITC) conjugate of the clone 3/23 (no. 09964D; Pharmingen, San Diego, Calif.), and likely knockout mice were identified by reduced CD40 expression. Characterization of mice as homozygous CD40 knockout mice was confirmed by PCR amplification of DNA extracted from blood by using DNAstat (Tel-Test, Friendship, Tex.). The primers and PCR conditions are described in references 7 and 12. The PCR products were resolved on a 1% agarose gel in the presence of 5 µg of ethidium bromide per ml to identify the 900-bp products in the CD40+/+ and CD40+/
mice, with a 2.1-bp
product from the neomycin cassette in the CD40/ mice.
ELISA.
Stool specimens were tested for the presence of
cryptosporidium-specific antigen (CSA) by using an enzyme-linked
immunosorbent assay (ELISA) kit (Prospect-T catalog no. 540-96;
Alexon, Sunnyvale, Calif.). Stool specimens were stored at 
70°C
until use and then thawed and resuspended by vortexing in 300 µl of
sample dilution buffer. The suspension was spun at 250 × g
for 10 min to remove solid debris, and then 200 µl of the supernatant
along with positive and negative controls supplied with the kit were
transferred to the wells of the 96-well anti-CSA ELISA plate. Plates
were incubated for 1 h at room temperature, washed, incubated for
30 min with enzyme conjugate, washed, and incubated for 10 min at room
temperature with substrate; stop buffer was then added, and results
were read on a Dynatech plate reader at 450 nm.
Tissue specimens. Livers and gall bladders were harvested from all mice, and small intestines were harvested from representative animals. Tissue for CD40 immunostaining was snap frozen in the vapor phase of liquid N2, and tissue for electron microscopy was fixed in 2.5% glutaraldehyde and postfixed in osmium tetroxide. Tissue for routine histology was fixed in 10% buffered formalin and paraffin embedded for sectioning and hematoxylin-and-eosin staining by standard methods. Representative intact gall bladders, each from a different mouse, were also preserved by each of the above-described methods.
Immunohistochemistry. Frozen sections of liver were thawed and air dried, and endogenous peroxidase was blocked with 6% H2O2 in PBS with 20% rat serum. One hundred microliters of a 1:20 dilution of rat anti-mouse CD40 (catalog no. RM6800; Caltag, San Francisco, Calif.) in PBS with 2% rat serum was added to each section and incubated at 4°C for 1 h in a humid chamber. After being washed, sections were treated with 100 µl of a 1:200 dilution of rat anti-mouse-horseradish peroxidase (cat R40007, Caltag) for 30 min at 4°C. Sections were incubated for 5 min with diaminobenzidine and then counterstained with hematoxylin. Specimens were blinded and scored as positive or negative for the presence of CD40 on BDE. Slides were viewed on a Leitz Ortholux microscope with incident UV and transmitted phase-contrast optics. Images were captured with an LG3 camera and processed with Adobe software.
TUNEL (terminal deoxynucleotidyltransferase-mediated dUTP-biotin nick end labeling) staining. HepG2 cells were cultured on glass coverslips in six-well tissue culture plates and infected with 106 C. parvum oocysts as previously described (9). The cells were then treated with culture supernatant containing CD40L fusion protein (13) for 18 h, and then cells were processed for detection of DNA fragmentation characteristic of apoptosis by using the Apotag kit (Oncor, Ltd., Gaithersburg, Md.) according to the manufacturer's instructions.
Reconstitution experiments. Donor mice were killed at 6 weeks of age by CO2 inhalation, and spleen cell suspensions were prepared at 5 × 107 cells/ml. Cells were washed and resuspended in Hanks balanced salt solution, and 5 × 106 splenocytes were injected into the peritoneal cavity of each recipient mouse. C. parvum-infected SCID recipients were infected at 4 weeks of age as described above and were used as recipients at 8 weeks, after two stool samples had tested positive for C. parvum infection by ELISA. At various intervals after reconstitution, blood of reconstituted SCID mice was stained with FITC-conjugated monoclonal antibodies to murine CD4 and CD8 (L3/T4 [Caltag catalog no. RM2401-3] and Ly 2 [Caltag catalog no. RM2204], respectively) and viewed on a Coulter Elite cytometer to confirm T-cell reconstitution.
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RESULTS |
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Abstract
Introduction
Materials & Methods
Results
Discussion
References
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Persistence of C. parvum infection in CD40 and CD40L knockout mice. The ELISA test for C. parvum antigen became positive with stool samples from all animals in the week following C. parvum infection. ELISA positivity was accompanied by the shedding of oocysts identified in stool smears by immunofluorescence microscopy and by acid-fast staining (not shown). Because the ELISA test with stool from uninfected animals was consistently negative while results from infected animals were consistently positive, we elected to use this test to monitor the course of C. parvum infection in the knockout animals. Results from the CD40 and CD40L knockout mice showed an increase in stool ELISA optical density (OD) over the first 2 weeks, with OD levels above 0.1 being maintained for 8 weeks or more (Fig. 1). Littermates with wild-type CD40 and CD40L genes also became infected as judged by their stool ELISA OD, but results of this test reverted to control values in the 4 weeks that followed infection.
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), homozygous CD40 knockout mice
(
), and wild-type B6 controls (
). 
, results for uninfected
animals. Results are the log means + 1 standard deviation for
groups of six to eight animals.
Tissue evidence for infection. The anti-CSA ELISA measures an antigen released during the course of infection but gives no indication of the location of infection or the severity of tissue damage. To address these issues, the livers, gall bladders, and intestines of infected and control mice were harvested for histology. Figure 2 shows the gall bladder wall of an uninfected control (Fig. 2a) and C. parvum associated with the gall bladder epithelium of an infected CD40L knockout mouse (Fig. 2b, arrow). The occurrence of C. parvum in the gall bladder was consistently associated with the presence of a mononuclear infiltrate in the underlying tissue. C. parvum was also seen attached to the crypts and villi of the jejenum and ileum (not shown); there was no inflammatory infiltrate in the lamina propria or muscularis coats of the bowel wall. Infection of small bile ducts within the liver was documented by electron microscopy (Fig. 2c, arrow). In the liver, C. parvum infection was associated with an inflammatory response in both the CD40 and CD40L knockout animals. We previously showed that CD40 was expressed on the BDE of boys with CD40L deficiency and cholangitis, so it was of interest to determine whether CD40 was also expressed on mouse bile ducts. The results of immunoperoxidase staining (Fig. 2d) show positive CD40 staining of a C. parvum-infected CD40L knockout animal. Portal veins (Fig. 2e) and adjacent small bile ducts were surrounded by a mixed cellular infiltrate comprising predominantly mononuclear cells but with some neutrophils. Sclerosis and obliteration of bile ducts were also seen (Fig. 2f, arrow).
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CD40L knockout effector cells fail to eliminate C. parvum from SCID mice. Adoptive transfer of spleen cells from the knockout animals into an environment containing CD40 was used to explore the role of CD40 and CD40L in the elimination of C. parvum. Thus, B6 SCID mice with intact CD40 expression were infected with C. parvum, and infection was verified by stool positivity in the ELISA test. These mice were then reconstituted with 5 × 106 spleen cells from uninfected CD40 and CD40L knockout donors. The SCID recipients of CD40 knockout T cells cleared the infection in the ensuing 7 weeks (Fig. 3), while the recipients of the CD40L knockout cells remained with positive stool ELISA tests.
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Apoptosis in C. parvum-infected cells in vitro induced by CD40L. To determine whether CD40L could interact directly with CD40 on a C. parvum-infected target cell, we used the CD40-positive cell line HepG2. We had previously determined that this line could be infected in vitro with C. parvum and that infection was reduced when a culture supernatant containing CD40L fusion protein was added (9). To determine whether apoptosis contributed to this effect, we cultured control and C. parvum-infected HepG2 cells with and without CD40L fusion protein and then stained them for DNA fragmentation by the TUNEL technique. No nuclear staining was observed in the HepG2 cells cultured with C. parvum or the CD40L fusion protein alone (not shown). Apoptotic cells were seen (Fig. 4) in cultures of HepG2 cells which were first infected with C. parvum and then exposed to CD40L for 18 h.
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DISCUSSION |
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Abstract
Introduction
Materials & Methods
Results
Discussion
References
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Our data indicate that CD40L and CD40 are necessary for mice to clear a C. parvum infection. This result is consistent with the finding that boys with CD40L deficiency, who have the hyper-IgM syndrome, are susceptible to severe and protracted cryptosporidium infections. A role for CD40-CD40L interactions in immunity to other intracellular pathogens, including Leishmania spp. (2, 11, 19) and P. carinii (26), has recently been reported, and our results indicate that C. parvum may be similarly handled. There are several mechanisms by which CD40-CD40L interactions may be required for immunity to intracellular parasites. CD40L can contribute to T-cell activation by binding to CD40 on macrophages, stimulating IL-12 production and the upregulation of costimulatory molecules such as B7 (11). CD40L might also convey an afferent signal to a T cell, allowing CD4+ cells which have bound antigen through the T-cell receptor to become more efficient helpers of B cells (23) and perhaps to advance through the activation pathway (7). An inability to make CD40L would therefore be expected to interfere with T-cell activation and hence with the clonal expansion of antigen-specific T cells (1), which is required for the expression of cell-mediated immunity. In the context of immunity to Leishmania, CD40 was important for conveying an afferent signal for macrophages that enhanced their production of IL-12 (11, 25), which in turn permitted a greater TH1 component of the T-cell response. This interpretation is consistent with our finding that spleen cells from CD40 knockout donors were able to clear C. parvum infection from SCID recipients, while they were not able to clear the infection from an environment devoid of CD40. Nevertheless, the afferent signal to T cells through CD40L is not obligatory for all T-cell-mediated responses. For example, CD40L-deficient mice are able to generate substantial CD8 and some CD4 T-cell responses to viruses such as lymphocytic choriomenigitis virus (17, 25), even though their CD4+ cells cannot receive a CD40L-mediated signal. Similarly, CD40L-deficient boys do not in general have severe herpesvirus or fungal infections (16), even though they are unable to switch the isotype of their antibody responses from IgM to IgG or IgA because they cannot make CD40L.
Another, and not necessarily exclusive, explanation for the persistence of C. parvum in CD40 and CD40L knockout mice is that C. parvum cannot be eliminated from the infected target cell unless a CD40-CD40L-mediated signal is delivered. CD40L is known to deliver effector signals to B cells, causing an isotype switch, and can also trigger an apoptotic pathway in other cells, such as fibroblasts (10). We had previously shown that inflamed human BDE expressed CD40, and in our present study we show that mouse BDE from C. parvum-infected animals is also positive for CD40. In an in vitro model we found previously that soluble CD40L sufficed to trigger DNA condensation in the CD40-positive HepG2 cell line when it was infected with C. parvum, and we have now used the more specific TUNEL technique to show that this condensation is associated with DNA fragmentation typical of apoptosis. HepG2 cells have many similarities with BDE cells (4), raising the possibility that their responses may serve as a model for the consequences of CD40L binding to CD40 on a C. parvum-infected BDE cell.
Other host defense factors thought to contribute to C. parvum immunity include IFN- and IL-12, and these cytokines are
also known to interact with the CD40-CD40L pathway. IFN-, for
example, upregulates expression of CD40 (24), among other
cell surface determinants, and IL-12 boosts the IFN- component of
T-cell responses. Treatment with IL-12 prior to infection with C. parvum prevented or greatly reduced infection in neonatal SCID and
normal mice. However, established infections were not ameliorated by
IL-12 treatment (22). CD40L induces macrophages to produce
inflammatory cytokines, including tumor necrosis factor alpha, IL-1
,
IL-6, and IL-8, many of which can affect BDE cells (24).
Given the range of T-cell interactions which can lead to the production of cytokines which might in turn regulate CD40 expression on
C. parvum-infected cells, it is not surprising that
immunity to C. parvum could fail in certain primary and
secondary immunodeficiency states.
Experimental approaches using knockout animals can simplify study design by reducing the number of variables. In the context of C. parvum infection, the CD40L knockout mice may well serve as an animal model for C. parvum infection of the biliary tree in boys with X-linked immunodeficiency with hyper-IgM syndrome. To define the role of CD40L in C. parvum immunity and to distinguish between the potential contributions of the afferent and efferent signaling pathways of CD40L, further adoptive transfer experiments are likely to be necessary.
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ACKNOWLEDGMENTS |
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We are grateful to Leslie Bloomquist for help with the histology and to Tony Valentine for help with fluorescence-activated cell sorter analysis. We thank Graham Vesey at Macquarie University for a gift of monoclonal anticryptosporidial antibodies.
This research was supported by grants from the NIAID, NIH, and from the March of Dimes.
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FOOTNOTES |
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* Corresponding author. Mailing address: B140, University of Colorado School of Medicine, 4200 East 9th Ave., Denver, CO 80262. Phone: (303) 315-7463. Fax: (303) 315-4892. E-mail: Mary.Cosyns{at}uchsc.edu.
Editor: J. M. Mansfield
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Infect Immun, February 1998, p. 603-607, Vol. 66, No. 2
0019-9567/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.
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