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. 2004 Jul;72(7):3812-22.
doi: 10.1128/IAI.72.7.3812-3822.2004.

Infection with Toxoplasma gondii reduces established and developing Th2 responses induced by Nippostrongylus brasiliensis infection

Oliver Liesenfeld  1 , Ildiko R Dunay, Klaus J Erb
Affiliations

Infection with Toxoplasma gondii reduces established and developing Th2 responses induced by Nippostrongylus brasiliensis infection

Oliver Liesenfeld et al. Infect Immun. 2004 Jul.

Abstract

Oral infection of C57BL/6 mice with 100 cysts of the protozoan parasite Toxoplasma gondii results in the development of small intestinal Th1-type immunopathology. In contrast, infection with intestinal helminths results in the development of protective Th2-type responses. We investigated whether infection with the helminth Nippostrongylus brasiliensis influences the development of T. gondii-induced Th1 responses and immunopathology in C57BL/6 mice infected with T. gondii. Prior as well as simultaneous infection of mice with N. brasiliensis did not alter the course of infection with 100 cysts of T. gondii. Coinfected mice produced high levels of interleukin-12 (IL-12) and gamma interferon (IFN-gamma), developed small intestinal immunopathology, and died at the same time as mice infected with T. gondii. Interestingly, local and systemic N. brasiliensis-induced Th2 responses, including IL-4 and IL-5 production by mesenteric lymph node and spleen cells and numbers of intestinal goblet cells and blood eosinophils, were markedly lower in coinfected than in N. brasiliensis-infected mice. Similar effects were seen when infection with 10 T. gondii cysts was administered following infection with N. brasiliensis. Infection of C57BL/6 mice with 10 T. gondii cysts prior to coinfection with N. brasiliensis inhibited the development of helminth-induced Th2 responses and was associated with higher and prolonged N. brasiliensis egg production. In contrast, oral administration of Toxoplasma lysate prior to N. brasiliensis infection had only a minor and short-lived effect on Th2 responses. Thus, N. brasiliensis-induced Th2 responses fail to alter T. gondii-induced Th1 responses and immunopathology, most likely because Th1 responses develop unchanged in C57BL/6 mice with a prior or simultaneous infection with N. brasiliensis. Our findings contribute to the understanding of immune regulation in coinfected animals and may assist in the design of immunotherapies for human Th1 and Th2 disorders.

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Figures

FIG. 1.
FIG. 1.
Infection with N. brasiliensis does not prevent early death and intestinal pathology in C57BL/6 mice infected with 100 cysts of T. gondii. Mice were infected with N. brasiliensis (750 LIII larvae s.c.) and orally challenged with 100 cysts of T. gondii 7 days thereafter. Mortality (A) was documented daily. Small intestines were removed from mice infected with N. brasiliensis (C), N. brasiliensis plus T. gondii (D), or T. gondii (E) at 7 days after infection with T. gondii or 14 days after infection with N. brasiliensis, immediately fixed, and stained with H&E. Arrows in panel C indicate goblet cells; arrows in panels D and E delineate the borders between the mucosal surface and lumen of the small intestines filled with necrotic material (original magnification, ×40). (B) The length of small intestinal necrosis in coinfected mice was determined in H&E-stained sections by using a ruler. Results are expressed as mean + SD. n.d., not detectable. The length of necrosis did not differ significantly in coinfected mice and those infected with T. gondii alone; necrosis was not detectable in N. brasiliensis-infected mice (P < 0.001 versus mice infected with N. brasiliensis).
FIG. 2.
FIG. 2.
Coinfection with T. gondii inhibits systemic and local Th2 immune responses in mice with established N. brasiliensis infection. C57BL/6 mice were infected with N. brasiliensis (750 LIII larvae s.c.) and orally challenged with 100 cysts of T. gondii 7 days thereafter. (A) At 7 days after T. gondii infection, blood was obtained. Blood smears were prepared and analyzed following Pappenheim staining; concentrations of total IgE, IFN-γ, and TNF-α in serum were determined by ELISA as described in Materials and Methods. Horizontal lines indicate numbers or concentrations in naive control mice. Results (expressed as mean + SD) of one representative experiment of three performed are shown. *, numbers of eosinophils per 100 white cells were significantly reduced in coinfected mice compared to mice infected with N. brasiliensis alone (P = 0.0022). **, TNF-α levels were significantly increased in coinfected mice compared to mice infected with T. gondii alone (P > 0.05). (B) Spleen and MLN cells were prepared and cultured in the presence of ConA (or TLA, as indicated by hatched bars) for 48 h. Levels of IL-4, IL-5, and IFN-γ in supernatants were determined by ELISA. Horizontal lines indicate cytokine levels in naive mice. Results (expressed as mean + SD) of one representative experiment of three performed are shown. *, P < 0.002 compared to levels in mice infected with N. brasiliensis alone; **, P < 0.01 compared to mice infected with N. brasiliensis alone. (C) Numbers of small intestinal goblet cells in three villi chosen at random were determined microscopically; the vertical line indicates goblet cell numbers in naive mice. Pooled results obtained by two independent investigators + SD are given (*, P = 0.0009 versus N. brasiliensis-infected mice).
FIG. 3.
FIG. 3.
Down-regulation of N. brasiliensis-induced Th2 responses by T. gondii is dependent on the genetic background of mice. BALB/c mice were infected with N. brasiliensis (750 LIII larvae s.c.) and orally challenged with 10 cysts of T. gondii 7 days thereafter. (A) At 7 days after T. gondii infection, blood was obtained. Blood smears were prepared and analyzed following Pappenheim staining. Horizontal lines indicate levels in naive mice. Results (expressed as mean + SD) of one representative experiment of three performed are shown. *, P = 0.038 compared to mice infected with N. brasiliensis alone. (B) Spleen and MLN cells were prepared and cultured in the presence of ConA (or TLA, as indicated by hatched bars) for 48 h. Levels of IL-4, IL-5, and IFN-γ in supernatants were determined by ELISA. Horizontal lines indicate cytokine levels in noninfected mice. Results (expressed as mean + SD) of one representative experiment of three performed are shown.
FIG. 4.
FIG. 4.
Prior infection with T. gondii suppresses the development of N. brasiliensis-induced Th2 responses. C57BL/6 mice were infected with 10 cysts of T. gondii and challenged s.c. with 750 LIII larvae of N. brasiliensis 2 or 4 weeks thereafter. (A) At 14 days after infection with N. brasiliensis, blood was obtained. Blood smears were prepared and analyzed following Pappenheim staining; concentrations of total IgE in serum were determined by ELISA. Vertical lines indicate levels in naive control mice. Results (expressed as mean + SD) of one representative experiment of three performed are shown. *, P < 0.001 compared to mice infected with N. brasiliensis alone. (B and C) Spleen (B) and MLN (C) cells were prepared and cultured in the presence of ConA for 48 h. Levels of IL-4, IL-5, and IFN-γ in supernatants were determined by ELISA. Vertical lines indicate cytokine levels in naive mice. Results (expressed as mean + SD) of one representative experiment of three performed are shown. *, P < 0.02 compared to mice infected with N. brasiliensis alone. **, P < 0.025 compared to mice infected with N. brasiliensis alone. (D) N. brasiliensis egg production was determined microscopically from group samples of feces collected for 24 h at the indicated time points. n.d., not detectable.
FIG. 4.
FIG. 4.
Prior infection with T. gondii suppresses the development of N. brasiliensis-induced Th2 responses. C57BL/6 mice were infected with 10 cysts of T. gondii and challenged s.c. with 750 LIII larvae of N. brasiliensis 2 or 4 weeks thereafter. (A) At 14 days after infection with N. brasiliensis, blood was obtained. Blood smears were prepared and analyzed following Pappenheim staining; concentrations of total IgE in serum were determined by ELISA. Vertical lines indicate levels in naive control mice. Results (expressed as mean + SD) of one representative experiment of three performed are shown. *, P < 0.001 compared to mice infected with N. brasiliensis alone. (B and C) Spleen (B) and MLN (C) cells were prepared and cultured in the presence of ConA for 48 h. Levels of IL-4, IL-5, and IFN-γ in supernatants were determined by ELISA. Vertical lines indicate cytokine levels in naive mice. Results (expressed as mean + SD) of one representative experiment of three performed are shown. *, P < 0.02 compared to mice infected with N. brasiliensis alone. **, P < 0.025 compared to mice infected with N. brasiliensis alone. (D) N. brasiliensis egg production was determined microscopically from group samples of feces collected for 24 h at the indicated time points. n.d., not detectable.
FIG. 5.
FIG. 5.
Oral administration of TLA results in weak and short-lived suppression of N. brasiliensis-induced Th2 responses. Groups of mice were orally given 1,000 μg of TLA by gavage and infected with 750 LIII larvae of N. brasiliensis s.c. 7, 14, and 28 days thereafter. (A) At 14 days after infection with N. brasiliensis, blood smears were prepared and analyzed by Pappenheim staining; total serum IgE concentrations were determined by ELISA. Vertical lines indicate levels in noninfected control mice. Results (expressed as mean + SD) of one representative experiment are shown. *, P < 0.02 compared to mice infected with N. brasiliensis. (B) To compare levels of IFN-γ production, C57BL/6 mice either were given 1,000 μg of TLA by gavage or were infected with 10 cysts of T. gondii orally. At the indicated time points, MLN were isolated and IFN-γ production was measured by ELISA following in vitro restimulation with TLA.
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