[Show abstract][Hide abstract] ABSTRACT: One of the most advantageous research aspects of the murine model of filariasis, Litomosoides sigmodontis, is the availability of mouse strains with varying susceptibility to the nematode infection. In C57BL/6 mice, L. sigmodontis worms are largely eliminated in this strain by day 40 post-infection and never produce their offspring, microfilariae (Mf). This provides a unique opportunity to decipher potential immune pathways that are required by filariae to achieve a successful infection. In this study we tracked worm development and patency, the production of microfilariae and thus the transmission life-stage, in Rag2IL-2Rγ −/− mice which are deficient in T, B and NK cell populations.
Although worm burden was comparable between wildtype (WT) and Rag2IL-2Rγ −/− mice on d30, by day 72 post-infection, parasites in Rag2IL-2Rγ −/− mice were still in abundance, freely motile and all mice presented high quantities of Mf both at the site of infection, the thoracic cavity (TC), and in peripheral blood. Levels of cytokine (IL-4, IL-6, TNFα) and chemokine (MIP-2, RANTES, Eotaxin) parameters were generally low in the TC of infected Rag2IL-2Rγ −/− mice at both time-points. The frequency of neutrophils however was higher in Rag2IL-2Rγ −/− mice whereas eosinophils and macrophage populations, including alternatively activated macrophages, were elevated in WT controls.
Our data highlight that adaptive immune responses prevent the development of patent L. sigmodontis infections in semi-susceptible C57BL/6 mice and suggest that induction of such responses may offer a strategy to prevent transmission of human filariasis.
[Show abstract][Hide abstract] ABSTRACT: 37 million individuals are currently infected with Onchocerca volvulus (O. volvulus), a parasitic nematode that elicits various dermal manifestations and eye damage in man. Disease control is primarily based on distributing ivermectin in mass drug administration (MDA) programmes which aim at breaking transmission by eliminating microfilariae (MF), the worm's offspring. The majority of infected individuals present generalized onchocerciasis, which is characterized by hyporesponsive immune responses and high parasite burden including MF. Recently, in areas that have been part of MDA programmes, individuals have been identified that present nodules but are amicrofilaridermic (a-MF) and our previous study showed that this group has a distinct immune profile. Expanding on those findings we determined the immune responses of O. volvulus-infected individuals to a Plasmodium-derived antigen MSP-1 (merozoite surface protein-1), which is required by the parasite to enter erythrocytes.
Isolated PBMCs from O. volvulus-infected individuals (164 MF+ and 46 a-MF) and non-infected volunteers from the same region (NEN), were stimulated with MSP-1 and the resulting supernatant screened for the presence of IL-5, IL-13, IFN-γ, TNF-α, IL-6, IL-17A and IL-10. These findings were then further analyzed following regression analysis using the covariates MF, ivermectin (IVM) and region. The latter referred to the Central or Ashanti regions of Ghana, which, at the time sampling, had received 8 or 1 round of MDA respectively.
IL-5, IL-13 and IFN-γ responses to MSP-1 were not altered between NEN and O. volvulus-infected individuals nor were any associations revealed in the regression analysis. IL-10, IL-6 and TNF-α MSP-1 responses were, however, significantly elevated in cultures from infected individuals. Interestingly, when compared to a-MF individuals, MSP-induced IL-17A responses were significantly higher in MF+ patients. Following multivariable regression analysis these IL-10, IL-6, TNF-α and IL-17A responses were all dominantly associated with the regional covariate.
Consequently, areas with a lowered infection pressure due to IVM MDA appear to influence bystander responses to Plasmodium-derived antigens in community members even if they have not regularly participated in the therapy.
[Show abstract][Hide abstract] ABSTRACT: Schistosome infections are renowned for their ability to induce regulatory networks such as regulatory T cells (Treg) that control immune responses against homologous and heterologous antigens such as allergies. However, in the case of co-infections with hepatitis C virus (HCV), schistosomes accentuate disease progression and we hypothesized that expanding schistosome-induced Treg populations change their phenotype and could thereby suppress beneficial anti-HCV responses. We therefore analysed effector T cells and n/iTreg subsets applying the markers Granzyme B (GrzB) and Helios in Egyptian cohorts of HCV mono-infected (HCV), schistosome-co-infected (Sm/HCV) and infection-free individuals. Interestingly, viral load and liver transaminases were significantly elevated in Sm/HCV individuals when compared to HCV patients. Moreover, overall Treg frequencies and Helios(pos) Treg were not elevated in Sm/HCV individuals, but frequencies of GrzB(+) Treg were significantly increased. Simultaneously, GrzB(+) CD8(+) T cells were not suppressed in co-infected individuals. This study demonstrates that in Sm/HCV co-infected cohorts, liver disease is aggravated with enhanced virus replication and Treg do not expand but rather change their phenotype with GrzB possibly being a more reliable marker than Helios for iTreg. Therefore, curing concurrent schistosome disease could be an important prerequisite for successful HCV treatment as co-infected individuals respond poorly to interferon therapy.
[Show abstract][Hide abstract] ABSTRACT: Helminths immunomodulate their hosts and induce a regulatory, anti-inflammatory milieu that prevents allergies and autoimmune diseases. Helminth immunomodulation may benefit sepsis outcome by preventing exacerbated inflammation and severe pathology, but the influence on bacterial clearance remains unclear. To address this, mice were chronically infected with the filarial nematode Litomosoides sigmodontis (L.s.) and the outcome of acute systemic inflammation caused by i.p. Escherichia coli injection was determined. L.s. infection significantly improved E. coli-induced hypothermia, bacterial clearance and sepsis survival and correlated with reduced concentrations of associated pro-inflammatory cytokines/chemokines and a less pronounced pro-inflammatory macrophage gene expression profile. Improved sepsis outcome in L.s.-infected animals was mediated by macrophages, but independent of the alternatively activated macrophage subset. Endosymbiotic Wolbachia bacteria that are present in most human pathogenic filariae, as well as L.s., signal via TLR2 and modulate macrophage function. Here, gene expression profiles of peritoneal macrophages from L.s.-infected mice revealed a downregulation of genes involved in TLR signaling, and pulsing of macrophages in vitro with L.s. extract reduced LPS-triggered activation. Subsequent transfer improved sepsis outcome in naïve mice in a Wolbachia- and TLR2-dependent manner. In vivo, phagocytosis was increased in macrophages from L.s.-infected wild type, but not TLR2-deficient animals. In association, L.s. infection neither improved bacterial clearance in TLR2-deficient animals nor ameliorated E. coli-induced hypothermia and sepsis survival. These results indicate that chronic L.s. infection has a dual beneficial effect on bacterial sepsis, reducing pro-inflammatory immune responses and improving bacterial control. Thus, helminths and their antigens may not only improve the outcome of autoimmune and allergic diseases, but may also present new therapeutic approaches for acute inflammatory diseases that do not impair bacterial control.
[Show abstract][Hide abstract] ABSTRACT: Author Summary
Onchocerciasis, also known as river blindness is a tropical disease causing health and socioeconomic problems in endemic communities especially sub-Saharan Africa. The disease is transmitted by a filarial nematode called Onchocerca volvulus , which is spread by the bite of infected Simulium black flies. Characteristic disease symptoms include dermatological disorders and eye lesions that can lead to blindness. Two polar forms of clinical manifestations can occur: generalized onchocerciasis (GEO) presenting mild skin disease or the hyperreactive form (HO) exhibiting severe skin disorders and inflammation. The immunological determinants behind such disease polarization are still not fully clarified. Here, we compared the immune profiles of individuals presenting these two polar forms with those of endemic normals (EN): individuals who have no clinical or parasitological evidence of infection despite ongoing exposure to the infectious agent. We could show that HO individuals, in contrast to GEO and EN, simultaneously presented elevated Th17 and Th2 profiles which were accompanied by reduced numbers of Foxp3<sup>+</sup> regulatory T cells. This study provides initial evidence that elevated frequencies of Th17 and Th2 cells form part of the immune network associated with severe onchocerciasis.
[Show abstract][Hide abstract] ABSTRACT: Schistosomes infections are renowned for their ability to induce regulatory networks such as regulatory T cells (Treg) that control immune responses against homologous and heterologous antigens such as allergies. However, in the case of co-infections with Hepatitis C virus (HCV), the schistosomes accentuate disease progression and we hypothesized that expanding schistosome-induced Treg populations change their phenotype and could thereby suppress beneficial anti-HCV responses. We therefore analyzed effector T cells and n/iTreg subsets applying the markers Granzyme B (GrzB) and Helios in Egyptian cohorts of HCV mono-infected (HCV), schistosome-coinfected (Sm/HCV) and infection-free individuals. Interestingly, viral load and liver transaminases were significantly elevated in Sm/HCV individuals when compared to HCV patients. Moreover, overall Treg frequencies and HeliosposTreg were not elevated in Sm/HCV individuals but frequencies of GrzB+Treg were significantly increased. Simultaneously, GrzB+ CD8+ T cells were not suppressed in co-infected individuals. This study demonstrates that in Sm/HCV co-infected cohorts, liver disease is aggravated with enhanced virus replication and Treg do not expand but rather change their phenotype with GrzB possibly being a more reliable marker than Helios for iTreg. Therefore, curing concurrent schistosome disease could be an important pre-requisite for successful HCV treatment since co-infected individuals respond poorly to interferon therapy.This article is protected by copyright. All rights reserved.
[Show abstract][Hide abstract] ABSTRACT: Background
Schistosomiasis, a chronic helminth infection, elicits distinct immune responses within the host, ranging from an initial TH1 and subsequent TH2 phase to a regulatory state, and is associated with dampened allergic reactions within the host.
We sought to evaluate whether non-transplacental helminth infection during pregnancy alters the offspring's susceptibility to allergy.
Ovalbumin-induced allergic airway inflammation was analyzed in offspring from Schistosoma mansoni–infected mothers mated during the TH1, TH2, or regulatory phase of infection. Embryos derived from in vitro fertilized oocytes of acutely infected females were transferred into uninfected foster mice to determine the role of placental environment. The fetomaternal unit was further characterized by helminth-specific immune responses and microarray analyses. Eventually, IFN-γ–deficient mice were infected to evaluate the role of this predominant cytokine on the offspring's allergy phenotype.
We demonstrate that offspring from schistosome-infected mothers that were mated in the TH1 and regulatory phases, but not the TH2 immune phase, are protected against the onset of allergic airway inflammation. Interestingly, these effects were associated with distinctly altered schistosome-specific cytokine and gene expression profiles within the fetomaternal interface. Furthermore, we identified that it is not the transfer of helminth antigens but rather maternally derived IFN-γ during the acute phase of infection that is essential for the progeny's protective immune phenotype.
Overall, we present a novel immune phase–dependent coherency between the maternal immune responses during schistosomiasis and the progeny's predisposition to allergy. Therefore, we propose to include helminth-mediated transmaternal immune modulation into the expanded hygiene hypothesis.
Journal of Allergy and Clinical Immunology 12/2014; 134(6). DOI:10.1016/j.jaci.2014.05.034 · 11.48 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: A significant proportion of disease burden in resource poor tropical communities is due to parasitic infections. Such chronic ailments not only result in higher rates of morbidity and mortality but effects the overall wealth of the country too. Nevertheless, simply the presence and intensity of infection can lead to malnutrition, anaemia, poor school performances and stunted growth. Thankfully, such issues are becoming prominent in discussions about public health and with the continual improvement in diagnostics it is clear that concurrent polyparasitism remains prominent in underdeveloped rural areas. The risk factors and consequences of polyparasitism appear to depend on a multitude of factors including gender, age, geographical setting, infection intensity and the host’s overall physical health. Co-infections of Plasmodium and helminths are widespread due to the similarities in ecological requirements for disease transmission and strongly influence parasitaemia, anaemia and hepatosplenomegaly. The absolute influence on one another however remains unclear although most studies agree that ascariasis “helps” and hookworms “hinder.” The underlying aetiology also requires further investigation but it is hypothesized that the strong Th2 and regulatory networks induced by the helminths control malaria-induced pro-inflammatory reactions. This chapter surveys our current understanding about how helminths, such as schistosomes and filariae, influence Plasmodium infection in endemic areas. In addition, we provide an overview about the immune mechanisms that have been elucidated in appropriate co-infection rodent models. If our future goals are to assist individuals suffering from severe poverty, then it is essential to consider all aspects of their life-styles including the unfortunate health burden of multiple parasitic burden. Furthermore, understanding the influence of parasites will provide more appropriate control measures that include critical variations in economic and ecological factors in a particular endemic area and may reveal that not one glove fits all.
Advances in Experimental Medicine and Biology 09/2014; 828:99-129. DOI:10.1007/978-1-4939-1489-0_5 · 1.96 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Schistosomiasis is a severe and chronic disease caused by the parasitic trematode Schistosoma mansoni after deposition of eggs in the liver and intestines. The immune response to S. mansoni eggs is characterized by increased Th2 cells, eosinophilia, and high serum IgE levels. Granulomas are formed around the eggs to protect the organs against tissue damage caused by toxic products that are secreted from the eggs. Egg-derived components have further been shown to activate the IgE-mediated release of IL-4 and IL-13 from basophils, suggesting that basophils could be involved in protection against a fatal course of infection. Using T cell-specific IL-4/IL-13-deficient mice and basophil-deficient Mcpt8Cre mice, we determined the contribution of Th2 cells and basophils for protective immunity against S. mansoni egg-induced pathology during the patent stage of infection. Our results demonstrate that T cell-derived IL-4/IL-13 was essential for granuloma formation, IgE production, basophilia, differentiation of alternatively activated macrophages, and protection against fatal infection. Although basophils were recruited into liver granulomas, they appeared to be dispensable as a source of IL-4/IL-13 both for differentiation of Th2 cells and for prevention of weight loss and mortality.
The Journal of Immunology 08/2014; 193(7). DOI:10.4049/jimmunol.1401155 · 4.92 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Overall asthmatic symptoms can be controlled with diverse therapeutic agents. However, certain symptomatic individuals remain at risk for serious morbidity and mortality which prompts the identification of novel therapeutic targets and treatment strategies. Thus, using an adjuvant-free TH 2 murine model we have deciphered the role of IL-1 signalling during allergic airway inflammation (AAI). Since functional IL-1β depends on inflammasome activation we first studied asthmatic manifestations in specific inflammasome-deficient (NLRP3(-/-) and ASC(-/-) ) and IL-1 receptor type 1(-/-) (IL-1R1(-/-) ) mice on the BALB/c background. To verify the onset of disease we assessed cellular infiltration in the bronchial regions, lung pathology, airway hyper-responsiveness and OVA-specific immune responses. In the absence of NLRP3 inflammasome-mediated IL-1β release all symptoms of AAI were reduced except OVA-specific immunoglobulin levels. To address whether manipulating IL-1 signalling reduced asthmatic development we administered the IL-1R antagonist Anakinra (Kineret®) during critical immunological time-points: sensitization or challenge. Amelioration of asthmatic symptoms was only observed when Anakinra was administered during OVA challenge. Our findings indicate that blocking IL-1 signalling could be a potential complementary therapy for allergic airway inflammation.
[Show abstract][Hide abstract] ABSTRACT: Mass drug administration (MDA) programmes against Onchocerca volvulus use ivermectin (IVM) which targets microfilariae (MF), the worm's offspring. Most infected individuals are hyporesponsive and present regulated immune responses despite high parasite burden. Recently, with MDA programmes, the existence of amicrofilaridermic (a-MF) individuals has become apparent but little is known about their immune responses. Within this immunoepidemiological study, we compared parasitology, pathology and immune profiles in infection-free volunteers and infected individuals that were MF(+) or a-MF. The latter stemmed from villages in either Central or Ashanti regions of Ghana which, at the time of the study, had received up to eight or only one round of MDA respectively. Interestingly, a-MF patients had fewer nodules and decreased IL-10 responses to all tested stimuli. On the other hand, this patient group displayed contrary IL-5 profiles following in vitro stimulation or in plasma and the dampened response in the latter correlated to reduced eosinophils and associated factors but elevated neutrophils. Furthermore, multivariable regression analysis with covariates MF, IVM or the region (Central vs. Ashanti) revealed that immune responses were associated with different covariates: whereas O. volvulus-specific IL-5 responses were primarily associated with MF, IL-10 secretion had a negative correlation with times of individual IVM therapy (IIT). All plasma parameters (eosinophil cationic protein, IL-5, eosinophils and neutrophils) were highly associated with MF. With regards to IL-17 secretion, although no differences were observed between the groups to filarial-specific or bystander stimuli, these responses were highly associated with the region. These data indicate that immune responses are affected by both, IIT and the rounds of IVM MDA within the community. Consequently, it appears that a lowered infection pressure due to IVM MDA may affect the immune profile of community members even if they have not regularly participated in the programmes.
[Show abstract][Hide abstract] ABSTRACT: Fatalities from schistosome infections arise due to granulomatous, immune-mediated responses to eggs that become trapped in host tissues. Schistosome-specific immune responses are characterized by initial Th1 responses and our previous studies demonstrated that Myd88-deficient mice failed to initiate such responses in vivo. Paradoxically, schistosomal antigens fail to stimulate innate cells to release pro-inflammatory cytokines in vitro. Since S. mansoni infection is an intestinal disease, we hypothesized that commensal bacteria could act as bystander activators of the intestinal innate immune system to instigate Th1 responses. Using a broad spectrum of orally-administered antibiotics and antimycotics we analyzed schistosome-infected mice that were simultaneously depleted of gut bacteria. After depletion there was significantly less inflammation in the intestine which was accompanied by decreased intestinal granuloma development. In contrast, liver pathology remained unaltered. In addition, schistosome-specific immune responses were skewed and fecal egg excretion was diminished. This study demonstrates that host microbiota can act as a third partner in instigating helminth-specific immune responses.
[Show abstract][Hide abstract] ABSTRACT: The prevalence of autoimmune and allergic disorders has dramatically increased in developed countries, and it is believed that our ‘cleaner living’ reduces exposure to certain microorganisms and leads to deviated and/or reduced regulation of the immune system. In substantiation of this health hygiene hypothesis, multiple epidemiological studies and animal models have characterized the protective immune responses induced by helminths during auto-inflammatory disorders. The beneficial effects of such helminths, like schistosomes and filariae, are thought to lie in their immunomodulatory capacity, which can be induced by different life-cycle stages or components thereof. In addition to suppressing autoimmunity recent evidence indicates that concurrent helminth infections also counterbalance exacerbated pro-inflammatory immune responses that occur during sepsis, improving survival. As with allergy, epidemiological studies have observed a steady rise in severe sepsis cases and although this may have resulted from several factors (immunosuppressive drugs, chemotherapy, transplantation, increased awareness and increased surgical procedures), it is tempting to hypothesize that the lack of helminth infections in Western countries may have contributed to this phenomenon. This review summarizes how helminths modulate host immunity during sepsis, such as manipulating macrophage activation and provides an overview about the possible implications that may arise during overwhelming bacterial co-infections.
This well written review gives a comprehensive overview on the immunopathology of sepsis and the modulation of immune responses by helminths. It provides evidence that helminths or components thereof may improve the outcome of severe infections. This will allow the development of therapeutic strategies to fight infections and sepsis.
Pathogens and Disease 08/2013; 69(2). DOI:10.1111/2049-632X.12080 · 2.40 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The continual rise of asthma in industrialised countries stands in strong contrast to the situation in developing lands. According to the modified Hygiene Hypothesis, helminths play a major role in suppressing bystander immune responses to allergens, and both epidemiological and experimental studies suggest that the tropical parasitic trematode Schistosoma mansoni elicits such effects. The focus of this study was to investigate which developmental stages of schistosome infection confer suppression of allergic airway inflammation (AAI) using ovalbumin (OVA) as a model allergen. Moreover, we assessed the functional role and localization of infection-induced CD4(+)Foxp3(+) regulatory T cells (Treg) in mediating such suppressive effects. Therefore, AAI was elicited using OVA/adjuvant sensitizations with subsequent OVA aerosolic challenge and was induced during various stages of infection, as well as after successful anti-helminthic treatment with praziquantel. The role of Treg was determined by specifically depleting Treg in a genetically modified mouse model (DEREG) during schistosome infection. Alterations in AAI were determined by cell infiltration levels into the bronchial system, OVA-specific IgE and Th2 type responses, airway hyper-sensitivity and lung pathology. Our results demonstrate that schistosome infection leads to a suppression of OVA-induced AAI when mice are challenged during the patent phase of infection: production of eggs by fecund female worms. Moreover, this ameliorating effect does not persist after anti-helminthic treatment, and depletion of Treg reverts suppression, resulting in aggravated AAI responses. This is most likely due to a delayed reconstitution of Treg in infected-depleted animals which have strong ongoing immune responses. In summary, we conclude that schistosome-mediated suppression of AAI requires the presence of viable eggs and infection-driven Treg cells. These data provide evidence that helminth derived products could be incorporated into treatment strategies that specifically target suppression of immune responses in AAI by inducing Treg cells.
[Show abstract][Hide abstract] ABSTRACT: Whereas Th17 cells are associated with aggravated inflammation, regulatory T cells (Tregs) provide an environment to control overt responses. Nevertheless, Tregs display a certain degree of plasticity demonstrating that T cell differentiation processes are not absolute. Previously, we showed that human Treg clones induced B cells to produce IgG4. Here we focus on the actions of freshly isolated CD4(+)CD25(+)Foxp3(+)CD127(dim) Tregs on Ig production by B cells and the consequences of prior TLR activation of B cells. In the absence of TLR stimuli, Tregs, but not conventional T cells, dampened B cell proliferation, plasma cell formation and, with the exception of IgG4, all other Ig production. Although IgG4 levels were unchanged in total B cell:Treg co-cultures, levels were increased in Treg co-cultures of naive, but not memory, B cells. Triggering TLR on B cells skewed both Ig and cytokine secretion patterns and, surprisingly, Tregs within TLR4- and TLR9- but not TLR2-triggered B cell co-cultures up-regulated retinoic acid related orphan receptor (RORC) and produced IL-17. These data indicate that under conditions like bacterial or viral infections, B cells can escape Treg control, and provides an explanation as to why patients suffering from allergy or helminth infections display polar immunopathological symptoms despite being exposed to the same agent.
[Show abstract][Hide abstract] ABSTRACT: In order to guarantee the fulfillment of their complex lifecycle, adult filarial nematodes release millions of microfilariae (MF), which are taken up by mosquito vectors. The current strategy to eliminate lymphatic filariasis as a public health problem focuses upon interrupting this transmission through annual mass drug administration (MDA). It remains unclear however, how many rounds of MDA are required to achieve low enough levels of MF to cease transmission. Interestingly, with the development of further diagnostic tools a relatively neglected cohort of asymptomatic (non-lymphedema) amicrofilaremic (latent) individuals has become apparent. Indeed, epidemiological studies have suggested that there are equal numbers of patent (MF(+)) and latent individuals. Since the latter represent a roadblock for transmission, we studied differences in immune responses of infected asymptomatic male individuals (n = 159) presenting either patent (n = 92 MF(+)) or latent (n = 67 MF(-)) manifestations of Wuchereria bancrofti. These individuals were selected on the basis of MF, circulating filarial antigen in plasma and detectable worm nests. Immunological profiles of either Th1/Th17, Th2, regulatory or innate responses were determined after stimulation of freshly isolated PBMCs with either filarial-specific extract or bystander stimuli. In addition, levels of total and filarial-specific antibodies, both IgG subclasses and IgE, were ascertained from plasma. Results from these individuals were compared with those from 22 healthy volunteers from the same endemic area. Interestingly, we observed that in contrast to MF(+) patients, latent infected individuals had lower numbers of worm nests and increased adaptive immune responses including antigen-specific IL-5. These data highlight the immunosuppressive status of MF(+) individuals, regardless of age or clinical hydrocele and reveal immunological profiles associated with latency and immune-mediated suppression of parasite transmission.
[Show abstract][Hide abstract] ABSTRACT: Commonly described as masters of regulation parasitic helminth infections provide a fascinating insight into the complexity of our immune system. As with many other pathogens helminths have developed complex evasion strategies and the immune response of the host has to find a balance between eliciting severe damage to eliminate the parasite or limiting damage and thereby accepting the infection. Nevertheless, one should not forget that these infections still pose a serious public health problem and can elicit severe disfigurement or death in the individual. An interesting spin-off of helminth manipulation on host responses is the apparent prevention of autoimmune diseases or allergy although the actual mechanisms remain unclear. It is well known that Toll-like-receptors (TLR) and non-TLR PRRs play a critical role in initiating innate immune responses which in turn create appropriate adaptive immune reactions. Helminths comprise of a multitude of (glyco)-proteins and (glyco)-lipids and some have been shown to trigger TLR, or alter TLR-mediated responses. Such reactions of course alter adaptive immunity as well. This review will address the consequences of TLR-triggering by helminth antigens and the downstream effect on B cell and regulatory T cell (Treg) actions.
Frontiers in Immunology 02/2012; 3:8. DOI:10.3389/fimmu.2012.00008
[Show abstract][Hide abstract] ABSTRACT: Early during Gram-negative sepsis, excessive release of pro-inflammatory cytokines can cause septic shock that is often followed by a state of immune paralysis characterized by the failure to mount adaptive immunity towards secondary microbial infections. Especially, the early mechanisms responsible for such immune hypo-responsiveness are unclear. Here, we show that TLR4 is the key immune sensing receptor to initiate paralysis of T-cell immunity after bacterial sepsis. Downstream of TLR4, signalling through TRIF but not MyD88 impaired the development of specific T-cell immunity against secondary infections. We identified type I interferon (IFN) released from splenic macrophages as the critical factor causing T-cell immune paralysis. Early during sepsis, type I IFN acted selectively on dendritic cells (DCs) by impairing antigen presentation and secretion of pro-inflammatory cytokines. Our results reveal a novel immune regulatory role for type I IFN in the initiation of septic immune paralysis, which is distinct from its well-known immune stimulatory effects. Moreover, we identify potential molecular targets for therapeutic intervention to overcome impairment of T-cell immunity after sepsis.
The EMBO Journal 01/2012; 31(1):201-13. DOI:10.1038/emboj.2011.380 · 10.43 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: TLR2 and TLR4 are crucial for recognition of Chlamydia pneumoniae in vivo, since infected TLR2/4 double-deficient mice are unable to control the infection as evidenced by severe loss of body weight and progressive lethal pneumonia. Unexpectedly, these mice display higher pulmonary levels of the protective cytokine IFNγ than wild type mice. We show here, that antigen-specific CD4(+) T-cells are responsible for the observed IFNγ-secretion in vivo and their frequency is higher in TLR2/4 double-deficient than in wild type mice. The capacity of TLR2/4 double-deficient dendritic cells to re-stimulate CD4(+) T-cells did not differ from wild type dendritic cells. However, the frequency of CD4(+)CD25(+)Foxp3(+) T-cells was considerably higher in wild type compared to TLR2/4 double-deficient mice and was inversely related to the number of IFNγ-secreting CD4(+) effector T-cells. Despite increased IFNγ-levels, at least one IFNγ-mediated response, protective NO-secretion, could not be induced in the absence of TLR2 and 4. In summary, CD4(+)CD25(+)Foxp3(+) regulatory T-cells fail to expand in the absence of TLR2 and TLR4 during pulmonary infection with C. pneumoniae, which in turn enhances the frequency of CD4(+)IFNγ(+) effector T-cells. Failure of IFNγ to induce NO in TLR2/4 double-deficient cells represents one possible mechanism why TLR2/4 double-deficient mice are unable to control pneumonia caused by C. pneumoniae and succumb to the infection.
PLoS ONE 11/2011; 6(11):e26101. DOI:10.1371/journal.pone.0026101 · 3.23 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Inflammasomes are multi-protein complexes that serve as platforms for caspase-1 activation and subsequent proteolytic maturation
of interleukin 1β (IL-1β) within innate immune cells. The Nlrp3 inflammasome is the most fully characterised. It is activated
by various endogenous and exogenous danger signals such as environmental irritants, signals of tissue damage and pathogens.
The broad spectrum of activators is reflected at the physiological level in its implication in normal and dysregulated immune
responses, including various autoinflammatory diseases and the defence against numerous pathogens. Here, we summarise the
present data on the activation of the Nlrp3 inflammasome by eukaryotic pathogens. Recent genetic studies using mice deficient
in inflammasome components demonstrate the involvement of the inflammasome in the outcome of infection with the fungus Candida albicans, the helminth Schistosoma mansoni, as well as the malarial parasite Plasmodium berghei. Altered immune responses were respectively linked to the ability of live fungi, schistosomal egg antigen (SEA) or malarial
hemozoin to activate the inflammasome and induce secretion of mature IL-1β. These initial findings suggest that inflammasome
activation may serve as a common and potentially druggable pathway in the defence against eukaryotic pathogens.