Heligmosomoides Polygyrus Infection Research Articles

Maternal Infection and altered fetal immune programming.

Abstract The maternal-fetal interface involves complex and balanced interactions between mother and fetus, which support the development of the fetal immune system. While we know maternal helminth infection during pregnancy is known to disrupt this relationship and affect neonatal immune development, the fundamental mechanisms that drive fetal immune programming is not completely understood. To further examine how maternal parasitic infection influences offspring immunity, we established a model in which female mice prior to mating are infected with the persistent mouse intestinal helminth, Heligmosomoides polygyrus (HP). One week after infection, female mice are mated, and the progeny are aged to adulthood. The offspring are then challenged with influenza virus. Intriguingly, we found that offspring born from mothers with HP infections were less susceptible to influenza challenge than offspring born from uninfected mothers. This data implies that the effects of maternal helminth infection are long lasting, and potentially involve fetal programming during the early development of the immune system.

Modulation of LPS-Induced Neurodegeneration by Intestinal Helminth Infection in Ageing Mice.

Parasitic helminths induce a transient, short-term inflammation at the beginning of infection, but in persistent infection may suppress the systemic immune response by enhancing the activity of regulatory M2 macrophages. The aim of the study was to determine how nematode infection affects age-related neuroinflammation, especially macrophages in the nervous tissue. Here, intraperitoneal LPS-induced systemic inflammation resulting in brain neurodegeneration was enhanced by prolonged Heligmosomoides polygyrus infection in C57BL/6 mice. The changes in the brain coincided with the increase in M1 macrophages, reduced survivin level, enhanced APP and GFAP expression, chitin-like chains deposition in the brain and deterioration behaviour manifestations. These changes were also observed in transgenic C57BL/6 mice predisposed to develop neurodegeneration typical for Alzheimer's disease in response to pathogenic stimuli. Interestingly, in mice infected with the nematode only, the greater M2 macrophage population resulted in better results in the forced swim test. Given the growing burden of neurodegenerative diseases, understanding such interactive associations can have significant implications for ageing health strategies and disease monitoring.

Ablation of cDC2 development by triple mutations within the Zeb2 enhancer.

The divergence of the common dendritic cell progenitor1-3 (CDP) into the conventional type 1 and type 2 dendritic cell (cDC1 and cDC2, respectively) lineages4,5 is poorly understood. Some transcription factors act in the commitment of already specified progenitors-such as BATF3, which stabilizes Irf8 autoactivation at the +32 kb Irf8 enhancer4,6-but the mechanisms controlling the initial divergence of CDPs remain unknown. Here we report the transcriptional basis of CDP divergence and describe the first requirements for pre-cDC2 specification. Genetic epistasis analysis7 suggested that Nfil3 acts upstream of Id2, Batf3 and Zeb2 in cDC1 development but did not reveal its mechanism or targets. Analysis of newly generated NFIL3 reporter mice showed extremely transient NFIL3 expression during cDC1 specification. CUT&RUN and chromatin immunoprecipitation followed by sequencing identified endogenous NFIL3 binding in the -165 kb Zeb2 enhancer8 at three sites that also bind the CCAAT-enhancer-binding proteins C/EBPα and C/EBPβ. In vivo mutational analysis using CRISPR-Cas9 targeting showed that these NFIL3-C/EBP sites are functionally redundant, with C/EBPs supporting and NFIL3 repressing Zeb2 expression at these sites. A triple mutation of all three NFIL3-C/EBP sites ablated Zeb2 expression in myeloid, but not lymphoid progenitors, causing the complete loss of pre-cDC2 specification and mature cDC2 development in vivo. These micedid not generate T helper 2 (TH2) cell responses against Heligmosomoides polygyrus infection, consistent with cDC2 supporting TH2 responses to helminths9-11. Thus, CDP divergence into cDC1 or cDC2 is controlled by competition between NFIL3 and C/EBPs at the -165 kb Zeb2 enhancer.

Single-cell multi-omic analysis identify heterogeneity and distinct features in fate-mapped tissue-resident alternatively activated macrophages

Abstract Peritoneal cavity cells play pivotal roles in inflammation, repair, and maintaining homeostasis in response to pathogenic infections and tissue injury. Two major tissue-resident macrophages (TRMs) are large peritoneal macrophages (LPMs) and small peritoneal macrophages (SPMs). These are the major macrophage subsets in the peritoneal cavity and originate from embryogenic (LPMs) or bone-marrow-derived myeloid precursors (SPMs). CITE-seq (Cellular Indexing of Transcriptomes and Epitopes by Sequencing) provides simultaneous information for single cells in both cell-surface protein and gene expression levels. Here, we used CITE-seq to profile peritoneal cells by an oligonucleotide-labeled antibody panel designed to react with 189 unique mouse cell surface antigens. We identify 14 markers exclusively expressed on TRMs but not other immune cell types. These markers can classify phenotype differences between LPMs and SPMs during IL-4 stimulation. We further profile fate-mapped TRMs by scRNA-seq and identified more heterogenous phenotypes of TRMs that originated from embryogenic rather than bone-marrow-derived myeloid precursors. Notably, serum amyloid A-3 (Saa3) and platelet factor 4 (Pf4), can distinguish TRM clusters from alternative activation to IL-4 stimulation and Heligmosomoides polygyrus infection. Hence, we identify distinct markers that can be used to distinguish the different origins and heterogenous TRM phenotypes under steady state and type 2 immune responses.

Defined Intestinal Regions Are Drained by Specific Lymph Nodes That Mount Distinct Th1 and Th2 Responses Against Schistosoma mansoni Eggs.

The balance of type 1 and type 2 immune responses plays a crucial role in anti-helminth immunity and can either support chronic infection or drive type 2 mediated expulsion of the parasite. Helminth antigens and secreted molecules directly influence this balance and induce a favorable immunological environment for the parasite’s survival. However, less is known if the site of infection also influences the balance of type 1 and type 2 immunity. Here, we report that tissue-specific immune responses are mounted against helminth antigens, which elicited strong IL-4 responses when injected into the skin, while the same antigen, delivered into the intestinal subserosa, induced increased IFN-γ and reduced Th2 responses. Immune responses in individual mesenteric lymph nodes that drain defined regions of the intestine furthermore displayed a site-specific pattern of type 1 and type 2 immunity after Schistosoma mansoni or Heligmosomoides polygyrus infection. S. mansoni egg-specific Th2 responses were detectable in all mesenteric lymph nodes but Th1 responses were only present in those draining the colon, while H. polygyrus infection elicited mixed Th1 and Th2 responses in the lymph nodes associated with the site of infection. Similar site-specific type 1 and type 2 immune responses were observed in the draining lymph nodes after the controlled delivery of S. mansoni eggs into different segments of the small and large intestine using microsurgical techniques. Different subsets of intestinal dendritic cells were hereby responsible for the uptake and priming of Th1 and Th2 responses against helminth antigens. Migratory CD11b+CD103− and especially CD11b+CD103+ DC2s transported S. mansoni egg antigens to the draining lymph nodes to induce Th1 and Th2 responses, while CD103+ DC1s induced only IFN-γ responses. In contrast, H. polygyrus antigens were predominantly transported by CD11b+CD103− DC2s and CD103+ DC1s and all DC subsets induced similar Th1 but weaker Th2 responses, compared to S. mansoni egg antigens. The development of adaptive anti-helminth immune responses is therefore influenced by the antigen itself, the uptake and priming characteristics of antigen-positive dendritic cell subsets and the site of infection, which shape the level of Th1 and Th2 responses in order to create a favorable immunological environment for the parasite.

Increased reactivation of murine gammaherpesvirus-68 during Heligmosomoides polygyrus infection

Abstract A vast majority of people are infected with a herpesvirus. These viruses are double stranded DNA viruses that avoid eradication by the immune system by becoming latent. Certain signals, such as immune repression, can lead to reactivation of the virus. Reactivation of gamma herpesviruses is associated with pathologies, such as lymphomas and tumors. Past studies have shown that infection with helminths, extracellular parasitic worms, during gamma herpesvirus latency can cause reactivation. Helminths are known to secrete immunomodulatory factors that suppress host inflammation. The aim of the current study is to determine how prior helminth infection leads to increased reactivation of murine gammaherpesvirus-68 (MHV68). In this study, mice were or were not infected with Heligmosomoides polygyrus (HP), and then infected with MHV68. We found that infection with HP increased the reactivation of virus and the number of infected cells. However, there was no difference in acute replication of the virus between HP infected mice and HP uninfected mice. This suggests that the helminth infection specifically alters viral reactivation. The increased reactivation was only seen in a conventional mouse facility, but not in a barrier mouse facility, suggesting dependence on a microbiota component. Further work is required to determine how HP infection alters immune signals, such as IL-4 and STAT6 signaling, to cause increased MHV68 reactivation. Whether HP alters the permissiveness of cells to MHV68 infection should also be explored.

TPL-2 restricts Ccl24-dependent immunity to Heligmosomoides polygyrus.

TPL-2 (COT, MAP3K8) kinase activates the MEK1/2-ERK1/2 MAPK signaling pathway in innate immune responses following TLR, TNFR1 and IL-1R stimulation. TPL-2 contributes to type-1/Th17-mediated autoimmunity and control of intracellular pathogens. We recently demonstrated TPL-2 reduces severe airway allergy to house dust mite by negatively regulating type-2 responses. In the present study, we found that TPL-2 deficiency resulted in resistance to Heligmosomoides polygyrus infection, with accelerated worm expulsion, reduced fecal egg burden and reduced worm fitness. Using co-housing experiments, we found resistance to infection in TPL-2 deficient mice (Map3k8–/–) was independent of microbiota alterations in H. polygyrus infected WT and Map3k8–/–mice. Additionally, our data demonstrated immunity to H. polygyrus infection in TPL-2 deficient mice was not due to dysregulated type-2 immune responses. Genome-wide analysis of intestinal tissue from infected TPL-2-deficient mice identified elevated expression of genes involved in chemotaxis and homing of leukocytes and cells, including Ccl24 and alternatively activated genes. Indeed, Map3k8–/–mice had a significant influx of eosinophils, neutrophils, monocytes and Il4GFP+ T cells. Conditional knockout experiments demonstrated that specific deletion of TPL-2 in CD11c+ cells, but not Villin+ epithelial cells, LysM+ myeloid cells or CD4+ T cells, led to accelerated resistance to H. polygyrus. In line with a central role of CD11c+ cells, CD11c+ CD11b+ cells isolated from TPL-2-deficient mice had elevated Ccl24. Finally, Ccl24 neutralization in TPL-2 deficient mice significantly decreased the expression of Arg1, Retnla, Chil3 and Ear11 correlating with a loss of resistance to H. polygyrus. These observations suggest that TPL-2-regulated Ccl24 in CD11c+CD11b+ cells prevents accelerated type-2 mediated immunity to H. polygyrus. Collectively, this study identifies a previously unappreciated role for TPL-2 controlling immune responses to H. polygyrus infection by restricting Ccl24 production.

Interleukin 4 promotes the development of ex-Foxp3 Th2 cells during immunity to intestinal helminths.

Immunity to intestinal helminth infections requires the rapid activation of T helper 2 cells (Th2 cells). However, simultaneous expansion of CD4+Foxp3+ regulatory T cells (T reg cells) impedes protective responses, resulting in chronic infections. The ratio between T reg and effector T cells can therefore determine the outcome of infection. The redifferentiation of T reg cells into Th cells has been identified in hyperinflammatory diseases. In this study, we asked whether ex-T reg Th2 cells develop and contribute to type-2 immunity. Using multigene reporter and fate-reporter systems, we demonstrate that a significant proportion of Th2 cells derive from Foxp3+ cells after Heligmosomoides polygyrus infection and airway allergy. Ex-Foxp3 Th2 cells exhibit characteristic Th2 effector functions and provide immunity to H. polygyrus Through selective deletion of Il4ra on Foxp3+ cells, we further demonstrate IL-4 is required for the development of ex-Foxp3 Th2 cells. Collectively, our findings indicate that converting T reg cells into Th2 cells could concomitantly enhance Th2 cells and limit T reg cell-mediated suppression.

Cutting Edge: IL-4, IL-21, and IFN-γ Interact To Govern T-bet and CD11c Expression in TLR-Activated B Cells.

T-bet and CD11c expression in B cells is linked with IgG2c isotype switching, virus-specific immune responses, and humoral autoimmunity. However, the activation requisites and regulatory cues governing T-bet and CD11c expression in B cells remain poorly defined. In this article, we reveal a relationship among TLR engagement, IL-4, IL-21, and IFN-γ that regulates T-bet expression in B cells. We find that IL-21 or IFN-γ directly promote T-bet expression in the context of TLR engagement. Further, IL-4 antagonizes T-bet induction. Finally, IL-21, but not IFN-γ, promotes CD11c expression independent of T-bet. Using influenza virus and Heligmosomoides polygyrus infections, we show that these interactions function in vivo to determine whether T-bet(+) and CD11c(+) B cells are formed. These findings suggest that T-bet(+) B cells seen in health and disease share the common initiating features of TLR-driven activation within this circumscribed cytokine milieu.

IL-4-producing ILC2s are required for the differentiation of TH2 cells following Heligmosomoides polygyrus infection.

Immunity to many human and murine gastrointestinal helminth parasites requires interleukin-4 (IL-4)-directed type 2 helper (TH2) differentiation of CD4+ T cells to elicit type-2 immunity. Despite a good understanding of the inflammatory cascade elicited following helminth infection, the initial source of IL-4 is unclear. Previous studies using the rat helminth parasite Nippostronglyus brasiliensis, identified an important role for basophil-derived IL-4 for TH2 differentiation. However, basophils are redundant for TH2 differentiation following infection with the natural helminth parasite of mice Heligmosomoides polygyrus, indicating that other sources of IL-4 are required. In this study using H. polygyrus, which is controlled by IL-4-dependent immunity, we identified that group-2 innate lymphoid cells (ILC2s) produced significant amounts of IL-4 and IL-2 following H. polygyrus infection. Leukotriene D4 was sufficient to stimulate IL-4 secretion by ILC2s, and the supernatant from activated ILC2s could potently drive TH2 differentiation in vitro in an IL-4-dependent manner. Furthermore, specific deletion of IL-4 from ILC2s compromised TH2 differentiation in vivo. Overall, this study highlights a previously unrecognized and important role for ILC2-derived IL-4 for TH2 differentiation in a natural TH2-dependent model of human helminthiasis.

Concerted activity of IgG1 antibodies and IL-4/IL-25-dependent effector cells trap helminth larvae in the tissues following vaccination with defined secreted antigens, providing sterile immunity to challenge infection.

Over 25% of the world's population are infected with helminth parasites, the majority of which colonise the gastrointestinal tract. However, no vaccine is yet available for human use, and mechanisms of protective immunity remain unclear. In the mouse model of Heligmosomoides polygyrus infection, vaccination with excretory-secretory (HES) antigens from adult parasites elicits sterilising immunity. Notably, three purified HES antigens (VAL-1, -2 and -3) are sufficient for effective vaccination. Protection is fully dependent upon specific IgG1 antibodies, but passive transfer confers only partial immunity to infection, indicating that cellular components are also required. Moreover, immune mice show greater cellular infiltration associated with trapping of larvae in the gut wall prior to their maturation. Intra-vital imaging of infected intestinal tissue revealed a four-fold increase in extravasation by LysM+GFP+ myeloid cells in vaccinated mice, and the massing of these cells around immature larvae. Mice deficient in FcRγ chain or C3 complement component remain fully immune, suggesting that in the presence of antibodies that directly neutralise parasite molecules, the myeloid compartment may attack larvae more quickly and effectively. Immunity to challenge infection was compromised in IL-4Rα- and IL-25-deficient mice, despite levels of specific antibody comparable to immune wild-type controls, while deficiencies in basophils, eosinophils or mast cells or CCR2-dependent inflammatory monocytes did not diminish immunity. Finally, we identify a suite of previously uncharacterised heat-labile vaccine antigens with homologs in human and veterinary parasites that together promote full immunity. Taken together, these data indicate that vaccine-induced immunity to intestinal helminths involves IgG1 antibodies directed against secreted proteins acting in concert with IL-25-dependent Type 2 myeloid effector populations.

Heligmosomoides polygyrus infection reduces severity of type 1 diabetes induced by multiple low-dose streptozotocin in mice via STAT6- and IL-10-independent mechanisms

Some parasitic helminths are known to protect their hosts from allergic and autoimmune disorders. Here, we tested the effects of a gastrointestinal nematode, Heligmosomoides polygyrus (Hp), on streptozotocin (STZ)-induced type 1 diabetes (T1D) in mice. Hp infection significantly suppressed hyperglycemia induced by multiple low-dose administration of STZ, but did not affect hyperglycemia induced by single high-dose administration of STZ. In the multiple low dose model, Hp infection prevented a decrease in pancreatic islet size. The augmentation of TNF-α and IL-1β expression in the pancreas was abrogated by Hp infection. The genetic absence of IL-10 or STAT6 did not abrogate the anti-hyperglycemic effect of Hp. Hp has a suppressive effect on immune mechanism-mediated experimental T1D via Th2 polarization-independent mechanisms.

Heligmosmoides polygyrus fourth stages induce protection against DSS‐induced colitis and change opioid expression in the intestine

Primary exposure of mice to the nematode Heligmosomoides polygyrus infection reduces inflammation in an experimental model of colitis. The aim of the present investigation was to evaluate whether the reduced inflammation provoked by H.polygyrus L4 larvae in BALB/c mice treated with dextran sulphate sodium is associated with changed expression of opioids in the small intestine and colon. Colitis was induced by 5% Dextran sulphate sodium (DSS) oral administration for 3days before oral infection with 200 infective larvae (L3) H.polygyrus until the end of the experiment, 6days post-infection. Clinical disease symptoms were monitored daily. The expressions of proopiomelanocortin POMC1, MOR1 (Oprm1) - opioid receptor and β-endorphin were determined by RT-PCR, Western blot and immunoassay, respectively, in the colon and small intestine of mice. RT-PCR analysis of colon tissues showed up-regulation of the expression of POMC and MOR1 opioid-dependent genes in mice with DSS-induced colitis. H.polygyrus L4 larvae inhibited DSS-induced colitis symptoms that were correlated with increased IL-1β, TNF-α, IL-6, myeloperoxidase (MPO) concentration, macrophages infiltration and MOR1, POMC and β-endorphin increased expression in the small intestine and inhibition of those in the colon.

Heligmosomoides polygyrus infection is associated with lower MHC class II gene expression in Apodemus flavicollis: Indication for immune suppression?

Due to their key role in recognizing foreign antigens and triggering the subsequent immune response the genes of the major histocompatibility complex (MHC) provide a potential target for parasites to attack in order to evade detection and expulsion from the host. A diminished MHC gene expression results in less activated T cells and might serve as a gateway for pathogens and parasites. Some parasites are suspected to be immune suppressors and promote co-infections of other parasites even in other parts of the body. In our study we found indications that the gut dwelling nematode Heligmosomoides polygyrus might exert a systemic immunosuppressive effect in yellow-necked mice (Apodemus flavicollis). The amount of hepatic MHC class II DRB gene RNA transcripts in infected mice was negatively associated with infection intensity with H. polygyrus. The hepatic expression of immunosuppressive cytokines, such as transforming growth factor β and interleukin 10 was not associated with H. polygyrus infection. We did not find direct positive associations of H. polygyrus with other helminth species. But the prevalence and infection intensity of the nematodes Syphacia stroma and Trichuris muris were higher in multiple infected individuals. Furthermore, our data indicated antagonistic effects in the helminth community of A. flavicollis as cestode infection correlated negatively with H. polygyrus and helminth species richness. Our study shows that expression analyses of immune relevant genes can also be performed in wildlife, opening new aspects and possibilities for future ecological and evolutionary research.

Enhanced Protection against Heligmosomoides polygyrus in IL-2 Receptor .BETA.-Chain Overexpressed Transgenic Mice with Intestinal Mastocytosis

IL-2 receptor β-chain overexpressed transgenic (Tg2Rβ) mice lack NK cells, but the development of other lymphocyte subsets and macrophages remained apparently intact. These mice also exhibit intestinal mastocytosis. Helminth infection induces various immune responses, such as mast cells, goblet cells, eosinophils and IgE, mediated by Th2 cytokines. IL-4 is also important in the regulation of resistance and susceptibility to Heligmosomoides polygyrus infection. However, there are contradictory results about the relation between resistance to H. polygyrus and intestinal mastocytosis. The present study showed that Tg2Rβ mice suppressed worm fecundity with mastocytosis without an increase of the levels of goblet cells, eosinophils and IgE compared with control mice. These results clearly indicated that mast cells have the ability for to protect against H. polygyrus infection. However, additional studies are required to evaluate protective effector mechanisms against H. polygyrus.

Corrigendum

Parasite ImmunologyVolume 29, Issue 10 p. 539-539 Free Access Corrigendum This article corrects the following: Heligmosomoides polygyrus infection down-regulates eotaxin concentration and CCR3 expression on lung eosinophils in murine allergic pulmonary inflammation J. RZEPECKA, K. DONSKOW-SCHMELTER, M. DOLIGALSKA, Volume 29Issue 8Parasite Immunology pages: 405-413 First Published online: July 23, 2007 First published: 19 September 2007 https://doi.org/10.1111/j.1365-3024.2007.00978.xAboutSectionsPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat In Rzepecka et al. [1], Table 1 and Table 2 were set incorrectly. The Tables should have appeared as follows: Table 1. Eosinophilic response 6 weeks after infection of BALB/c mice with H. polygyrus. The number of eosinophils in five mice per group. *P < 0·05 compared to noninfected mice No. of eosinophils Bone marrow (×105) Blood (×102/mL) Peritoneum (×105) BALF Intestine (per VCU) Noninfected 11 ± 1·0 37 ± 2·0 5 ± 1·0 undetectable 11 ± 2·0 Heligmosomoides polygyrus 20 ± 1·0* 38 ± 7·0 22 ± 2·0* undetectable 6 ± 0·9* Table 2. Three days after last intranasal application of ova airway challenge BALFs were prepared and the number of leukocytes and eosinophils determined. Shown are the mean number of leukocytes, eosinophils and % of eosinophils ± SD determined in five individual mice per group (mice analysed were from one experiment; the same pattern of the cells response were obtained at least twice in independent experiments). *P < 0·05, compared to values obtained in ova-only treated mice BALF ‘ova’ ‘Hp + ova’ Number of leukocytes 2·4 × 106 ± 5·0 × 104 1·0 × 106 ± 6·0 × 104* Number of eosinophils 1·1 × 106 ± 2 × 105 3·4 × 105 ± 1·8 × 105* % of eosinophils 46·2 ± 6·1 33·4 ± 3·9* The authors apologize for the errors. REFERENCE 1 Rzepecka J, Donskow-Schmelter K, Doligalska M. Heligmosomoides polygyrus infection down regulates eotaxin concentration and CCR3 expression on lung eosinophils in murine allergic pulmonary inflammation. Parasite Immunology 2007; 29: 405– 413. Wiley Online LibraryCASPubMedWeb of Science®Google Scholar Volume29, Issue10October 2007Pages 539-539 ReferencesRelatedInformation

Divergent Metabolic Adaptations to Intestinal Parasitic Nematode Infection in Mice Susceptible or Resistant to Obesity

Diet-induced obesity results from increased ingestion of energy-dense food and sedentary lifestyle in genetically susceptible individuals. An environmental factor that may have shaped our energy homeostasis throughout evolution is parasitic nematode infection. To test the hypothesis that a metabolically "thrifty phenotype" is advantageous during intestinal nematode infection, we compared the responses to Heligmosomoides polygyrus infection between 2 mouse strains: obesity-prone C57Bl/6J vs obesity-resistant SWR/J. Metabolic phenotyping was performed using indirect calorimetry, dual energy x-ray absorptiometry, and magnetic resonance imaging scanning. Gene expression was assessed by quantitative reverse-transcription polymerase chain reaction and immunohistochemistry. Body weight was maintained in both strains during nematode infection via different mechanisms. There was no apparent change in energy expenditure between the strains; however, SWR/J mice exhibited a marked hyperphagia (calorie intake 60% higher than C57Bl/6J) to maintain body weight. The importance of hyperphagia was confirmed by severe weight loss in a group of infected SWR/J mice whose food intake was restricted to that of naïve mice. Furthermore, SWR/J mice expelled nematodes more rapidly than C57Bl/6J mice, an effect related to a T helper cell 2 immune response. C57Bl/6J mice are more energy efficient during parasitic nematode infection, which may explain their ability to tolerate the infection. SWR/J mice, on the other hand, require an increase in food intake to maintain energy stores during nematode infection. In addition, a strong T helper cell 2-mediated immune response that facilitates a prompt clearance of nematode infection in SWR/J mice may have evolved to conserve energy in this strain.

Heligmosomoides polygyrus infection down‐regulates eotaxin concentration and CCR3 expression on lung eosinophils in murine allergic pulmonary inflammation

There is growing evidence that helminth infections might suppress allergic responses by mechanisms potentially involving regulatory T lymphocytes, cytokines, helminth molecules and polyclonal IgE. Heligmosomoides polygyrus infection in mice is associated with reduced local and systemic immune responses, thus providing an excellent model to study the mechanisms of immune regulation. In this research, we examined the way that nematode infection modulates the influx of eosinophils into the airways of asthmatic mice. We observed a reduction in the total number and percentage of lung eosinophils that coincided with decreased levels of eotaxin in bronchoalveolar lavage fluid (BALF), lower expression of the CCR3 receptor on eosinophils and impaired chemotaxis of these cells toward eotaxin. We conclude that allergen-induced immune response was down-regulated as production of Th1 (IFN-gamma)-, Th2 (IL-4, IL-5)- and Treg (IL-10)-related cytokines as well as IL-6 and TNF-alpha was diminished upon nematode infection. We postulate that attenuation of allergic inflammation during H. polygyrus infection is a consequence of the dichotomy of the immune response in the face of concurrent antigenic challenge.

Expansion and activation of CD4(+)CD25(+) regulatory T cells in Heligmosomoides polygyrus infection.

Regulatory T cell responses to infectious organisms influence not only immunity and immunopathology, but also responses to bystander antigens. Mice infected with the gastrointestinal nematode parasite Heligmosomoides polygyrus show an early Th2-dominated immune response (days 7–14), but by day 28 a strongly regulatory profile is evident with antigen-specific IL-10 release and elevated frequency of CD4+ T cells bearing surface TGF-β. CD4+CD25+ T cells from infected mice show enhanced capacity to block in vitro effector T cell proliferation. CD4+CD25+ cell numbers expand dramatically during infection, with parallel growth of both CD25+Foxp3+ and CD25+Foxp3– subsets. CTLA-4 and glucocorticoid-induced tolerance-associated receptor, also associated with regulatory T cell function, become more prominent, due to both expanded CD25+ cell numbers and increased expression among the CD25– population. Both intensity and frequency of CD103 expression by CD4+ T cells rise significantly, with greatest expansion among CD25+Foxp3+ cells. While TGF-β expression is observed among both CD25+Foxp3+ and CD25+Foxp3– subsets, it is the latter population which shows higher TGF-β staining following infection. These data demonstrate in a chronic helminth infection that Foxp3+ regulatory T cells are stimulated, increasing CD103 expression in particular, but that significant changes occur to other populations including expansion of CD25+TGF-β+Foxp3– cells, and induction of CTLA-4 on CD25– non-regulatory lymphocytes.

Nematode Infection in Alymphoplasia (aly) Mice: Worm Species‐Dependent Differential Effect of Defects of the Gut‐Associated Lymphatic Tissue System

Mice homologous for the alymphoplasia mutation (aly) show the systemic absence of secondary lymphoid tissues, with disorganized splenic architecture, including the absence of the germinal centre and follicular dendritic cells. In this study, we examined the influence of defects of gut-associated lymphoid tissue (GALT), such as Peyer's patches and the mesenteric lymph nodes, on the host response to helminth infection in aly/aly mice. The present study showed that most of the worms were expelled by day 7 after Nippostrongylus brasiliensis infection in both control aly/+ and aly/aly mice. In aly/aly mice, the number of peripheral blood eosinophils, intestinal goblet cells and mucosal mast cells were increased by N. brasiliensis infection in aly/aly mice to the same level as in the controls. Conversely, aly/aly mice developed more severe Heligmosomoides polygyrus infections than control aly/+ mice, as demonstrated by increased faecal egg counts, with reduced immune responses such as the numbers of intestinal goblet cells and mucosal mast cells. These results suggested that the dependency of GALT in activation of Th2 responses against gastrointestinal nematodes was different depending on the species of nematode.