Overview
Our laboratory integrates immunology with molecular parasitology to understand how parasites evade and direct host immune systems to their own advantage. Our investigations are both at the reductionist level of individual molecules, and at the system level in terms of the whole-body outcome, and we aim to develop new strategies to intervene and cure disease. This objective requires us to use multidisciplinary expertise encompassing cellular immunology, parasite biology, protein chemistry and genomics, at three levels (see Schematic below)
Molecules
The individual parasite gene products that modulate host immunity and adapt to the host environment
Cells
The subsets of innate and adaptive immune system cells which initiate, control and impose immunity
Systems
The whole-body impact of infection on allergy and autoimmunity and molecular interventions to inhibit disease
Molecules
Our focus is on proteins and glycoconjugates secreted by live parasites which are likely to interact with the host (see the review by Maizels, Smits and McSorley in Immunity 2018), and the identification of these products requires a combination of genomics, transcriptomics and proteomics.
Nematode parasites have sizeable genomes, at 1-3 x 109 bp which is up to 10% of the size of their mammalian hosts. Helminth genome sequencing, available at WormBase Parasite, together with targeted transcriptome databases allow us to match data from proteomic analyses, in which we focus on parasite secreted (“ES” : excreted/secreted) antigens such as those we described for Brugia malayi in Hewitson et al (2008) and for H. polygyrus in Hewitson et al (2011).
Currently we study products from gene families that have evolved in helminth parasites to down-regulate or divert the host immune system. Some of the major helminth gene sets are shown below
TGM | TGF-β Μimics | H. polygyrus |  |
VAL | Venom Allergen-Like | B. malayi H. polygyrus |  |
ALT | Abundant Larval Transcript | B. malayi | |
MIF | Macrophage migration inhibition factor | B. malayi |  |
CTL | C-type Lectin Receptor | T. canis |  |
APY | Apyrases | H. polygyrus |
Cells
Parasites which live in mammalian hosts for long periods are successful xenografts, and must survive by altering the host cellular immune response to attenuate or ablate attack. Certainly, parasites have evolved a web of mechanisms for diverting host immune responses. We are dissecting this system by analysing the status, phenotype and specificity of host immune cell populations. We are particularly interested in two dominant, but competing, host cell populations: the Th2 and Treg subsets.
Th2 responses are virtually universal among helminth parasite infections (Maizels and Gause 2023). Currently, we are analysing the initiation of Th2 responses in vivo, in concert with identifying the parasite molecules which induce this reaction. For example, the first responder to gut invasion is the tuft cell. We are establishing which host receptors and cells recognise Th2-driving ligands from nematodes, and the sequence of events which generates overriding type-2 responses. Cells of both the innate and adaptive immune systems synergise in this regard. Several approaches are being matched for this end: in vitro differentiated or purified cell populations (eg dendritic cells and mast cells), T cells from TCR-transgenic mice, and knockout animals in which defined cytokines, receptors or cell populations are deficient.
Regulatory T cells are a dominant factor in many infection settings (see review by Maizels and Smith 2011). We have defined Treg populations in chronic helminth infection (see “Regulatory T cells in Parasite Infection“), and have tested the hypothesis that these are responsible for the suppression of key T cell functions such as antigen-specific proliferation and secretion of pro-inflammatory cytokines. A combination of flow cytometry (both surface and intracellular staining of lymphocytes), cell fractionation and co-culture, and the use of cytokine knockout mice, have been applied to this study. Depletion of Tregs in vivohas also been accomplished by antibody-mediated and genetic strategies.
The choice between effector Th2 and regulatory T cell is one of great import for infection outcome. The role of dendritic cells (DCs) in this dichotomy is being studied, using both in vitro-differentiated DCs exposed to various helminth products, and ex vivo purified DCs, taken from tissues exposed to active infection in vivo.
A further important cell population in infection is the B cell. We also discovered a “Breg”-like population in helminth infected mice (Wilson et al 2010).
Systems
There is now little doubt that Immune down-regulation effected by helminth infections can spill over to modulate other responses, including allergies, autoimmune diseases, other infections and even responsiveness to vaccination. Allergies and helminth infections share a Th2-dominated immune response, and yet allergic disease is lowest in developing countries with high parasite prevalences. By studying the interaction between parasite infection and susceptibility to allergies, using chronic models of airway allergy, we are testing the “Hygiene Hypothesis”. This will permit us to probe the mechanisms for this important cross-regulatory phenomenon.
In models of animal airway allergy, we have found that helminth infections down-regulate inflammation, and indeed protection from allergy can be conferred by introducing secreted helminth proteins rather than live infection. This result is being pursued with a view to developing new therapies for allergy. The same infections also delay and mitigate autoimmune pathology such as experimental autoimmune encephalitis, a model for human multiple sclerosis. Again, the possibility of applying the natural suppressive effects of parasites (and their products) to critical disease conditions is one we are pursuing.
In addition to manipulating systemic responses to exo-allergens and auto-antigens, a major objective is to use our knowledge of parasite immunomodulatory tactics to reverse their immunosuppression and achieve elimination of disease. Several avenues are open to us: we are studying the benefits of specific intervention to block Treg activity; we plan to modify vaccine formulations (and vaccine antigen epitopes) to exclude Treg stimulating components; and we can vaccinate with the immunomodulatory molecules themselves in order to pre-empt parasite suppression in vivo.