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Infection and Immunity, January 2007, p. 481-487, Vol. 75, No. 1
0019-9567/07/$08.00+0     doi:10.1128/IAI.01237-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

High Levels of CXCL10 Are Produced by Intestinal Epithelial Cells in AIDS Patients with Active Cryptosporidiosis but Not after Reconstitution of Immunity

Heuy-Ching Wang,¹ Sara M. Dann,¹ Pablo C. Okhuysen,² Dorothy E. Lewis,³ Cynthia L. Chappell,² Douglas G. Adler,^2, and A. Clinton White Jr.^1,3*

Infectious Disease Section, Department of Medicine,¹ Department of Immunology, Baylor College of Medicine,³ School of Public Health and School of Medicine, University of Texas Health Sciences Center, Houston, Texas²

Received 3 August 2006/ Returned for modification 16 September 2006/ Accepted 4 October 2006

	ABSTRACT

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Chemokines play key roles in attracting immune cells to sites of infections. However, few data on chemokine expression in the gut during human infections are available. We examined expression of chemokines in intestinal tissues of AIDS patients during active Cryptosporidium infection and during resolution of such an infection. The chemokines and cytokines in cell lysates from jejunal biopsy tissues were assayed by a 22-multiplex bead immunoassay. CXCL10 (IP-10) and its receptor, CXCR3, in sections were studied by immunohistochemistry. In biopsies from AIDS patients with active cryptosporidiosis, four chemokines (CXCL10, CCL11 [eotaxin], CCL5 [RANTES], and CCL2 [monocyte chemoattractant protein 1]) and three cytokines (interleukin-1 [IL-1], IL-10, and granulocyte colony-stimulating factor) were detected. The level of CXCL10 was significantly increased in AIDS patients with cryptosporidiosis compared to the level in AIDS patients without cryptosporidiosis or in normal volunteers (median in AIDS patients with cryptosporidiosis, 508 pg/mg protein, compared to 111 pg/mg and 72 pg/mg protein in AIDS patients without cryptosporidiosis and in normal volunteers, respectively [P < 0.05 and P < 0.005, respectively, as determined by a Mann-Whitney test]). The level of CXCL10 correlated with the parasite burden (as measured by the number of Cryptosporidium oocysts in the stools) and also with the IL-1 concentration (Pearson correlation values, 0.961 [P < 0.01] and 0.737 [P < 0.05]). As determined by immunohistochemistry, CXCL10 localized to epithelial cells at the site of infection. Following effective antiparasite and antiretroviral therapy, Cryptosporidium infections resolved, and the levels of CXCL10 decreased to normal levels. We hypothesized that CXCL10 plays an important role in the resolution of cryptosporidiosis by attracting immune effector cells to the site of infection. By contrast, in AIDS patients lacking effector cells, CXCL10 may contribute to the immunopathogenesis by recruiting inflammatory cells.

	INTRODUCTION

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Cryptosporidiosis is a major cause of diarrheal illness worldwide. In normal hosts, cryptosporidiosis is a self-limiting diarrheal illness (23). In immunocompromised individuals, cryptosporidiosis can lead to chronic and severe diarrhea. Cryptosporidiosis in AIDS patients is a debilitating illness that can accelerate human immunodeficiency virus (HIV) infection. Studies have revealed that AIDS patients with cryptosporidiosis have a shorter survival time than AIDS patients without cryptosporidiosis (16). Despite the prevalence and grim prognosis of cryptosporidiosis in individuals with AIDS, antiparasite therapies are effective only in the context of immune recovery.

Chemokines are small proteins that function as potent mediators of inflammation due to their ability to recruit and activate specific leukocytes. Chemokines are separated into groups based on the number and location of cysteine residues. CC chemokines contain adjacent cysteine residues, whereas the cysteine residues of CXC chemokines are separated by a single amino acid. CC chemokines, such as CCL5 (or RANTES), are key chemoattractants for lymphocytes, monocytes, and eosinophils. Most CXC chemokines (including interleukin-8 [IL-8]) contain an internal glutamate-leucine-arginine (ELR) motif, bind to a range of receptors (including CXCR1, CXCR2, etc.), and primarily attract granulocytes. The second subgroup of CXC chemokines lacks the ELR motif and binds exclusively to the receptor CXCR3. This group of chemokines includes gamma interferon (IFN-)-inducible protein 10 (CXCL10 or IP-10), monokine induced by IFN- (CXCL9 or Mig), and interferon-inducible T-cell alpha chemoattractant (CXCL11 or I-TAC). All three of these chemokines can be produced by intestinal epithelial cells and induced by IFN- treatment (3, 21). CXCR3 is expressed only on a subset of lymphocytes and monocytes, but this subset includes most intestinal T cells (18). Among T lymphocytes, CXCR3 is expressed mainly on cells that produce IFN- (24), which is a key mediator of resolution of intracellular infections, including cryptosporidiosis. Previous murine and in vitro studies of the role of chemokines in cryptosporidiosis have suggested that IL-8, RANTES, and the CXCR3 ligands are produced in response to Cryptosporidium infection (2, 12, 15, 20). The only data for human infections are data from studies of stools (1, 9). In order to elucidate the roles of chemokines in AIDS-associated cryptosporidiosis, we examined intestinal tissues for the presence of chemokines and cytokines during active Cryptosporidium infection and during resolution of such an infection. We found that CXCL10 is associated with symptomatic disease.

	MATERIALS AND METHODS

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Patients. Sixteen human subjects in Houston, TX, consented to undergo upper endoscopy with jejunal biopsies. These subjects included eight AIDS patients with chronic diarrhea and Cryptosporidium oocysts in their stools (seven African Americans [four males and three females] and one Hispanic male), five healthy volunteers (three African Americans [1 male and two females] and two Caucasians [one male and one female]), and three AIDS patients without cryptosporidiosis (all African Americans [two males and one female]). Three of the eight AIDS patients with cryptosporidiosis were biopsied again after highly active antiretroviral therapy (HAART) was started (17). Subjects were also asked to provide 24-h stool collections for oocyst quantitation. Stool samples were weighed and subsequently diluted 1:4 with 10% buffered formalin and kept at 4°C until assays were performed. Jejunal biopsy specimens were fixed with formalin or embedded in optimal-cutting-temperature (OCT) compound and snap frozen in liquid nitrogen.

Tissue lysate extracts. Protein extracts were prepared from jejunal biopsies embedded in OCT compound by washing them twice with a phosphate-buffered saline lysis buffer containing 0.05% NaN₃, 0.5% Triton X-100, 1 mM phenylmethylsulfonyl fluoride, and protease inhibitors (Complete Mini protease inhibitor cocktail; Roche Diagnostics, Indianapolis, IN). After OCT compound removal, the tissues were minced in 1 ml of lysis buffer with a sterile disposable homogenizer on ice for 5 min. The homogenates from the tissues were then sonicated for 1 min on ice. After centrifugation at 10,000 x g for 15 min, the supernatant was collected and stored at –80°C or immediately assayed to determine the protein concentration with a bicinchoninic acid protein assay kit (Pierce, Rockford, IL).

Multiplex bead assay. The levels of cytokines and chemokines were determined in lysate extracts from jejunal biopsy specimens in duplicate using a multiplex bead assay (human cytokine multiplex kit; LINCO Research, Inc., St. Charles, MO) that simultaneously quantifies 22 human cytokines and chemokines, including IL-1ß, IL-2, IL-4, IL-5, IL-6, IL-7, IL-8, IL-10, IL-12(p70), IL-13, IL-15, IL-17, IL-1, IFN-, granulocyte colony-stimulating factor, granulocyte-macrophage colony-stimulating factor, tumor necrosis factor alpha (TNF-), CCL11/eotaxin, CCL2/monocyte chemoattractant protein 1, CCL3/MIP-1, CXCL10/IP-10, and CCL5/RANTES. Briefly, aliquots of the lysates were added to individual wells of a microtiter plate. An antibody-immobilized bead cocktail was then added to each well, vortexed, and incubated for 1 h at 25°C. Detection was performed by adding a detection antibody cocktail and then streptavidin-phycoerythrin to each well. The wells were washed, and the beads were resuspended in sheath fluid. The beads from each well were read with a Luminex 100 machine (Luminex Corporation, Austin, TX). The detection range for the LINCOplex assay is reported to be 3.2 to 10,000 pg of cytokine/ml, but this was not standardized with tissue specimens. The results for all cytokines are expressed below in pg of cytokine/mg of protein.

Quantitative immunofluorescence assay. All stools collected were examined for the presence of Cryptosporidium, and oocysts were quantitated by a direct immunofluorescence assay as described previously (6). Briefly, a preserved sample was agitated until complete suspension was achieved. A 5-µl aliquot was removed, placed in a defined area of a glass slide, and allowed to air dry. The slide was incubated with a fluorescein isothiocyanate-labeled monoclonal antibody to Cryptosporidium oocysts (Merifluor Cryptosporidium kit; Meridian Bioscience Inc., Cincinnati, OH). Positive and negative controls were included with each assay. Oocysts in 10x40 fields were counted by fluorescence microscopy. The number of oocysts per milliliter of stool was calculated from the mean of triplicate assays. The fecal oocyst excretion for each patient was expressed as the mean concentration of oocysts in all stools collected over 24 h.

Immunohistochemistry. Paraffin-embedded jejunal biopsy sections (5 µm) were dewaxed in xylene and rehydrated by sequential passage through a graded alcohol series into distilled water. Heat-induced antigen retrieval was performed by boiling sections in 0.01 M citrate buffer at pH 6.0 in a microwave oven for a total of 15 min. Nonspecific binding sites were blocked with 4% normal horse serum-phosphate-buffered saline. Immunostaining was performed using a Vectastain Elite ABC universal kit (Vector Labs, Burlingame, CA). Briefly, sections were incubated with anti-CXCR3 (R&D Systems, Minneapolis, MN) or anti-CXCL10/IP-10 (PeproTech, Inc., Rocky Hill, NJ) and then with biotinylated secondary antibody. After washing, sections were incubated with streptavidin-biotin complex-coupled peroxidase for 30 min. Immunostained sections were developed with AEC (red) or DAB (brown) (Vector Labs) and counterstained with hematoxylin (Vector Labs).

Statistical analysis. The analytic procedures were performed using the Mann-Whitney test for nonparametric data. Correlation coefficients were calculated by using Pearson's correlation. A P value of <0.05 was considered statistically significant. The statistical analysis was performed using the MINITAB software program (Minitab, Inc., State College, PA).

	RESULTS

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Level of CXCL10 is increased in the jejunum of AIDS patients with cryptosporidiosis. We assessed 22 chemokine and cytokine levels in the jejunal biopsy lysates from eight AIDS patients with chronic diarrhea and detectable Cryptosporidium, five healthy volunteers, and three AIDS patients without cryptosporidiosis. Of the 22 chemokines and cytokines, only 4 chemokines (CCL11, CCL2, CXCL10, and CCL5) and 3 cytokines (IL-10, IL-1, and granulocyte colony-stimulating factor) were detected in jejunal biopsies from AIDS patients with active cryptosporidiosis (Table 1). The CXCL10 and IL-1 concentrations were significantly increased in AIDS patients with cryptosporidiosis compared to the concentrations in normal volunteers without cryptosporidiosis, and the median increases in the levels of CXCL10 and IL-1 were 7.06- and 4.94-fold, respectively (Table 2 and Fig. 1) (P < 0.005, as determined by a Mann-Whitney test). In addition, the level of mucosal CCL11 was 3.21-fold higher in jejunal tissues from AIDS patients with cryptosporidiosis (Table 2 and Fig. 1) (P < 0.05, as determined by a Mann-Whitney test). Interestingly, the CXCL10 concentrations for AIDS patients with cryptosporidiosis were significantly higher than the levels for AIDS-only controls (Table 2 and Fig. 1) (P < 0.05, as determined by a Mann-Whitney test). The concentration of CXCL10 for control patients with AIDS was also increased compared with the concentration for normal healthy volunteers (Table 2 and Fig. 1) (P < 0.05, as determined by a Mann-Whitney test). The concentration of IL-1 for AIDS patients with cryptosporidiosis was significantly elevated compared with the concentration for normal volunteers (Table 2 and Fig. 1) (P < 0.05, as determined by a Mann-Whitney test). However, the level of IL-1 was also increased in tissues from AIDS-only controls. The levels of CCL11 in tissues from AIDS patients with cryptosporidiosis were significantly increased compared to the levels for normal controls (Table 2 and Fig. 1) (P < 0.05, as determined by a Mann-Whitney test). However, the CCL11 concentrations were variable in the AIDS-only controls, and, perhaps due to the small numbers, the concentrations in patients with AIDS and cryptosporidiosis were not significantly different from the concentrations in the AIDS-only controls (Table 2, Fig. 1).

View larger version (20K): [in this window] [in a new window]   FIG. 1. CXCL10 (A), IL-1 (B), and CCL11 (C) levels in jejunal biopsies from patients with AIDS-associated cryptosporidiosis (AIDS/crypto), AIDS-only patients, and normal volunteers. The horizontal lines indicate mean values for the groups. NS, not significant.

CXCL10 concentrations correlate with IL-1 concentrations in biopsies from patients with AIDS-related intestinal cryptosporidiosis.

View larger version (12K): [in this window] [in a new window]   FIG. 2. Correlation between the production of CXCL10 and the production of IL-1 in the jejunal biopsies from patients with AIDS-associated cryptosporidiosis (Pearson correlation value, 0.737 [P < 0.05]).

View larger version (9K): [in this window] [in a new window]   FIG. 3. Correlation between the level of CXCL10/IP-10 in jejunal biopsies and the log number of Cryptosporidium oocysts in the stools from patients with cryptosporidiosis-associated AIDS (Pearson correlation value, 0.961 [P < 0.01]).

View larger version (103K): [in this window] [in a new window]   FIG. 4. CXCL10 expression in intestinal epithelial cells in patients with AIDS-associated cryptosporidiosis. Sections of jejunal biopsies from patients with AIDS-associated cryptosporidiosis, AIDS-only patients, and normal volunteers were examined by using immunohistochemistry. The sections are representative sections stained with antibody to CXCL10 (brown) or CXCR3 (red) and counterstained with hematoxylin. (A, B, C, E, and F) Magnification, x200. The arrows in panel D (magnification, x400) indicate Cryptosporidium on the epithelial cells.

View larger version (21K): [in this window] [in a new window]   FIG. 5. Mucosal levels of CXCL10 (A), IL-1 (B), and CCL11 (C) in patients with AIDS-associated cryptosporidiosis before HAART () and during HAART () and in normal healthy volunteers (). The brackets indicate significance for a comparison between patients with AIDS-associated cryptosporidiosis before HAART and healthy volunteers (P < 0.05, as determined by a Mann-Whitney test).

	DISCUSSION

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Lacroix-Lamande and colleagues previously observed expression of CXCL9, CXCL10, and CXCL11 in murine tissues and epithelial cell lines in response to Cryptosporidium infection (10). These authors proposed that these chemokines attract CXCR3-positive cells to the site of infection. The CXCR3-positive cells then produce IFN-, which in turn mediates parasite clearance. Lacroix-Lamande and colleagues noted that expression of CXCL10 in mice with cryptosporidiosis was enhanced by IFN- but could be induced directly by infection of epithelial cells (3, 10, 21). In AIDS patients, the depletion of effector T cells may lead to increased numbers of parasites. Since infection of epithelial cells can directly stimulate release of CXCL10, the heavy infection could cause exaggerated production of CXCL10. Indeed, we noted a correlation between parasite burden and CXCL10 production. In previous studies whose results were confirmed here, we noted the absence of IFN- in intestinal biopsies of AIDS patients with cryptosporidiosis (22). Thus, the heavy parasite burden may have directly induced production of CXCL10 without a requirement for IFN-. Successful antiretroviral therapy restores the number of CD4 cells in intestinal tissues (5, 19). This may lead to Cryptosporidium clearance, which in turn results in a decrease in production of CXCL10 by enterocytes, as was noted in treated patients. The decrease in the level of CXCL10 might also reduce the inflammatory responses in intestinal mucosa and lead to amelioration of the chronic diarrhea.

In vitro and animal studies showed that Cryptosporidium infection is characterized by production of other chemokines, including IL-8 and RANTES, and proinflammatory cytokines, such as TNF- (2, 12, 15, 20). However, mediators such as IL-8 and TNF- were not found consistently, and when they were found, only low levels were detected in stools of children with cryptosporidiosis in Brazil and Haiti (1, 9). In the current study, we did not detect IL-8. The previous human studies were performed with children who were presumably not infected with HIV. If the levels were even modestly lower in patients with HIV or in adults, IL-8 may not have been detected. Negative results could have been due to problems with the assay sensitivity when tissue homogenates were used. However, studies of the histopathology of the intestines of patients with AIDS-associated cryptosporidiosis revealed increased numbers of lymphocytes and plasma cells but not increased numbers of neutrophils or eosinophils unless there was a coexisting cytomegalovirus infection (4, 14). Similarly, the biopsies studied here also did not reveal increased numbers of neutrophils. Thus, the histopathology is not consistent with a prominent role for IL-8 in this infection, whereas our data showing increased mucosal CXCL10 levels are consistent with the histopathology. We also detected RANTES in our patients. However, the levels were similar to those in the controls.

We noted increased expression of the eosinophil chemoattractant CCL11 (eotaxin) in our AIDS patients with cryptosporidiosis. This contrasts with the lack of tissue eosinophilia. CXCL10 has been shown to antagonize CCL11 function (13) and may have done this in the present study.

The CXCL10 expression noted may have adverse effects. For example, CXCL10 increases the rate of HIV replication in cultured infected cells (11). Epidemiologic data have shown that there is acceleration of disease in HIV patients with cryptosporidiosis. This observation may be explained in part by the increase in the CXCL10-dependent influx of lymphocytes and macrophages into the intestinal lamina propria and the intraepithelial compartment, which might facilitate HIV infection and T-cell destruction. The gut, in turn, is now recognized as the major site of lymphocyte depletion in HIV patients (8).

We propose the following model of HIV and Cryptosporidium coinfection. First, the depletion of CD4 T cells in AIDS patients leads to an increased parasite burden in the gut. The increased parasite burden in turn induces CXCL10 expression by epithelial cells. In normal hosts, CXCL10 may recruit CXCR3-positive effector cells, which eliminate the parasite-infected cells and control the parasite burden. By contrast, the few CXCR3 cells in AIDS patients are unable to eliminate the parasite but instead are themselves targets for HIV infection or activation-induced destruction. CXCL10 may also recruit inflammatory cells and stimulate IL-1 production. The latter might worsen intestinal dysfunction. We believe that these findings highlight the double edge of the immune response in cryptosporidiosis, which can be both curative and part of the pathogenesis.

	ACKNOWLEDGMENTS

 
This work was supported by the National Institutes of Health (grant R01 AI041735 to A.C.W.), the Baylor UT Houston Center for AIDS Research (grant P30 AI36211), the Texas Gulf Coast Digestive Diseases Center (grant P30 DK056338), and the UTHHSC GCRC (grant M01-RR 02558). This study was also supported by the National Center for Environmental Research STAR Program of the Environmental Protection Agency (grant GR828035-01-0 to C.L.C.) and the U.S. Food and Drug Administration (grant FD-U-001621-01 to P.C.O.).

	FOOTNOTES

 
* Corresponding author. Mailing address: Infectious Disease Section, Department of Medicine, Baylor College of Medicine, One Baylor Plaza, 525D, Houston, TX 77030. Phone: (713) 798-6846. Fax: (713) 790-0681. E-mail: arthurw{at}bcm.tmc.edu.

Published ahead of print on 16 October 2006.

Editor: W. A. Petri, Jr.

Present address: Division of Gastroenterology, University of Utah, Salt Lake City, UT.

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This Article Abstract Full Text (PDF) Other Versions of this Article: IAI.01237-06v1 75/1/481    most recent Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Reprints and Permissions Copyright Information Books from ASM Press MicrobeWorld Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Wang, H.-C. Articles by White, A. C. Search for Related Content PubMed PubMed Citation Articles by Wang, H.-C. Articles by White, A. C., Jr.