Work in this laboratory focuses on the host-parasite relationship in nematode infections. To be infected with worms is the norm for children in developing countries and helminth infections are also common in vertebrate wildlife populations. Thus, the vertebrate immune system probably evolved in the presence of worm infection and may operate optimally in this context. Helminths are known to polarize the immune response towards Th2 responses, epitomized by high levels of IgE and eosinophilia. They have also recently been shown to induce the development of regulatory T cells. Our work can be divided into the following areas, all of which revolve around defining how the parasite affects and interacts with the host immune system.
Most children in developing countries are infected by worms.
Ascaris worms expelled from a child.
Mechanisms of Th2 and T reg polarisiation
Helminths are the classic inducers of Th2 responses and we have recently shown that Th2 polarization is associated with resistance to gastrointestinal (GI) nematode infections in humans (Faulkner et al. 2002, Turner et al. 2003). Although much is known about the pathways of Th1 response induction via the dendritic cell (DC), the mechanisms that drive Th2 responses remain to be elucidated. One hypothesis has been that Th2 polarization occurs by default in the absence of DC activation. However recent studies have shown that helminth products are able to actively mature DCs and affect the expression of surface markers and cytokines. Key questions remain, however. What are the parasite signals given to the dendritic cell that drive maturation and activation. Also, what are the signals received by the T-cell from the dendritic cell that drive a Th2 phenotype? (see figure). We are using excretory - secretory products (ES) from two strains of the parasite Trichuris that induce different immune responses to explore the mechanisms of T cell polarization in dendritic cell cultures. Analysis of ES by proteomics and glycomics will define potential molecular signals potentially driving Th1, Th2 and Treg induction.
Schematic representation of phenotype induction in T-helper cells and the consequences for anti-GI nematode immune responses. Pathogen-associated molecular patterns (PAMPs) from worms trigger pattern-response receptors (PRRs) on antigen-presenting cells of the innate immune system, including dendritic cells (DCs). Activated DCs then polarise T-helper cell phenotype. Different PAMPs induce individual DCs to influence T-helper cells towards a TH1, TH2 or Treg phenotype. Polarised T-helper cells then differentially recruit or suppress distinct immune effectors with distinct consequences for anti-worm responses. Bacterial PAMPs are known to trigger TH1 responses, and GI nematode PAMPs are known to trigger TH2 responses. Other actions shown for GI nematode PAMPs are hypothetical. Blue panel: innate immune compartment; Yellow panel: adaptive immune compartment. Cytokine signals associated with adaptive phases of the immune response are shown in italics.
Co-infection studies in man
The distribution of major pathogenic helminths coincides geographically with many devastating microbial diseases, including tuberculosis, HIV and malaria. The current state of knowledge raises important issues about the effect de-worming could have on susceptibility to, and pathological outcome in, these infections. It has been anticipated that the removal of worms might increase resistance to bystander infections by affecting the TH1/TH2 balance and restoring "normal" levels of T-cell responsiveness to antigens. However, given that worm-mediated immunomodulation reduces inflammatory responses by the induction of Tregs, it might also be speculated that worms could be beneficial in populations affected by infectious diseases with severe immunopathological effects (e.g., cerebral malaria). The legitimate question therefore arises as to whether de-worming could be a double-edged sword? Our own studies in Cameroon suggest that whole blood cytokine response profiles to GI nematode antigens are highly plastic, varying between different age groups and localities and also showing nematode-species-specific effects (Jackson et al., 2004). This suggests that the consequences of treatment could differ between populations, age groups, or individuals with differing infection histories.
We are setting up projects with the aim of providing information on how de-worming may affect the development of the host immune response to important bystander pathogens, with particular reference to malaria. These studies will build on evidence emerging from our most recent fieldwork that GI nematode infection affects innate responses to pathogen-associated molecular patterns (PAMPs).
The hygiene hypothesis
The hygiene hypothesis suggests that the rapid increase in allergies and autoimmune diseases in the developed world is due to improved hygiene and therefore less exposure to pathogens and commensal organisms. Studies have shown that children who attend day nursery, have older siblings, and are brought up in a farming environment are protected from the development of allergy. We believe that helminth infection may be important in driving such protection by the induction of Tregs (see figure). We are investigating the possibility that continuous exposure to animal helminth parasites may also induce Tregs although the infections may not fully progress as they would in their normal host organism.
The role of Retinoids in the biology of nematodes
Model of the structure of Ov FAR 1.
We have recently described a structurally novel type of retinol binding protein (Ov FAR 1) which is secreted by nematode parasites (Garofalo et al 2002, 2003).
The protein has no known counterpart in humans and as retinol has been shown to be critical for parasite survival this molecule has potential as a target for rational drug design.
Currently little is known about the role of retinoids and retinoid binding proteins in the biology of the parasites and their role in the host parasite relationship. We are developing methods using RNAi to knock down the expression of this molecule in the gastrointestinal nematode Heligmosomoides polygyrus which if there is a resultant phentotype may give us greater insight into its role in the parasite biology and evaluate if worms that do not express this molecule affect the host immune response.
H. Faulkner, J. Turner, J. Kamgno, S.D. Pion, M. Boussinesq and J.E. Bradley. 2002. Age- and infection intensity-dependent cytokine and antibody production in human trichuriasis: the importance of IgE. J Infect Dis. 185 665-72.
Garofalo, A., Kläger, S.L., Rowlinson, M-C., Nirmalan, N., Klion, A., Allen, J.E., Kennedy, M.W., and Bradley J.E. (2002) The FAR proteins of filarial nematodes: secretion, glycosylation and lipid binding characteristics. Mol Biochem. Parasitol. 200:161-70.
Turner J., Faulkner, H., Kamgno, J., Cormont, F., Van Snick,J., Else, K., Grencis, R., Behnke, J., Boussinesq, M., and Bradley, J.E. (2003) Th-2 Like Cytokine Responses Correlate with Age-dependent Reduction in Worm Burdens in a Human Intestinal Nematode Infection. J Infect Dis 188: 1768-1755.
Garofalo, A., Rowlinson, M-C.,Hughes, J., Kelly, S.M., Price, N., Cooper, A., Kennedy, M.W., Bradley, J.E. (2003) The FAR protein family of Caenorhabditis elegans Differential ligand binding properties, structural characteristics and developmental regulation J Biol Chem 278: 8065-74.
Jackson, J.A. Turner, J.D. Rentoul, L., Faulkner, H., Behnke, J.M., Hoyle, M., Grencis, R.K., Else, K.J., Kamgno, J., Boussinesq, M., Bradley. J.E. (2004) T helper cell type 2 responsiveness predicts future susceptibility to gastrointestinal nematodes in humans. J Infect Dis 190: 1804-1811.