Toxocara canis: Molecular basis of immune recognition and evasion

Toxocara canis has extraordinary abilities to survive for many years in the tissues of diverse vertebrate species, as well as to develop to maturity in the intestinal tract of its definitive canid host. Human disease is caused by larval stages invading musculature, brain and the eye, and immune mechanisms appear to be ineffective at eliminating the infection. Survival of T. canis larvae can be attributed to two molecular strategies evolved by the parasite. Firstly, it releases quantities of ‘excretory–secretory’ products which include lectins, mucins and enzymes that interact with and modulate host immunity. For example, one lectin (CTL-1) is very similar to mammalian lectins, required for tissue inflammation, suggesting that T. canis may interfere with leucocyte extravasation into infected sites. The second strategy is the elaboration of a specialised mucin-rich surface coat; this is loosely attached to the parasite epicuticle in a fashion that permits rapid escape when host antibodies and cells adhere, resulting in an inflammatory reaction around a newly vacated focus. The mucins have been characterised as bearing multiple glycan side-chains, consisting of a blood-group-like trisaccharide with one or two O-methylation modifications. Both the lectins and these trisaccharides are targeted by host antibodies, with anti-lectin antibodies showing particular diagnostic promise. Antibodies to the mono-methylated trisaccharide appear to be T. canis-specific, as this epitope is not found in the closely related Toxocara cati, but all other antigenic determinants are very similar between the two species. This distinction may be important in designing new and more accurate diagnostic tests. Further tools to control toxocariasis could also arise from understanding the molecular cues and steps involved in larval development. In vitro-cultivated larvae express high levels of four mRNAs that are translationally silenced, as the proteins they encode are not detectable in cultured larvae. However, these appear to be produced once the parasite has entered the mammalian host, as they are recognised by specific antibodies in infected patients. Elucidating the function of these genes, or analysing if micro-RNA translational silencing suppresses production of the proteins, may point towards new drug targets for tissue-phase parasites in humans

IL-6 controls susceptibility to helminth infection by impeding Th2 responsiveness and altering the Treg phenotype in vivo

IL-6 plays a pivotal role in favoring T-cell commitment toward a Th17 cell rather than Treg-cell phenotype, as established through in vitro model systems. We predicted that in the absence of IL-6, mice infected with the gastrointestinal helminth Heligmosomoides polygyrus would show reduced Th17-cell responses, but also enhanced Treg-cell activity and consequently greater susceptibility. Surprisingly, worm expulsion was markedly potentiated in IL-6-deficient mice, with significantly stronger adaptive Th2 responses in both IL-6−/− mice and BALB/c recipients of neutralizing anti-IL-6 monoclonal Ab. Although IL-6-deficient mice showed lower steady-state Th17-cell levels, IL-6-independent Th17-cell responses occurred during in vivo infection. We excluded the Th17 response as a factor in protection, as Ab neutralization did not modify immunity to H. polygyrus infection in BALB/c mice. Resistance did correlate with significant changes to the associated Treg-cell phenotype however, as IL-6-deficient mice displayed reduced expression of Foxp3, Helios, and GATA-3, and enhanced production of cytokines within the Treg-cell population. Administration of an anti-IL-2:IL-2 complex boosted Treg-cell proportions in vivo, reduced adaptive Th2 responses to WT levels, and fully restored susceptibility to H. polygyrus in IL-6-deficient mice. Thus, in vivo, IL-6 limits the Th2 response, modifies the Treg-cell phenotype, and promotes host susceptibility following helminth infection

Macrobiota — helminths as active participants and partners of the microbiota in host intestinal homeostasis

Important insights have recently been gained in our understanding of the intricate relationship in the intestinal milieu between the vertebrate host mucosal immune response, commensal bacteria, and helminths. Helminths are metazoan worms (macrobiota) and trigger immune responses that include potent regulatory components capable of controlling harmful inflammation, protecting barrier function and mitigating tissue damage. They can secrete a variety of products that directly affect immune regulatory function but they also have the capacity to influence the composition of microbiota, which can also then impact immune function. Conversely, changes in microbiota can affect susceptibility to helminth infection, indicating that crosstalk between these two disparate groups of endobiota can play an essential role in host intestinal immune function and homeostasis

Parasite immunomodulation and polymorphisms of the immune system

Parasites are accomplished evaders of host immunity. Their evasion strategies have shaped every facet of the immune system, driving diversity within gene families and immune gene polymorphisms within populations. New studies published recently in BMC Biology and Journal of Experimental Medicine document parasite-associated immunosuppression in natural populations and suggest that host genetic variants favoring resistance to parasites may be detrimental in the absence of infection

Regulation of immunity and allergy by helminth parasites

There is increasing interest in helminth parasite modulation of the immune system, both from the fundamental perspective of the “arms race” between host and parasite, and equally importantly, to understand if parasites offer new pathways to abate and control untoward immune responses in humans. This article reviews the epidemiological and experimental evidence for parasite down‐regulation of host immunity and immunopathology, in allergy and other immune disorders, and recent progress towards defining the mechanisms and molecular mediators which parasites exploit in order to modulate their host. Among these are novel products that interfere with epithelial cell alarmins, dendritic cell activation, macrophage function and T‐cell responsiveness through the promotion of an immunoregulatory environment. These modulatory effects assist parasites to establish and survive, while dampening immune reactivity to allergens, autoantigens and microbiome determinants

Immunology: the neuronal pathway to mucosal immunity

Type 2 immunity at mucosal surfaces is thought to be initiated by type 2 innate lymphoid cells. New studies report that these cells are themselves activated by the neuropeptide neuromedin U, produced by cholinergic neurons in the gut and in airways

Myeloid Cell Phenotypes in Susceptibility and Resistance to Helminth Parasite Infections

Many major tropical diseases are caused by long-lived helminth parasites that are able to survive by modulation of the host immune system, including the innate compartment of myeloid cells. In particular, dendritic cells and macrophages show markedly altered phenotypes during parasite infections. In addition, many specialized subsets such as eosinophils and basophils expand dramatically in response to these pathogens. The changes in phenotype and function, and their effects on both immunity to infection and reactivity to bystander antigens such as allergens, are discussed

Alarming dendritic cells for Th2 induction

There is an ever-increasing understanding of the mechanisms by which pathogens such as bacteria, viruses, and protozoa activate dendritic cells (DCs) to drive T helper type 1 (Th1) responses, but we know much less about how these cells elicit Th2 responses. This gap in our knowledge puts us at a distinct disadvantage in designing therapeutics for certain immune-mediated diseases. However, progress is being made with the identification of novel endogenous tissue factors that can enhance Th2 induction by DCs

Inflammatory bowel disease

Inflammatory bowel disease (IBD) is an immunological disorder, encompassing Crohn’s disease and ulcerative colitis, which are characterized by chronic intestinal inflammation targeted at harmless commensal bacteria and food antigens. Although the aetiology of IBD remains unclear, environmental factors in susceptible individuals appear to trigger immunological responses that inflame and damage tissues of the digestive tract. Prevalence of IBD is markedly higher in industrialized and affluent countries [1] (see Fig. 1). Evidence of a major underlying role for genetic predisposition to IBD raises the likelihood that the origins of disease and the susceptibility of the current human ‘immunome’ is the evolutionary consequence of marked and prolonged genetic selective pressure exerted by infectious pathogens [3]