Toxoplasma gondii: difference of invasion into tissue of digestive organs between susceptible and resistant strain and influence of IFN-gamma in mice inoculated with the cysts perorally

Because it is widely accepted that there is a significant difference in susceptibility to chronic infection by Toxoplasma gondii among inbred mouse strains with different genetic backgrounds, we compared the distribution of the protozoa in digestive organs at early stages of infection between resistant (BALB/c) and susceptible (C57BL/ 6) mice after peroral infection with Fukaya strain cysts. Furthermore, to determine the influence of interferon gamma (IFN-gamma) on the infectivity of the cysts to the digestive tract, homozygous IFN-gamma knockout mice were utilized. Quantitative competitive polymerase chain reaction (QC-PCR) was employed to assess the distribution of T. gondii in different organs at various times after ingestion of cysts. SAG1, a T. gondii-specific gene, was detected in the small intestine and the caecum in wild-type C57BL/6 mice and in the whole digestive tract in IFN-gamma knockout C57BL/6 at 24 hr after infection. No detectable reaction in QC-PCR was observed in BALB/c mice at 24 hr after ingestion of the cysts. Destruction of the IFN-gamma gene showed less effect on the resistance to infection in BALB/c mice, but remarkable augmentation of infectivity of T. gondii to the rectum and peripheral blood was observed in C57BL/6 mice.     

Aging and the immune response. I. Antibody formation and chronic infection in Toxoplasma gondii-infected mice

Studies were performed to determine the effect of aging on the antibody response and cyst formations after infection with a relatively avirulent strain of the intracellular parasite Toxoplasma gondii. When compared with young mice (4 months), aged mice showed a significant decrease in the magnitude of humoral immune response to infection. This decrease was observed at the peak of the acute infection and also during chronic infection. Evaluation of the presence of Toxoplasma cysts, a measure of the latent infection, revealed that the numbers of tissue cysts present 11 weeks after infection increased with the age of the mice at time of infection. The larger numbers of cysts in older mice which had received the same inoculum size of T. gondii as young mice, together with our previous observations of increased susceptibility of these older mice to T. gondii, suggest that an age-related decrease in the early immune response to this infection allows an increased multiplication of the organism in vivo, leading to increased cyst numbers or death.     

Gonadal hormones in experimental Ancylostoma caninum infections in male Swiss albino mice

Ismail Bhai and Pandey A. K. 1982. Gonadal hormones in experimental Ancylostoma caninum infections in male Swiss albino mice. International Journal for Parasitology12: 589–591. Orchiectomy in mice increased their resistance to Ancylostoma caninum infection. Testosterone propionate increased the susceptibility of castrated animals to infection and also increased the survival of larvae in muscles, compared with sham-operated placebo-treated controls with intact testes. Estradiol benzoate increased the resistance of castrated mice as demonstrated by differential larval recoveries. The possible involvement of the small intestine as a barrier to infection and the influence of testosterone on host susceptibility to infection is discussed.     

The IFN-γ-inducible GTPase, Irga6, protects mice against Toxoplasma gondii but not against Plasmodium berghei and some other intracellular pathogens

Clearance of infection with intracellular pathogens in mice involves interferon-regulated GTPases of the IRG protein family. Experiments with mice genetically deficient in members of this family such as Irgm1(LRG-47), Irgm3(IGTP), and Irgd(IRG-47) has revealed a critical role in microbial clearance, especially for Toxoplasma gondii. The in vivo role of another member of this family, Irga6 (IIGP, IIGP1) has been studied in less detail. We investigated the susceptibility of two independently generated mouse strains deficient in Irga6 to in vivo infection with T. gondii, Mycobacterium tuberculosis, Leishmania mexicana, L. major, Listeria monocytogenes, Anaplasma phagocytophilum and Plasmodium berghei. Compared with wild-type mice, mice deficient in Irga6 showed increased susceptibility to oral and intraperitoneal infection with T. gondii but not to infection with the other organisms. Surprisingly, infection of Irga6-deficient mice with the related apicomplexan parasite, P. berghei, did not result in increased replication in the liver stage and no Irga6 (or any other IRG protein) was detected at the parasitophorous vacuole membrane in IFN-γ-induced wild-type cells infected with P. berghei in vitro. Susceptibility to infection with T. gondii was associated with increased mortality and reduced time to death, increased numbers of inflammatory foci in the brains and elevated parasite loads in brains of infected Irga6-deficient mice. In vitro, Irga6-deficient macrophages and fibroblasts stimulated with IFN-γ were defective in controlling parasite replication. Taken together, our results implicate Irga6 in the control of infection with T. gondii and further highlight the importance of the IRG system for resistance to this pathogen.     

Decreased resistance of B cell-deficient mice to infection with Toxoplasma gondii despite unimpaired expression of IFN-gamma, TNF-alpha, and inducible nitric oxide synthase

The role of B cells in resistance against Toxoplasma gondii was studied using B cell-deficient (muMT) mice. Following peroral infection with 10 cysts of the ME49 strain, all muMT mice survived the acute stage of the infection but died between 3 and 4 wk after infection. In contrast, all control mice were alive at 8 wk after infection. At the stage during which muMT animals succumbed to the infection, parasite replication and pathology were most evident in their brains; small numbers of tachyzoites were also detectable in their lungs. Significantly greater numbers of T. gondii cysts and areas of inflammation associated with tachyzoites were observed in brains of muMT than in control mice. Large areas of necrosis associated with numerous tachyzoites were observed only in brains of muMT mice. Anti-T. gondii IgG Abs were detected only in sera of control mice, whereas similar levels of IFN-gamma were detected in sera of both strains of mice. Amounts of mRNA for IFN-gamma, IL-10, and inducible NO synthase in the brain did not differ between infected muMT and control mice. Expression of mRNA for TNF-alpha was increased in brains of muMT mice. Administration of polyclonal rabbit anti-T. gondii IgG Ab prevented early mortality and pathology associated with tachyzoites in the brain in the infected muMT mice. These results indicate that B cells play an important role, most likely through their production of specific Abs, in resistance to persistent active (tachyzoite) infection with T. gondii in mice, especially in the brain and lung.     

Exacerbated susceptibility to infection-stimulated immunopathology in CD1d-deficient mice

Mice lacking functional CD1d genes were used to study mechanisms of resistance to the protozoan parasite Toxoplasma gondii. Wild-type (WT) BALB/c mice, CD1d-deficient BALB/c mice, and WT C57BL/6 mice all survived an acute oral infection with a low dose of mildly virulent strain ME49 T. gondii cysts. In contrast, most CD1d-deficient C57BL/6 mice died within 2 wk of infection. Despite having parasite burdens that were only slightly higher than WT mice, CD1d-deficient C57BL/6 mice displayed greater weight loss and intestinal pathology. In C57BL/6 mice, CD4(+) cells can cause intestinal pathology during T. gondii infection. Compared with WT mice, infected CD1d-deficient C57BL/6 mice had higher frequencies and numbers of activated (CD44(high)) CD4(+) cells in mesenteric lymph nodes. Depletion of CD4(+) cells from CD1d-deficient mice reduced weight loss and prolonged survival, demonstrating a functional role for CD4(+) cells in their increased susceptibility to T. gondii infection. CD1d-deficient mice are deficient in Valpha14(+) T cells, a major population of NKT cells. Involvement of these cells in resistance to T. gondii was investigated using gene-targeted Jalpha18-deficient C57BL/6 mice, which are deficient in Valpha14(+) T cells. These mice did not succumb to acute infection, but experienced greater weight loss and more deaths than B6 mice during chronic infection, indicating that Valpha14(+) cells contribute to resistance to T. gondii. The data identify CD4(+) cells as a significant component of the marked susceptibility to T. gondii infection observed in CD1d-deficient C57BL/6 mice, and establish T. gondii as a valuable tool for deciphering CD1d-dependent protective mechanisms.     

IL-10 is required for prevention of necrosis in the small intestine and mortality in both genetically resistant BALB/c and susceptible C57BL/6 mice following peroral infection with Toxoplasma gondii

The role for IL-10 in the immunopathogenesis of acute toxoplasmosis following peroral infection was examined in both genetically susceptible C57BL/6 and resistant BALB/c mice. C57BL/6-background IL-10-targeted mutant (IL-10-/-) mice all died in 2 wk after infection with 20 cysts of the ME49 strain, whereas only 20% of control mice succumbed. Histological studies revealed necrosis in the small and large intestines and livers of infected IL-10-/- mice. The necrosis in the small intestine was the most severe pathologic response and was not observed in control mice. Treatment of infected IL-10-/- mice with either anti-CD4 or anti-IFN-gamma mAb prevented intestinal pathology and significantly prolonged time to death. Treatment of these animals with anti-IL-12 mAb also prevented the pathology. Significantly greater amounts of IFN-gamma mRNA were detected in the lamina propria lymphocytes obtained from the small intestine of infected IL-10-/- mice than those from infected control mice. In common with C57BL/6-background IL-10-/- mice, BALB/c-background IL-10-/- mice all died developing intestinal pathology after infection. Control BALB/c mice all survived even after infection with 100 cysts and did not develop the intestinal lesions. Treatment with anti-IFN-gamma mAb prevented the pathology and prolonged time to death of the infected IL-10-/- mice. These results strongly suggest that IL-10 plays a critical role in down-regulating IFN-gamma production in the small intestine following sublethal peroral infection with Toxoplasma gondii and that this down-regulatory effect of IL-10 is required for prevention of development of IFN-gamma-mediated intestinal pathology and mortality in both genetically resistant BALB/c and susceptible C57BL/6 mice.     

Heat stress-induced modulation of host defense against Toxoplasma gondii infection in mice

This study examined the effects of burn injury on murine immune response against Toxoplasma gondii infection. Male C57BL/6 mice were divided into 3 groups: T. gondii infection (group T), burn injury (group B), and burn injury followed by T. gondii infection (group BT). The survival of group BT was significantly lower than those of group B and group T. Parasite abundance in the tissues was determined by quantitative competitive-polymerase chain reaction. Group BT exhibited significantly higher numbers of T. gondii than group T. Antibody production against T.g.HSP30 in group BT was significantly lower than that in group T, whereas no significant difference was observed in SAG1-specific antibody production. Delayed-type hypersensitivity (DTH) specific for 2,4-dinitrofluorobenzene (DNFB) of both group B and group BT was significantly lower than that of group T. One week after infection, serum interferon-gamma (IFN-gamma) and interleukin (IL)-10 levels in group BT were significantly lower, whereas serum IL-6 levels were significantly higher than in group T Serum TNF-alpha levels in both group T and group BT were elevated at 1 wk after infection, although there was no significant difference between them. Serum IFN-gamma, IL-10, and TNF-alpha levels in group B were not elevated during the experimental term. In conclusion, the impaired antigen-specific antibody production and DTH response, together with the modulated patterns of cytokine responses, seemed to be strongly involved in the development of burn-induced immunosuppression and the consequent increased susceptibility to T. gondii infection in mice.     

Toxoplasma gondii: decreased resistance to infection in mice due to estrogen

Exposure to pharmacological concentrations of potent estrogenic compounds, including 17 beta-estradiol, diethylstilbestrol, and alpha-dienestrol, increased the susceptibility of mice to Toxoplasma gondii as measured by brain cyst formation. Compounds with weak estrogenic activity or other hormonal activity, including 5 alpha-dihydrotestosterone, progesterone, and zearalanol, did not alter host resistance to infection. The ability of estrogens to alter susceptibility was inhibited by the estrogen antagonist, tamoxifen. The restoration of ovariectomized mice with normal physiological concentrations of estrogen had no effect on subsequent infection with T. gondii. These results indicate that pharmacological, but not physiological, levels of estrogen selectively alter host resistance to T. gondii, possibly through hormonal events.     

Maternal-fetal transmission of Toxoplasma gondii in interferon-gamma deficient pregnant mice

Toxoplasma gondii infection is generally asymptomatic in immunocompetent persons but can be life-threatening in immunocompromised persons and for fetuses in the case of maternal-fetal transmission. The effect of interferon (IFN)-gamma, which plays a crucial role in the protective immunity against T. gondii infection, on maternal-fetal transmission of T. gondii was analyzed by quantitative competitive polymerase chain reaction targeting T. gondii-specific SAG1 gene. T. gondii loads were obvious in uterus and placenta of wild type (WT) C57BL/6 (B6, susceptible strain) but not BALB/c (resistant strain) pregnant mice. Higher levels of T. gondii were detected in uterus and placenta of IFN-gamma knock-out (GKO) B6 and BALB/c than in those of WT mice. Furthermore, T. gondii was detected in fetus of GKO B6 but not GKO BALB/c, WT B6, or WT BALB/c mice. Thus, not only IFN-gamma but also genetic susceptibility to T. gondii infection was important for the protective immunity of maternal-fetal transmission of T. gondii to fetus via placenta. T. gondii-infected WT mice displayed a low delivery rate with high IFN-gamma production, whereas infected GKO mice did not. Additionally, mean body weight of neonates from T. gondii-infected GKO BALB/c pregnant mice was significantly lower than that of unaborted neonates from WT BALB/c pregnant mice, suggesting the effects of T. gondii infection on intrauterine growth retardation of fetus in pregnant GKO mice.     

Immune responses of mice intraduodenally infected with Toxoplasma gondii KI-1 tachyzoites

Toxoplasma gondii Korean isolate (KI-1) tachyzoites were inoculated intraduodenally to BALB/c mice using a silicon tube, and the course of infection and immune responses of mice were studied. Whereas control mice, that were infected intraperitoneally, died within day 7 post-infection (PI), the intraduodenally infected mice survived until day 9 PI (infection with 1 × 10(5) tachyzoites) or day 11 PI (with 1 × 10(6) tachyzoites). Based on histopathologic (Giemsa stain) and PCR (B1 gene) studies, it was suggested that tachyzoites, after entering the small intestine, invaded into endothelial cells, divided there, and propagated to other organs. PCR appeared to be more sensitive than histopathology to detect infected organs and tissues. The organisms spread over multiple organs by day 6 PI. However, proliferative responses of splenocytes and mesenteric lymph node (MLN) cells in response to con A or Toxoplasma lysate antigen decreased significantly, suggesting immunosuppression. Splenic CD4(+) and CD8(+) T-lymphocytes showed decreases in number until day 9 PI, whereas IFN-γ and IL-10 decreased slightly at day 6 PI and returned to normal levels by day 9 PI. No TNF-α was detected throughout the experimental period. The results showed that intraduodenal infection with KI-1 tachyzoites was successful but did not elicit significant mucosal immunity in mice and allowed dissemination of T. gondii organisms to systemic organs. The immunosuppression of mice included reduced lymphoproliferative responses to splenocytes and MLN cells to mitogen and low production of cytokines, such as IFN-γ, TNF-α, and IL-10, in response to T. gondii infection.     

Gene expression profiles in genetically different mice infected with Toxoplasma gondii: ALDH1A2, BEX2, EGR2, CCL3 and PLAU

Toxoplasma gondii can modulate host cell gene expression; however, determining gene expression levels in intermediate hosts after T. gondii infection is not known much. We selected 5 genes (ALDH1A2, BEX2, CCL3, EGR2 and PLAU) and compared the mRNA expression levels in the spleen, liver, lung and small intestine of genetically different mice infected with T. gondii. ALDH1A2 mRNA expressions of both mouse strains were markedly increased at day 1-4 postinfection (PI) and then decreased, and its expressions in the spleen and lung were significantly higher in C57BL/6 mice than those of BALB/c mice. BEX2 and CCR3 mRNA expressions of both mouse strains were significantly increased from day 7 PI and peaked at day 15-30 PI (P<0.05), especially high in the spleen liver or small intestine of C57BL/6 mice. EGR2 and PLAU mRNA expressions of both mouse strains were significantly increased after infection, especially high in the spleen and liver. However, their expression patterns were varied depending on the tissue and mouse strain. Taken together, T. gondii-susceptible C57BL/6 mice expressed higher levels of these 5 genes than did T. gondii-resistant BALB/c mice, particularly in the spleen and liver. And ALDH1A2 and PLAU expressions were increased acutely, whereas BEX2, CCL3 and EGR2 expressions were increased lately. Thus, these demonstrate that host genetic factors exert a strong impact on the expression of these 5 genes and their expression patterns were varied depending on the gene or tissue.     

Class I MHC genes and CD8+ T cells determine cyst number in Toxoplasma gondii infection

To determine roles of MHC class I and II genes in protection against Toxoplasma gondii, H-2 congenic and mutant mice were infected perorally with bradyzoites of T. gondii and brain cysts were enumerated 30 days later. As B10 mice (H-2b) are cyst susceptible and B10.A mice (H-2a) are cyst resistant, B10 congenic mice having the same alleles but different H-2 haplotypes were used to locate the controlling gene. Genes located at H-2L (i.e., class I genes) were found to regulate the number of brain cysts which form following peroral infection with T. gondii (p less than 0.001) with Ld being resistant and Lb being susceptible. The regulatory function of the H-2L gene product was confirmed through the study of D mutant (dm) mice. B10.D2-H-2dm1 (dm1) mice have a gain-loss mutation in Dd and Ld (i.e., recombination of Ld and Dd) and BALB/c-H-2dm2 (dm2) mice have a deletion of the Ld gene. Both these dm strains were cyst susceptible (p less than 0.001). These results provide the first direct evidence that class I genes regulate numbers of T. gondii cysts that form. In vivo ablation of CD8+ T cells with mAb YTS 169.4 converted cyst resistant B10.BAR12 mice to cyst susceptible. This result is consistent with a role for MHC restricted CD8+ cytotoxic (or suppressor) T cell regulation of cyst formation. A mutation in Ia in B6.C-H-2bm12 (bm12) mice amplified cyst numbers in susceptible mice, which is consistent with the importance of helper/inducer T cells in the induction of cytotoxic T cells. These findings are relevant to understanding the complex immunologic mechanisms that protect against T. gondii infection, development of protective preparations, and provide a conceptual basis for determining whether similar immunogenetic regulation of susceptibility is also operative in humans.     

Gender difference in ICER Igamma transgenic diabetic mouse

Few studies have been done to examine gender differences in diabetic mouse models. Here we examined a gender difference in Inducible cAMP Early Repressor (ICER) transgenic (Tg) mice, a diabetic mouse model. Longitudinal changes in diabetes and nephropathy were investigated in male and female Tg mice. Both male and female Tg mice developed severe diabetes early in life due to severely impaired insulin synthesis and decreased beta-cell numbers, but only female Tg mice became less hyperglycemic later in life, and most female Tg mice did not develop diabetic nephropathy. Even some female Tg mice that remained hyperglycemic showed less renal expansion than age-matched male Tg mice. Thus the gender difference in the severity of diabetes and diabetic nephropathy was evident with age in this model. This study indicates that sex hormones may play a role in glucose metabolism in diabetic conditions.     

Protection against Nippostrongylus brasiliensis infection in mice is independent of GM-CSF

Granulocyte macrophage-colony stimulating factor (GM-CSF) is a cytokine with the capacity to promote inflammation in a wide variety of infectious and inflammatory diseases. These conditions include allergic airway inflammation, which is driven by T-helper 2 (Th2) cells. Because of the importance of Th2 cells in parasite infections, we have investigated the role of GM-CSF in mice infected with the nematode Nippostrongylus brasiliensis. The effect of primary and secondary infection was investigated in mice lacking functional genes for GM-CSF (CSF2 genes) (ΔGM-CSF mice), and in mice lacking the cytokine receptor common β chain (Δβ mice), the latter being unable to signal in response to GM-CSF and interleukin (IL)-5. ΔGM-CSF mice showed no significant defect in parasite immunity, measured by larval numbers in the lungs, worm numbers in the intestine or egg numbers in the faeces, in either primary or secondary infection. By contrast, the Δβ mice showed increased parasite burden, with higher numbers of lung larvae after secondary infection and higher numbers of intestinal worms and faecal eggs after both primary and secondary infection. Unexpectedly, there were increased numbers of circulating eosinophils in the ΔGM-CSF mice, associated with significantly reduced larval numbers in the lungs. These results indicate that GM-CSF is redundant in protection against N. brasiliensis infection, and that the increased susceptibility of Δβ mice to infection is likely to be attributed to the lack of IL-5 signalling in these mice. The results suggest that clinical use of agents that neutralise GM-CSF may not be associated with increased risk of parasite infection.     

Bradyzoite-Induced Murine Toxoplasmosis: Stage Conversion, Pathogenesis, and Tissue Cyst Formation in Mice Fed Bradvzoites of - Different Strains of Toxoplasma gondii

ABSTRACT. The development of Toxoplasma gondii was studied in mice fed bradyzoites. At one hour after oral inoculation (HAI), bradyzoites were found in cells of the surface epithelium and the lamina propria of the small intestine, primarily the ileum. Division into two tachyzoites was first observed at 18 HA1 in the intestine. At 24 HAI, organisms were also seen in mesenteric lymph nodes. Organisms were first detected in the brain at six days after oral inoculation with bradyzoites (DAI) but not consistently until 10 DAI. Immunohistochemical staining with bradyzoite specific (BAG-5 antigen) anti-serum showed that bradyzoites retained their BAG-5 reactivity even after the first division into two tachyzoites in the intestine at 18 HAL BAG-5 positive organisms were not seen 2–5 DAI. BAG-5 antigens reappeared in T. gondii at 6 DAI. Whole mice and individual tissues of mice fed bradyzoites were bioassayed in cats and mice for the presence of bradyzoites. Feces of cats fed murine tissues were examined for oocyst shedding for short prepatent periods. Bradyzoites were present in the intestines of mice up to 12 HA1 but not at 18 HAI, and tachyzoites and not bradyzoites disseminated to other tissues from the intestine. Bradyzoites were again detected 6 DAI. Using the mouse bioassay, T. gondii was first detected in peripheral blood at 24 HA1 and more consistently at 48 HAL Using a pepsin-digestion procedure and mouse bioassay, organisms were demonstrated in many tissues of mice 15 and 49 DAI.     

Organ infectivity of Toxoplasma gondii in interferon-gamma knockout mice

To determine the influence of interferon (IFN)-gamma on the organ infectivity and on the genetic susceptibility of susceptible (C57BL/6) and resistant (BALB/c) strains after peroral infection with cysts of Toxoplasma gondii. IFN-gamma knockout (KO) mice in C57BL/6 and BALB/c backgrounds were utilized. The kinetics of the changes in T. gondii abundance were evaluated with a quantitative competitive polymerase chain reaction assay in various organs at different times after peroral infection. In IFN-gamma KO mice, a T. gondii-specific gene, SAG1, was detected in all organs examined, and the protozoan proliferated much more actively than in wild-type mice. The abundance of T. gondii was much higher in mesenteric lymph nodes and the heart than in other organs. In contrast, in the nervous system organs and kidneys, only a weakly detectable reaction was observed. Toxoplasma gondii grew at a more rapid rate in the organs of IFN-gamma KO C57BL/6 mice than in the organs of IFN-gamma KO BALB/c mice during the course of infection. Destruction of the IFN-gamma gene showed remarkable effects on the infectivity in both susceptible and resistant mice.     

The induction of acute ileitis by a single microbial antigen of Toxoplasma gondii

The role of specific microbial Ags in the induction of experimental inflammatory bowel disease is poorly understood. Oral infection of susceptible C57BL/6 mice with Toxoplasma gondii results in a lethal ileitis within 7-9 days postinfection. An immunodominant Ag of T. gondii (surface Ag 1 (SAG1)) that induces a robust B and T cell-specific response has been identified and a SAG1-deficient parasite (Deltasag1) engineered. We investigated the ability of Deltasag1 parasite to induce a lethal intestinal inflammatory response in susceptible mice. C57BL/6 mice orally infected with Deltasag1 parasites failed to develop ileitis. In vitro, the mutant parasites replicate in both enterocytes and dendritic cells. In vivo, infection with the mutant parasites was associated with a decrease in the chemokine and cytokine production within several compartments of the gut-associated cell population. RAG-deficient (RAG1(-/-)) mice are resistant to the development of the ileitis after T. gondii infection. Adoptive transfer of Ag-specific CD4(+) effector T lymphocytes isolated from C57BL/6-infected mice into RAG(-/-) mice conferred susceptibility to the development of the intestinal disease. In contrast, CD4(+) effector T lymphocytes from mice infected with the mutant Deltasag1 strain failed to transfer the pathology. In addition, resistant mice (BALB/c) that fail to develop ileitis following oral infection with T. gondii were rendered susceptible following intranasal presensitization with the SAG1 protein. This process was associated with a shift toward a Th1 response. These findings demonstrate that a single Ag (SAG1) of T. gondii can elicit a lethal inflammatory process in this experimental model of pathogen-driven ileitis.     

Expression of the poliovirus receptor in intestinal epithelial cells is not sufficient to permit poliovirus replication in the mouse gut.

Although the initial site of poliovirus replication in humans is the intestine, previously isolated transgenic mice which carry the human poliovirus receptor (PVR) gene (TgPVR mice), which develop poliomyelitis after intracerebral inoculation, are not susceptible to infection by the oral route. The low levels of PVR expressed in the TgPVR mouse intestine might explain the absence of poliovirus replication at that site. To ascertain whether PVR is the sole determinant of poliovirus susceptibility of the mouse intestine, we have generated transgenic mice by using the promoter for rat intestine fatty acid binding protein to direct PVR expression in mouse gut. Pvr was detected by immunohistochemistry in the enterocytes and M cells of transgenic mouse (TgFABP-PVR) small intestine. Upon oral inoculation with poliovirus, no increase in virus titer was detected in the feces of TgFABP-PVR mice, and no virus replication was observed in the small intestine, although poliovirus replicated in the brain after intracerebral inoculation. The failure of poliovirus to replicate in the TgFABP-PVR mouse small intestine was not due to lack of virus binding sites, because poliovirus could attach to fragments of small intestine from these mice. These results indicate that the inability of poliovirus to replicate in the mouse alimentary tract is not solely due to the absence of virus receptor, and other factors are involved in determining the ability of poliovirus to replicate in the mouse gut.     

Intraepithelial lymphocytes traffic to the intestine and enhance resistance to Toxoplasma gondii oral infection

Toxoplasma gondii Ag-primed intraepithelial lymphocytes (IEL) from the mouse intestine have been shown to be protective against an lethal parasite challenge when adoptively transferred into recipient mice. In the present study, we observed that Ag-primed IEL traffic to the intestine of naive mice following i.v. administration. Primed and CD8beta+ IEL were the most efficient cells at homing to the host organ. In congenic mice, IEL migrated from intestine within several hours posttransfer. On Ag reexposure, the primed IEL return to the intestine where they enhance resistance as determined by reduction in the number of brain cysts. Treatment of recipient mice with anti-alpha4 and anti-alphaE Abs partially inhibited IEL intestinal homing. The Ab treatment dramatically impaired resistance to a subsequent oral infection. These finding indicate that lymphocyte homing is an important parameter in establishing long term immunity to recurrent infection with this parasite.