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Infect Immun. Oct 2006; 74(10): 5926–5932.
PMCID: PMC1594938

Infection with Syphacia obvelata (Pinworm) Induces Protective Th2 Immune Responses and Influences Ovalbumin-Induced Allergic Reactions

Abstract

Infections with pinworms are common in rodent animal facilities. In this study, we show the consequence of an outbreak in a transgenic barrier facility of infection by Syphacia obvelata, a murine pinworm gastrointestinal nematode. Immune responses were defined in experimental infection studies with BALB/c mice. Infection with S. obvelata induced a transient Th2-type immune response with elevated interleukin 4 (IL-4), IL-5, and IL-13 cytokine production and parasite-specific immunoglobulin G1 (IgG1). In contrast, BALB/c mice deficient in IL-13, IL-4/13, or the IL-4 receptor alpha chain showed chronic disease, with a >100-fold higher parasite burden, increased gamma interferon production, parasite-specific IgG2b, and a default Th2 response. Interestingly, infected IL-4−/− BALB/c mice showed only slightly elevated parasite burdens compared to the control mice, suggesting that IL-13 plays the dominant role in the control of S. obvelata. The influence that pinworm infection has on the allergic response to a dietary antigen was found to be important. Helminth-infected mice immunized against ovalbumin (Ova) elicited more severe anaphylactic shock with reduced Ova-specific IL-4 and IL-5 than did noninfected controls, demonstrating that S. obvelata infection is able to influence nonrelated laboratory experiments. The latter outcome highlights the importance of maintaining mice for use as experimental models under pinworm-free conditions.

Pinworms of the order Oxyurina (Syphacia muris, Syphacia obvelata, and Aspiculuris tetraptera) are commonly found in laboratory animals. The direct transmission of these gastrointestinal (GI) nematodes by contaminated food, water, and bedding results in continual reexposure to the parasite, making the control of pinworms in animal holdings quite difficult (57). In particular, the conventionally used cellophane tape method to examine eggs is rather inaccurate and insensitive, at least in our hands (data not shown). S. obvelata, a mouse pinworm, inhabits the cecum of the host, where the female matures within 11 to 15 days. Gravid females deposit an average of 350 eggs at the perianal region, which develop into infective third-stage larvae within 20 to 24 h (8). Initially thought to be nonpathogenic (21, 22, 57), pinworm infection has been associated with rectal prolapse, mucoid enteritis, and intestinal impaction/intussusception (17, 22, 29). The gut-dwelling nematode has been shown to alter the humoral immune response to nonparasitic antigenic stimuli (50) and to influence the susceptibility of mice to other intestinal nematodes (31). More recently, mice infected with pinworms were demonstrated to terminate self-tolerance and to enhance neonatal induction of a Th2-associated autoimmune disease and T-cell memory (1).

Although little is known on pinworm immunity, extensive research on the immune responses elicited toward other intestinal parasites, such as Nippostrongylus brasiliensis, Trichuris muris, and Trichinella spiralis, has been well documented, with the most informative finding being the Th2-type immune response needed to mediate resistance and worm expulsion (19, 58, 60). The Th2 cytokines interleukin 4 (IL-4) and IL-13 are critical for host defense against nematode parasites (2). These two cytokines share several common biological properties with functional overlaps and discrete functions. This can be explained partially by both receptors sharing the IL-4 receptor alpha (IL-4Rα) chain (64). IL-4 is able to signal via the type 1 IL-4 receptor, a heterodimer between the IL-4Rα chain and the common gamma (γc) chain, as well as via the type 2 receptor, a heterodimer between the IL-4Rα chain and the IL-13 receptor alpha 1 (IL-13Rα1) chain. The type 2 receptor is the only functional receptor for IL-13 (6). IL-4Rα responsiveness is required for protective immunity against some gut-dwelling worm infections, such as those with N. brasiliensis, T. spiralis (16), and T. muris (12). Furthermore, expression of IL-4Rα on non-bone-marrow-derived cells, such as intestinal epithelial cells, goblet cells, and smooth muscle cells, is sufficient to expel N. brasiliensis, whereas T. spiralis expulsion requires IL-4Rα responsiveness on both bone marrow-derived cells (T cells and mast cells) and non-bone-marrow-derived cells (59).

In this study, we present the immune response elicited to a pinworm infection and demonstrate that IL-13 is the dominant cytokine required for the expulsion of S. obvelata. S. obvelata infection in BALB/c mice induced a protective response with elevated Th2 cytokines and specific immunoglobulin G1 (IgG1). Furthermore, we show that mice infected with S. obvelata have more severe anaphylactic reactions and reduced cytokine responses in a well-established allergy (ovalbumin [Ova]) model. The latter highlights the importance of maintaining mice under pinworm-free conditions.

MATERIALS AND METHODS

Mice.

Gamma interferon receptor-deficient (IFN-γR−/−) (25) and IL-12p40−/− (39) mice were generated in a 129/Sv/Ev background. IL-12p40−/− mice were backcrossed five times to C57BL/6 mice. IL-4−/− (48), IL-13−/− (42), IL-4/13−/− (43), and IL-4Rα−/− (47) mice were generated in a BALB/c background. All mice were kept at the animal facility at the Health Science Faculty, University of Cape Town (UCT), under specific-pathogen-free (SPF) conditions. In addition, mice were tested serologically for pinworm-specific IgG antibody prior to experiments. Eight- to 12-week-old mice were used for experiments performed in accordance with the guidelines of the Animal Ethics Research Board of UCT (Cape Town, South Africa).

Parasites and infection.

Infection and recovery of S. obvelata were done as described previously (56), with modifications. Briefly, eggs of S. obvelata used for infection were collected from the ceca of naturally infected mice (IL-13−/−, IL-4/13−/−, and IL-4Rα−/−) maintained in barrier facilities. The ceca were collected in 0.65% NaCl, sliced open, and submerged in a gauze mesh at the mouth of a conical flask for 1 to 2 h at 37°C to allow the worms to migrate out. Worm burdens were assessed on various days postinfection. After being washed (0.65% NaCl), worms were crushed and their eggs isolated by passage through 70-μm nylon cell strainers (BD Falcon, BD Biosciences, Belgium). Each mouse was inoculated orally with 500 eggs via a stomach tube.

Antigen.

A modified protocol for antigen preparation was used (55). Briefly, collected adult worms were separated from debris in a 40% Percoll (Sigma) column (1,500 rpm, 10 min). Recovered worms (pelleted with distilled H2O) were sonicated with 10% proteinase inhibitor (Sigma) at 19 watts (root mean square; Microsoni) on ice. Sonicated worms were centrifuged at 1,500 rpm for 10 min, and the resultant supernatant was filtered through a 0.2-μm acetate syringe filter (Schleicher and Schuell Microscience, Germany). The filtered protein was dialyzed (Spectrapor) overnight in a cold room (4°C), and the concentration was determined using a bicinchoninic acid kit (61). Samples were stored at −80°C until use.

Cell isolation and stimulation.

Spleens and mesenteric lymph nodes (MLN) were harvested, and single-cell suspensions were resuspended in Iscove's modified Dulbecco's medium supplemented with 10% heat-inactivated fetal calf serum, 2 mM l-glutamine, 100 U/ml penicillin, and 100 μg/ml streptomycin (Gibco, Life Technologies). Cells (2 × 106) were cultured at 37°C in 5% CO2 in flat-bottomed 48-well plates (Corning Inc.). Cells were stimulated with 20 μg/ml anti-CD3 (145-2c 11) and 50 μg/ml concanavalin A (Sigma-Aldrich, Germany). Cell-free supernatants were harvested after 96 h and stored at −80°C.

Antibody ELISA.

Analysis of antigen-specific IgG1, IgG2b, and IgE production was carried out by capture-enzyme-linked immunosorbent assay (ELISA). In brief, Nunc Immuno plates (Nunc, Denmark) were coated with S. obvelata antigen or ovalbumin (5 μg/ml) in carbonate-bicarbonate buffer, pH 9.6, overnight at 4°C. After blocking of the plates (2% milk powder in phosphate-buffered saline [PBS], 0.02% NaN3), three serial 10-fold dilutions of sera were added to the plates. Parasite-specific antibodies were detected using alkaline phosphatase-conjugated goat anti-IgG1 (B020-NK20), goat anti-IgG2b (F659-UF89), and rat anti-IgE (23G3) (all from Southern Biotechnology Associates). Total IgE was determined with monoclonal antibodies 84.1C and alkaline phosphatase-conjugated rat anti-IgE (23G3) for detection. Ova-specific IgE was used at 1 mg/ml.

Cytokine-specific ELISA.

Cytokine concentrations were determined by sandwich ELISA. Standards and antibodies were purchased from Pharmingen and detected using alkaline phosphatase-coupled streptavidin (Southern Biotechnology). Detection limits were as follows: for IFN-γ and IL-13, 46 pg/ml; for IL-4, 2 pg/ml; and for IL-5, 38 pg/ml (47).

Temperature.

Rectal temperatures were measured with a digital thermocouple thermometer (model BAT-12; Physitery Instruments Inc.) immediately after challenge, every 5 min for 10 min, and then every 10 min for the next 50 min. At the same time, mouse activity was assessed.

Immunization.

A modified immunization protocol was used (20). Pinworm-infected and noninfected mice were immunized intraperitoneally on days 14 and 21 with 50 μg grade V chicken egg Ova (Sigma-Aldrich) and 1.3% aluminum hydroxide (Imject alum; Pierce) suspended in PBS to a total volume of 200 μl. Nonimmunized control mice received only PBS plus alum.

Statistics.

Data are given as means ± standard deviations (SD), and the differences were tested using unpaired Student's t test or analysis of variance.

RESULTS

Outbreak of S. obvelata infection in an animal facility.

An outbreak of the GI nematode pinworm (S. obvelata) resulted in various degrees of acute and chronic infection in one of our SPF animal facilities. All mouse strains housed and maintained in the contaminated facility were infected. Counting of worms in the ceca of mice revealed that inbred strains BALB/c and C57BL/6 had relatively small burdens, with <50 worms isolated per mouse (Fig. (Fig.1).1). No worms were observed in 129/Sv wild-type mice, despite the presence of pinworm-specific antisera, which may indicate increased resistance in this mouse strain. Small worm burdens in type 1 cytokine-deficient mice (IL-12p40−/− and IFN-γR−/−) were also observed. In contrast, mice deficient in type 2 responses showed up to 20-fold increased worm burdens compared to those in wild-type controls. However, mice deficient in IL-13 showed significantly larger worm infestations than did IL-4−/− mice. Mice deficient in both IL-4 and IL-13 or in IL-4Rα revealed similarly large parasite burdens to those observed in IL-13-deficient mice. Together, these results indicate that the type 2 cytokines IL-4 and IL-13, but not the type 1 cytokines IFN-γ and IL-12, are involved in protection against S. obvelata infection. The results further indicate that IL-13 plays a more dominant role in host protection than does IL-4.

FIG. 1.
Syphacia obvelata susceptibilities of naturally infected mice maintained in a conventional animal facility. Results are expressed as numbers of worms found in the ceca. *, P < 0.05; **, P < 0.01 (significantly different ...

IL-4Rα signaling is essential for controlling pinworm infection.

An experimental S. obvelata model was established for further investigation. Pinworm-free BALB/c and IL-4Rα−/− mice were infected orally with 500 S. obvelata eggs and analyzed at different times postinfection (Fig. (Fig.2).2). After 3 weeks of infection, the first few worms were found in the ceca of infected BALB/c mice. Although these mice could control the infection, an average of 22 worms at 5 weeks postinfection were isolated, possibly due to subsequent reinfection, as a full life cycle requires 11 to 15 days (2). Infected IL-4Rα−/− mice were highly susceptible, with early (at 2 weeks postinfection) and markedly larger worm loads than those in the wild-type controls (Fig. (Fig.2).2). These results suggest that IL-4Rα responsiveness effectively induced host protection against S. obvelata infection.

FIG. 2.
Worm burdens in an experimental infection model. Mice orally inoculated with 500 S. obvelata eggs were monitored weekly for worm burdens. *, P < 0.05 (significantly different from BALB/c mice). Data for one representative of two experiments ...

Endogenous IL-13 but not IL-4 is crucial for worm expulsion.

To dissect the roles of IL-4 and IL-13 in host protective responses, IL-4−/−, IL-13−/−, IL-4/13−/−, and IL-4Rα−/− mice were infected orally with 500 S. obvelata eggs and analyzed at day 35 postinfection (Fig. (Fig.3).3). IL-13−/− mice, IL-4Rα−/− mice, and IL-4/IL-13 doubly deficient mice all had >100-fold larger worm burdens than did BALB/c controls. In contrast, IL-4−/− mice controlled the infection, with strikingly smaller worm burdens than those for other mutant mouse strains. Together, these results strongly suggest that IL-13 plays the major role in host protective responses leading to worm expulsion.

FIG. 3.
IL-4- and IL-13-mediated functions induce protective immunity to S. obvelata. BALB/c, IL-4−/−, IL-13−/−, IL-4/13−/−, and IL-4Rα−/− mice were infected orally with 500 S. obvelata eggs ...

S. obvelata infection induces a transient Th2-type immune response.

To determine the cytokine response elicited by S. obvelata, mice were sacrificed at different times postinfection, and their MLN and spleens were isolated. Anti-CD3-restimulated splenic T cells from infected BALB/c mice showed a transient cytokine response at day 7 postinfection, which declined significantly thereafter (Fig. (Fig.4).4). Both the Th1 cytokine IFN-γ and the Th2 cytokines IL-4, IL-5, and IL-13 were produced, with the last two present at >5 and 10 times higher concentrations, respectively, than that of IL-4. Infected IL-4Rα−/− splenic T cells showed a similar and transient IFN-γ response but an impaired Th2 response, with low IL-4, IL-5, and IL-13 production. A similar trend was also observed for restimulated MLN cells; however, the overall cytokine production was lower than that in the spleen (data not shown). The observed Th2 cytokine response was concomitant with a dominant type 2 antibody response, as determined by end-point dilution. S. obvelata-specific IgG1 (Fig. (Fig.5A)5A) showed a greater increase in antibody titer than did specific IgG2b (Fig. (Fig.5B)5B) compared to those in naïve controls. Total IgE antibody production was not influenced by the infection (Fig. (Fig.5C),5C), and specific IgE was low or undetectable (data not shown). In contrast, infected IL-4Rα−/− mice showed a shift towards type 1 antibody responses with impaired type 2 responses (Fig. 5A and C). Together, the data suggest that S. obvelata infection induces a predominantly Th2 immune response.

FIG. 4.
Immune responses to S. obvelata in BALB/c and IL-4Rα−/− mice. (A) IFN-γ, (B) IL-4, (C) IL-5, and (D) IL-13 production by anti-CD3-stimulated splenocytes was measured for S. obvelata-infected BALB/c and IL-4Rα−/− ...
FIG. 5.
S. obvelata-specific IgG1 (A) and IgG2b (B) levels. Sera collected from infected and noninfected mice were analyzed by ELISA on days 0 and 35. Results are expressed as means of optical densities at 405/492 nm (OD405/492). Data for one representative of ...

Pinworm infection has an influence on Ova-induced allergic reactions.

A pinworm outbreak within one of the SPF animal facilities coincided with some irregularities in mouse experiments, including ovalbumin (Ova)-induced responses. In order to experimentally investigate whether pinworm infection influences experiments, S. obvelata-infected and noninfected BALB/c mice were immunized intraperitoneally on days 14 and 21 postinfection with 50 μg Ova in alum. Intravenous challenge with 500 μg Ova on day 28 postinfection induced anaphylactic reactions, with marked temperature drops and some mortality, in mice (Fig. (Fig.6A).6A). This phenotype was more pronounced for S. obvelata-infected mice, with a consistent trend of greater temperature declines than those in noninfected, Ova-immunized mice. Spleen cells restimulated with Ova antigen in vitro resulted in IFN-γ, IL-4, IL-5, and IL-13 production. However, there were noticeable reductions in Ova-specific Th2 cytokines (IL-4 and IL-5) in mice infected with pinworm 14 days prior to being immunized (Fig. (Fig.5B).5B). Together, these data suggest that S. obvelata infection influences Ova-induced allergic reactions.

FIG. 6.
S. obvelata influences Ova-induced allergic reactions. (A) S. obvelata enhances hypothermia during Ova-induced anaphylaxis. Pinworm-infected mice immunized with ovalbumin demonstrated marked decreases in body temperature when challenged intravenously ...

DISCUSSION

Experimental murine models are highly informative in providing an understanding of the factors contributing to resistance or susceptibility to diseases in both humans and domesticated animals (19). However, the importance of sterility in housing and transporting laboratory animals is sometimes underestimated, potentially increasing mouse vulnerability to adventitious pathogens (49). In this study, we demonstrated the consequence of an outbreak in a transgenic mouse facility of infection with a common, highly contagious, rapidly spreading mouse nematode parasite, the pinworm (S. obvelata). Several gene-deficient mouse strains became severely and chronically infected. We defined S. obvelata-induced host immune responses and showed evidence for protective type 2 responses, with IL-13 (but not IL-4) being essential for resistance and parasite control. Furthermore, we provided experimental data demonstrating that S. obvelata infection can alter the outcome of an unrelated experiment, i.e., ovalbumin-induced allergic reactions.

The degree of infection with S. obvelata seems to depend on the mouse strain involved. Several inbred mouse strains (BALB/c, C57BL/6, and 129/Sv) and mice deficient in type 1 cytokines (IFN-γR−/− and IL-12p40−/−) were able to expel the worm, with small parasite burdens during infection. In contrast, mice deficient in the IL-4Rα chain, which is commonly used by the IL-4 and IL-13 receptors (15), became severely and chronically infected, harboring approximately 1,000 or more cecum-dwelling worms. Resistance was mainly mediated by IL-13, as mice deficient in this cytokine but not in IL-4 were highly susceptible, comparable to IL-4Rα-deficient or IL-4/IL-13 doubly deficient mice. A similar IL-4-independent but IL-13-dependent role has been documented for N. brasiliensis infection (38, 51) and highlights the important role of IL-13 in nematode infection. However, we cannot exclude the possibility that additional mechanisms contribute to the relative resistance of mice devoid of IL-4. Nevertheless, IL-4−/− mice are susceptible to infection, as demonstrated by their larger parasite burdens than those of BALB/c mice during natural infection (Fig. (Fig.1).1). Our results demonstrate that these mutant mice are prone to reinfection.

Further studies revealed that S. obvelata infection induces a transient Th2-type response, leading to a dominant type 2 cytokine-accompanied antigen-specific B-cell response with high antigen-specific IgG1 antibody titers. As expected from studies of previous helminth infections, the observed Th2 responses were IL-4Rα dependent, as mice deficient in the alpha chain were impaired, with a shift towards Th1 responses. Residual IL-4Rα-independent Th2 responses were seen, as previously published for other systems (5, 9, 46, 52).

In contrast to some other nematode infections, primary S. obvelata infection did not induce an increase in IgE and induced only poor antigen-specific IgE responses, at least for mice infected with 500 eggs. We found, however, some elevated polyclonal IgE production during continuous reinfection (data not shown). In contrast to N. brasiliensis, where as few as six infective larvae are able to induce an IL-4 response in the draining mesenteric lymph (36), S. obvelata induced only a very low response in the draining MLN (unpublished data), despite infection with 500 eggs. Also, anti-CD3-restimulated spleen cells had modest IL-4 production, while IL-5 and IL-13 were strongly induced (Fig. 4C and D). Since IL-4 mediates IgE isotype switching (14), the observed low level of IL-4 production may explain the moderate influence of the worm on the total IgE response.

Three common effector mechanisms, namely, eosinophilia, mastocytosis, and goblet cell hyperplasia, are characteristic features of infections with GI helminths. Their individual roles in the expulsion of parasites have been investigated intensively, yet their induction of protection still remains debatable. Studies showing a correlation between effector responses and parasite expulsion include those with Strongyloides venezuelensis and Trichinella spiralis, which are susceptible to the inhospitable environment created by mast cells. Similarly, eosinophils known for releasing potent cytotoxic and proinflammatory mediators have been demonstrated to protect against repeated exposure to GI parasites, such as T. spiralis. Goblet cell hyperplasia is associated with worm expulsion of Strongyloides ratti (7), Trichuris muris (11), and T. spiralis (18, 26), with N. brasiliensis (32, 44, 45) being the most efficient example, as it is vulnerable to both the goblet cell hyperplastic response and a qualitative change in mucin glycoproteins (34). In our study, mice infected with S. obvelata elicited no significant eosinophilia, mastocytosis, and/or goblet cell hyperplasia to suggest that any of these responses contributed to the expulsion of the nematode. Although the isolated roles of these immunological effector mechanisms were observed to be ineffective, when acting together they may expel pinworms.

In a study of autoimmune ovarian disease, an unusual antigen-specific Th2 response was observed, which was later associated with the discovery of Syphacia obvelata in mouse colonies. With this disease model, it was shown that pinworm infection modulates the neonatal response to a self peptide, resulting in a Th2 response with severe eosinophilic autoimmune ovarian disease (1). We thus investigated whether Syphacia obvelata infection could explain the discrepancies in our allergy studies. The possibility was confirmed, as BALB/c mice infected with S. obvelata responded with a more severe phenotype of experimentally induced anaphylaxis than that of sham-infected controls. Moreover, S. obvelata-infected mice concomitantly immunized with Ova-alum elicited lower levels of Ova-specific IL-4 and IL-5 during in vitro restimulation. Itami and colleagues (28) have similarly demonstrated the suppression of Th2 cytokines (IL-4 and IL-5) in an asthma model. In their study, a modulatory protein isolated from Ascaris suum (PAS-1) was shown to suppress eosinophilic airway inflammation and hyperresponsiveness and to inhibit cytokine release. These effects were attributed to the presence of the regulatory cytokine IL-10. Immune evasion mechanisms used by nematodes to affect host immunity are not uncommon (4) and have been shown in studies with T. spiralis, Heligmosomoides polygyrus (3, 13, 30, 35, 37, 53), N. brasiliensis (27), and A. suum (10, 33, 54).

The immune response to helminth infections is known to share key features with the allergic response. In particular, both diseases characteristically induce a Th2 response associated with high levels of IL-4, IL-5, and IL-13 production accompanied by eosinophilia and abundant IgE production (23, 24, 40). Developing countries where helminth infections are endemic are known to have reduced rates of allergic disease, which was recently supported by epidemiological and clinical studies suggesting an inverse association between helminth infection and atopy (41, 62). Despite the general consensus that helminth infections may protect individuals from allergic disease, not all experimental models support this notion (41), including the observed increased anaphylactic shock in pinworm-infected mice. It is possible that other factors, such as the intensity and continuity of infection (63) or the suppressive agents discussed above, may influence the progression to allergy.

In conclusion, we have shown that a Th2-type immune response is important for resistance to S. obvelata infection and that the GI nematode elicits a nonprotective immune response to ovalbumin allergy. These results highlight the importance of working under pinworm-free conditions when using experimental murine models for immunological investigation.

Acknowledgments

We thank A. McKenzie for the use of IL-13- and IL-4/13-deficient mice. E. Smith, R. Peterson, M. Simpson, and the UCT histology and animal facility staff are thanked for their excellent technical assistance. D. Herbert and J. Alexander are thanked for critically reading the manuscript.

This work was supported in part by the Medical Research Council (MRC) and National Research Foundation (NRF) of South Africa. Frank Brombacher is holder of a Wellcome Trust Research Senior Fellowship for Medical Science in South Africa (grant no. 056708/Z/99).

Notes

Editor: W. A. Petri, Jr.

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