Immune modulation by helminths and the impact on the development of type 2 diabetes
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Abstract:
The main objective of this
thesis is to improve the understanding of the role of helminth infections in
the development of insulin resistance, hence type 2 diabetes, and to gain
insight into the immunological mechanisms underlying this possible interaction.
To this end, we initiated a large scale cluster randomized controlled trial,
assessing the effect of anthelmintic treatment on insulin resistance and other
metabolic, as well as immunological parameters, in a rural area of Indonesia.
Deworming significantly reduced the prevalence of helminths, as well as
infection intensity. Although treatment did not lead to an increase of
whole-body insulin resistance at the community level, a significant increase in
insulin resistance was observed among helminth-infected subjects. Furthermore,
by comparing immune cells of helminth-infected Indonesians before and after
treatment, we gained insight into the specific cell populations that
participate in the type 2 and regulatory networks, and show that treatment
affects specific cell subsets in these networks. Altogether, the studies
described in this thesis show that helminth infections in humans, as well as
the administration of helminth molecules in obese mice, have a beneficial effect
on the insulin sensitivity, and have shed light on the immunomodulatory effects
of helminths.Keywords:
Deworming
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This thesis aimed at investigating the role of genetic and nutritional factors that affect the immune response to malaria in Tanzanian children. The introductory chapter (Chapter 1) reviews the importance of nutritional deficiencies, particularly of zinc, and presents the hypothesis that such deficiencies lead to impaired immunity and contribute to the burden of malaria. The chapter also describes current efforts to prevent malaria through intermittent preventive treatment, both in infants (IPTi) and pregnant women (IPTp). Sulfadoxinepyrimethamine is still used for first-line treatment of uncomplicated malaria, or, in many countries, to prevent malaria and anaemia in pregnancy. In malaria endemic areas, development of resistance to previously valuable antimalarial drugs has been continuously reported for decades. Thus our initial longitudinal study aimed at measuring the prevalence of resistance-associated mutations on dihydrofolate reductase (DHFR) and dihydropteroate synthase (DHPS) genes (dhfr and dhps) that confer parasite resistance to sulphadoxinepyrimethamine (SP) that was used as an interim antimalarial drug after chloroquine resistance. Although SP resistance-associated point mutations were highly prevalent, we observed an adequate parasite response to SP (Chapter 2). We speculated that the impact of the dhfr and dhps mutations on SP resistance may be dependent at least in part on the protective immunity that has developed in response to frequent exposure to infection and may be weighed down by host immunity in endemic areas and thus impacts in the continued use of the drug for treatment of malaria. The impact of other drugs with similar mechanisms of action used as antibiotics in selecting mutations responsible for SP resistance needs therefore to be studied for their modulating activity of the immune response. These findings underscore the relevance to further study the crucial involvement of the immune system in the development of protection against malaria but also affecting the efficacy of treatment modalities of malaria in various African conditions. In the subsequent cross-sectional studies, we assessed the effect of deficiencies of zinc and magnesium as well as iron deficiency anaemia on malaria-specific cytokine responses indicative of innate immunity to Plasmodium falciparum (Chapter 3). In this study, we used Plasmodium falciparum-parasitised red blood cells (pRBCs) as antigens for in vitro stimulation of peripheral blood mononuclear cells (PBMCs). Cytokines were measured in the supernatant of cultured PBMCs after 24 hours of stimulation. Zinc deficiency was associated with a marked increase in monocyte-derived TNF-α concentration in children with malarial infection but not in their uninfected peers. In children with malarial infection, iron deficiency anaemia was associated with elevated concentrations of TNF-α, whereas magnesium deficiency in children without malaria seemed to be associated with increased concentrations of IL-10. Our findings reflected plasticity in cytokine profiles of monocytes reacting to malaria infection under conditions of different nutrient deficiencies. Following the observation of the variable impact of micronutrients on innate cytokines, we evaluated the profile of both type I and type II cytokines and whether they were influenced by nutritional and malaria status (Chapter 4). The cytokine measurements were performed at day 7 of stimulation anticipating that this timing was optimal for measuring effects on these cytokines mainly derived from activated T-cells. The results indicated a variable influence of nutrient deficiencies on increased cytokine response with zinc deficiency and iron deficiency anemia having greater impact on type I and magnesium deficiency on type II cytokines. The subsequent study evaluated the plasma levels of naturally acquired antimalarial antibodies of variousIgG subclasses plus the total IgG and IgM levels and whether they were associated with zinc deficiency based on preceding chapters (Chapter 5). The results indicated a high variability in antibody levels with zinc deficiency, varying with age of the affected child. IgG3 appeared to be predominant across all age subgroups within < 5 yrs aged children providing clues that IgG3 might confer immune protection to malaria under conditions of zinc deficiency. Chapter 6 explored the association between CD36 deficiency, P. falciparum in vitro adherence on purified CD36 and anemia in children. CD36 is a receptor that occurs on the surface of activated immune cells and vascular endothelial cells and participates in phagocytosis and lipid metabolism. We hypothesized that it could play a fundamental role in cytoadherence of erythrocytes that are parasitized by Plasmodium. Our results showed that CD36 deficiency was associated with protection against the development of malarial anemia in children and that it may be mediated through reduced cytoadherence of infected red blood cells to vascular endothelium. These studies demonstrate that despite antimalarial drug resistance, there is a potential for optimizing the immunological protective capacity in the population to confer parasite clearance that can be variably influenced by micronutrient status. Improving nutritional status in this population could be rewarding not only to increase protection to malaria but possibly also to other infections.
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Dihydropteroate synthase
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Abstract The majority of experiments investigating the immune response to gastrointestinal helminth infection use a single bolus infection. However, in situ individuals are repeatedly infected with low doses. Therefore, to model natural infection, mice were repeatedly infected (trickle infection) with low doses of Trichuris muris . Trickle infection resulted in the slow acquisition of immunity reflected by a gradual increase in worm burden followed by a partial expulsion. Flow cytometry revealed that the CD4+ T cell response shifted from Th1 dominated to Th2 dominated, which coincided with an increase in Type 2 cytokines. The development of resistance following trickle infection was associated with increased worm expulsion effector mechanisms including goblet cell hyperplasia, Muc5ac production and increased epithelial cell turn over. Depletion of CD4+ T cells reversed resistance confirming their importance in protective immunity following trickle infection. In contrast, depletion of group 2 innate lymphoid cells did not alter protective immunity. T. muris trickle infection resulted in a dysbiotic mircrobiota which began to recover alpha diversity following the development of resistance. These data support trickle infection as a robust and informative model for analysis of immunity to chronic intestinal helminth infection more akin to that observed under natural infection conditions and confirms the importance of CD4+ T cell adaptive immunity in host protection. Author Summary Infection with parasitic worms (helminths) is a considerable cause of morbidity in humans. Understanding how we respond to infection is crucial to developing novel therapies. Laboratory models of helminth infection have been a valuable tool in understanding fundamental immune responses to infection. However, typically an individual mouse will be infected with a large, single-dose of the parasite. This is in contrast to the natural scenario in which individuals will receive frequent low level exposures. What is unknown is how repeated infection alters the development of immunity to infection. We have developed a laboratory model to tackle this question. We infected mice with the model helminth Trichuris muris on a weekly basis and assessed a range of responses in comparison with a more traditional infection system. We found striking differences in the dynamics of the infection, the host immune response, and in changes to host gut microbial populations. Our study shows how resistance to helminth infection can develop over time in response to repeat infection, and provides a model system that better reflects human immunity to this parasite.
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GIN parasite infections are a major disease problem in small ruminants. Haemonchus contortus is one of the most economically important GIN parasites causing global production losses. Anthelmintic drugs are the commonly used control method for most parasitic infections. However, development of widespread resistance to most current anthelmintics suggests alternative controls are needed. Such strategies may include breeding parasite-resistant sheep and the development of effective vaccines. Currently these approaches are limited due to deficits in our understanding of host-parasite relationships. In this thesis research is described which examined the potential role of cutaneous hypersensitivity reactions to measure and better understand the complexity of the sheep immune response to H. contortus. The first question focused on whether cutaneous hypersensitivity reactions to intradermal injections using distinct antigens (allergens and bacterial antigens) could predict worm resistance or susceptibility in sheep with known genetic worm resistance status. Hypersensitivity reactions were observed to various antigens but their use as a predictive tool for natural resistance in this cohort of sheep appeared limited as there was no correlation with parasitological values. The second aim was to quantify immunological responsiveness to different adjuvants and identify the T1 and T2 pathways contributing to their suitability for use with parasite vaccines. This study found that the putative T2 adjuvant DEAE showed persistence and significant correlations with faecal egg counts (FEC) and various immune parameters. The third aim was to determine whether an efficacious adult sheep vaccine could induce protection in young sheep and determine the immune correlates of the lamb response. This study showed that young vaccinated sheep had significant type 2 parasite specific post-vaccination and post-infection hypersensitivity reactions. A lack of a key immune cell in parasite resistance development, the eosinophil response, was inadequate in comparison to adult vaccine experiments suggesting an inability of young sheep to recruit eosinophils, which may play a role in loss of protective efficacy. In conclusion, these studies have demonstrated that cutaneous hypersensitivity responses with relevant antigens are an effective method of studying the inflammatory response against worm infection. They also allowed analysis of the inflammatory effects of adjuvants but were of limited value as a predictive tool for genetic resistance. Thus, it is suggested that further studies relating dermal hypersensitivity reactions to host-parasite responses may lead to a better understanding of host-parasite interactions and provide useful and easily measured markers to identify specific immune reactions in vaccinated and infected animals.
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Abstract Helminth infections, including hookworms and Schistosomes, can cause severe disability and death. Infection management and control would benefit from identification of biomarkers for early detection and prognosis. While animal models suggest that Trefoil Factor Family proteins (TFF2 and TFF3) and interleukin-33 (IL-33) -driven type 2 immune responses are critical mediators of tissue repair and worm clearance in the context of hookworm infection, very little is known about how they are modulated in the context of human helminth infection. We measured TFF2, TFF3, and IL-33 levels in serum from patients in Brazil infected with Hookworm and/or Schistosomes, and compared them to endemic and non-endemic controls. TFF2 was specifically elevated by Hookworm infection, not Schistosoma or co-infection. This elevation was more strongly correlated with age than with worm burden. To determine if this might apply more broadly to other species or regions, we measured TFFs and cytokine levels in both the serum and urine of Nigerian school children infected with S. haematobium . We found that serum levels of TFF2 and 3 were reduced by infection, but urine cytokine levels were increased (IL-1β, TNFα, IL-13, and IL-10). Finally, to determine if TFF2 and 3 might have immunosuppressive effects, we treated stimulated or unstimulated PMBCs with recombinant human TFF2 or TFF3 and measured proinflammatory cytokine levels. We found that rhTFF2, but not rhTFF3, was able to suppress TNF alpha and IFN gamma release from stimulated human PMBCs. Taken together, these data support a role for TFF proteins in human helminth infection. Author Summary Billions of people are infected with parasitic helminths across the globe, especially in resource poor regions. These infections can result in severe developmental delay, disability, and death. Adequate management of helminth infection would benefit from the identification of host biomarkers in easily obtained samples (e.g. serum or urine) that correlate to infection state. Our goal was to determine if specific proteins involved in tissue repair and immune modulation are altered by infection with specific helminth species in Brazil (hookworm) or Nigeria (blood fluke). One of these proteins, Trefoil Factor 2 (TFF2), was elevated in the serum of hookworm infected individuals, and decreased in the serum of blood fluke infected children. In the blood fluke-infected children, there were also significant increases in pro-inflammatory cytokines in the urine, where the eggs burst from host tissue. Further, in laboratory experiments, Trefoil Factor 2 reduced the release of pro-inflammatory cytokines from human blood cells. This suggests that at high levels TFF2 may suppress inflammation and could serve as a biomarker for infection or treatment efficacy.
Proinflammatory cytokine
Hookworm Infections
Helminth Infections
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Helminth Infections
Protozoan infection
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Elevated immunoglobulin E (IgE) levels are often associated with resistance to reinfection in human schistosomiasis. However, Although B cells are the source of schistosome-specific IgE, little is known about B cell subsets or their functions in this infection. We evaluated B cells and their expression of the low-affinity IgE receptor (CD23) in a unique cohort of men occupationally exposed to Schistosoma mansoni and longitudinally followed up through multiple treatments with praziquantel, cures, and reinfections.Resistance levels were calculated on the basis of documented water exposure and reinfection data over many years. The CD23(+) B cell subset was evaluated in whole blood by flow cytometry. Serum antibody isotype and soluble CD23 (sCD23) concentrations were measured by enzyme-linked immunosorbent assay.Expression of membrane CD23 (mCD23) on B cells correlated with the development of resistance against S. mansoni. Higher levels of plasma sCD23, the cleaved form of mCD23, also correlated with resistance and other markers of resistance to reinfection, such as eosinophilia.CD23 may be involved in the development of resistance to schistosome infection through its role in IgE regulation. Understanding these complex host-parasite interactions may lead to insights into the development, mechanisms, and regulation of resistance to reinfection with S. mansoni.
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Hygiene hypothesis
Helminth Infections
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In their review, the authors state that the very low incidence and prevalence of IBD in sub-Saharan Africa cannot be explained by genetic factors since in Black populations of the U.S.A. and U.K., the incidence of these diseases is approaching that of the white populations. Beside helminths whose intestinal infestation is frequent in sub-Saharan Africa, other micro-organisms such as atypical mycobacteria, lactobacilli, etc, might have been reduced in Western population. This is a new variant of the Hygiene hypothesis. After Rook et al., these micro-organisms were acting as adjuvants for induction of T regulatory cells which, associated with antigen-presenting cells secrete IL-10 and TGF-beta, inhibiting the maturation of CD4 T cells to Th1 and Th2 effector cells, and consequently reducing the occurrence of Th1-mediated diseases like Crohn's disease and Th2-mediated diseases like ulcerative colitis. The effects of intestinal helminths on host immunity have been studied in Ethiopian Jews emigrated to Israel. Thorough studies before and after deworming have demonstrated that chronic helminth infestation provokes a state of chronic immune activation with anergy, reversible after deworming. Administration of ova of Trichuris suis, an helminth non pathogenic in man, has given encouraging results in the treatment o Crohn's disease and ulcerative colitis with a good safety record but long-term trials are needed since the potentially harmful effects of helminths on immunity.
Hygiene hypothesis
Deworming
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