Immunocompetence and helminth community of the white-toothed shrew, <Emphasis Type="Italic">Crocidura russula</Emphasis> from the Montseny Natural Park,Spain

Host immunocompetence assessed by spleen size and response to phytohaemagglutinin (PHA) injection may give some indications on the control of parasite infection and on host mediation effect, through immunity, on parasite community structure. We investigated the helminth community and immunocompetence of the white-toothed shrew in a small area to test the relationship between immunocompetence and intensity of helminth infection. At the proximate level and if spleen mass and PHA response reflect the level of immunocompetence, we expected that individuals with a large spleen or a high PHA response should harbour a lower parasite load than individuals with relatively small spleen or low PHA response. In addition, we predicted that the structure of the helminth community should be mediated by the host’s immune defence. Spleen mass was linked to helminth infection. Nematodes and cestodes were negatively associated within hosts. PHA response was not related to total helminth intensity of infection but was negatively related to cestode intensity and positively to nematode intensity. This result suggests either a differential modulating effect on immunity by the two groups of worms or the existence of an antagonistic association between nematodes and cestodes mediated by the immune response of the host.     

On the hunt for helminths: innate immune cells in the recognition and response to helminth parasites

The generation of protective immunity to helminth parasites is critically dependent upon the development of a CD4⁺ T helper type 2 cytokine response. However, the host–parasite interactions responsible for initiating this response are poorly understood. This review will discuss recent advances in our understanding of how helminth-derived products are recognized by innate immune cells. Specifically, interactions between helminth excretory/secretory products and host Toll-like receptors and lectins will be discussed as well as the putative functions of helminth proteases and chitin in activating and recruiting innate immune cells. In addition, the functional significance of pattern recognition by epithelial cells, granulocytes, dendritic cells and macrophages including expression of alarmins, thymic stromal lymphopoetin, interleukin (IL)-25, IL-33 and Notch ligands in the development of adaptive anti-parasite Th2 cytokine responses will be examined.     

Toll-like receptor 4 (TLR4) is required for protective immunity to larval Strongyloides stercoralis in mice

TLR4 is important for immunity to various unicellular organisms and has been implicated in the immune responses to helminth parasites. The immune response against helminths is generally Th2-mediated and studies have shown that TLR4 is required for the development of a Th2 response against allergens and helminth antigens in mice. C3H/HeJ mice, which have a point mutation in the Tlr4 gene, were used in this study to determine the role of TLR4 in protective immunity to the nematode Strongyloides stercoralis. It was demonstrated that TLR4 was not required for killing larval S. stercoralis during the innate immune response, but was required for killing the parasites during the adaptive immune response. No differences were seen in the IL-5 and IFN-gamma responses, antibody responses or cell recruitment between wild type and C3H/HeJ mice after immunization. Protective immunity was restored in immunized C3H/HeJ mice by the addition of wild type peritoneal exudate cells in the environment of the larvae. It was therefore concluded that the inability of TLR4-mutant mice to kill larval S. stercoralis during the adaptive immune response is due to a defect in the effector cells recruited to the microenvironment of the larvae.     

Chemokines and chemokine receptors: Insights from human disease and experimental models of helminthiasis

Infection with helminth parasites affects more than 1.5 billion people and is concentrated in global areas of extreme poverty, having a significant impact on public health, social life and the economy. Upon entry into the host, helminth parasites often migrate through specific tissues triggering host immunity. The immune response triggered by helminth infections is complex and depends on parasite load, site of infection, acuteness/chronicity of the infection and is species-dependent. In general, susceptibility or resistance to the infection involves the participation of the innate immune response and then the balance between several effector CD4⁺ T cells subsets, such as Th1, Th2, Th9, Th17, Tfh and Treg, coordinated by immune mediators such as cytokines and chemokines. Chemokines guide the recruitment and activation of leukocytes under inflammatory and homeostatic states. The chemokine system has been associated with several diseases and experimental models with a significant inflammatory component, including infection with helminth parasites. Therefore, this critical review will highlight the main findings concerning chemokine responses elicited by the interaction between helminth parasites and the hosts’ immune system, hence contributing to the understanding of the relevance of chemokine synthesis and biology in the immunological response to infection by parasitic helminths.     

Filarial parasites develop faster and reproduce earlier in response to host immune effectors that determine filarial life expectancy

Humans and other mammals mount vigorous immune assaults against helminth parasites, yet there are intriguing reports that the immune response can enhance rather than impair parasite development. It has been hypothesized that helminths, like many free-living organisms, should optimize their development and reproduction in response to cues predicting future life expectancy. However, immune-dependent development by helminth parasites has so far eluded such evolutionary explanation. By manipulating various arms of the immune response of experimental hosts, we show that filarial nematodes, the parasites responsible for debilitating diseases in humans like river blindness and elephantiasis, accelerate their development in response to the IL-5 driven eosinophilia they encounter when infecting a host. Consequently they produce microfilariae, their transmission stages, earlier and in greater numbers. Eosinophilia is a primary host determinant of filarial life expectancy, operating both at larval and at late adult stages in anatomically and temporally separate locations, and is implicated in vaccine-mediated protection. Filarial nematodes are therefore able to adjust their reproductive schedules in response to an environmental predictor of their probability of survival, as proposed by evolutionary theory, thereby mitigating the effects of the immune attack to which helminths are most susceptible. Enhancing protective immunity against filarial nematodes, for example through vaccination, may be less effective at reducing transmission than would be expected and may, at worst, lead to increased transmission and, hence, pathology.     

Supplemented nutrition decreases helminth burden and increases drug efficacy in a natural host–helminth system

Gastrointestinal (GI) helminths are common parasites of humans, wildlife, and livestock, causing chronic infections. In humans and wildlife, poor nutrition or limited resources can compromise an individual''s immune response, predisposing them to higher helminth burdens. This relationship has been tested in laboratory models by investigating infection outcomes following reductions of specific nutrients. However, much less is known about how diet supplementation can impact susceptibility to infection, acquisition of immunity, and drug efficacy in natural host–helminth systems. We experimentally supplemented the diet of wood mice (Apodemus sylvaticus) with high-quality nutrition and measured resistance to the common GI nematode Heligmosomoides polygyrus. To test whether diet can enhance immunity to reinfection, we also administered anthelmintic treatment in both natural and captive populations. Supplemented wood mice were more resistant to H. polygyrus infection, cleared worms more efficiently after treatment, avoided a post-treatment infection rebound, produced stronger general and parasite-specific antibody responses, and maintained better body condition. In addition, when applied in conjunction with anthelmintic treatment, supplemented nutrition significantly reduced H. polygyrus transmission potential. These results show the rapid and extensive benefits of a well-balanced diet and have important implications for both disease control and wildlife health under changing environmental conditions.     

Arthropod-transmitted Parasites: Mechanisms of Immune Interaction

Knowledge of arthropod immune mechanisms has been based to alarge extent on studies of non-medically important arthropod-microbialinteractions. Investigations involving arthropods and theirimmune responses against helminth and protozoan parasites theytransmit to vertebrate hosts are relatively limited. Data availablestrongly suggest that effective responses against these parasitesare hemocyte mediated reactions, with blood cells involved inparasite recognition and effector mechanisms. It also is apparentthat parasites are very successful in evading immune destructionin compatible arthropodparasite associations by avoiding immunedetection and/or by actively inhibiting the immune processes.However, an understanding of immune evasion mechanisms operatingon behalf of the parasite is dependent on a more thorough understandingof parasite recognition, signal transduction, and effector mechanismsinvolved in arthropod immunity. Limited data are available onhemocyte recognition events, and nothing is known about thetransduction processes whereby cells convert extracellular signalsto intracellular messages that activate effector mechanisms.Any significant progress in these important areas of researchwill be limited until successful in vitro hemocyte culturesare developed. Convincing data are available from a varietyof arthropod-parasite systems that phenol oxidases play a majorrole in effector mechanisms of the immune response. However,critical biochemical studies are needed to clarify their substratespecificities and the uniqueness of these enzymes. It is essentialthat we identify specific substrates involved in effector mechanisms,and their potential storage forms, if we are to begin to understandimmune processes in arthropods. The sensitivity of HPLC withelectrochemical detection provides a valuable tool for theseinvestigations. The next several years should prove excitingin regard to our understanding of molecular/biochemical processesof arthropod immunity.     

Mast cell responses to helminth infection

Mast cells have been suggested to be major effector cells in the immune response to infection with helminths. It is now clear, however, that mast cells are heterogeneous and have a diversity of important functions. In this review, Timothy Lee, Mark Swieter and Dean Befus point out that much of the confusion about the role of mast cells in immunity stems from methods and interpretations which are inadequate for the diversity of roles played by these cells in host responses to parasites. Classical histochemistry may fail to reveal active mast cells, and studies using chemical antagonists are difficult to interpret until we know more about the action of the drugs. The authors show that current research is extending our knowledge of mast cell heterogeneity, and helping to define the powerful array of mediators that they can use to orchestrate the immune response to helminth infections.     

A mechanistic model of developing immunity to Teladorsagia circumcincta infection in lambs

Acquired immunity influences the severity of parasitic disease, but modelling the effects of acquired immunity in helminth infections has proved challenging. This may be due to a lack of suitable immunological data, or to the perceived complexity of modelling the immune response. We have developed a model of T. circumcincta infection in domestic sheep that incorporates the effects of acquired immunity on parasite establishment and fecundity. A large data set from commercially managed populations of Scottish Blackface sheep was used, which included relationships between IgA activity and worm length, and between worm length and fecundity. Use was also made of a recently published meta-analysis of parasite establishment rates. This realistic but simple model of nematode infection emulates observed patterns of faecal egg counts. The end-of-season faecal egg counts are remarkably robust to perturbations in the majority of the parameters, possibly because of priming of the immune system early in the season, reducing parasite establishment and growth and, therefore, faecal egg counts. Lowering the amount of early infection leads to higher end-of-season egg counts. The periparturient rise in egg counts in ewes appears to have an important role in supplying infection for the priming of the immune response. This feedback in the immune priming suggests that nematode infections may be difficult to eliminate.     

The Effect of Maternal Helminth Infection on Maternal and Neonatal Immune Function and Immunity to Tuberculosis

Background

M. tuberculosis and helminth infection each affects one third of the world population. Helminth infections down regulate cell mediated immune responses and this may contribute to lower efficacy of BCG vaccination and higher prevalence of tuberculosis.

Objective

To determine the effect of maternal helminth infection on maternal and neonatal immune function and immunity to TB.

Methods

In this cross sectional study, eighty five pregnant women were screened for parasitic and latent TB infections using Kato-Katz and QFT-GIT tests, respectively. IFN-γ and IL-4 ELISpot on Cord blood Mononuclear Cells, and total IgE and TB specific IgG ELISA on cord blood plasma was performed to investigate the possible effect of maternal helminth and/or latent TB co-infection on maternal and neonatal immune function and immunity to TB.

Result

The prevalence of helminth infections in pregnant women was 27% (n = 23), with Schistosoma mansoni the most common helminth species observed (20% of women were infected). Among the total of 85 study participants 25.8% were QFT-GIT positive and 17% had an indeterminate result. The mean total IgE value of cord blood was significantly higher in helminth positive than negative women (0.76 vs 0.47, p = 0.042). Cross placental transfer of TB specific IgG was significantly higher in helminth positive (21.9±7.9) than negative (12.3±5.1), p = 0.002) Latent TB Infection positive participants. The IFN-γ response of CBMCs to ESAT-6/CFP-10 cocktail (50 vs 116, p = 0.018) and PPD (58 vs 123, p = 0.02) was significantly lower in helminth positive than negative participants. There was no significant difference in IL-4 response of CBMCs between helminth negative and positive participants.

Conclusions

Maternal helminth infection had a significant association with the IFN-γ response of CBMCs, total IgE and cross placental transfer of TB specific IgG. Therefore, further studies should be conducted to determine the effect of these factors on neonatal immune response to BCG vaccination.     

Immunobiology of hookworm infection

Hookworms infect almost one billion people and are a major cause of iron-deficiency anaemia in developing countries of the tropics. Despite their prevalence and the morbidity they cause, little is known about the immune response to this complex eukaryotic parasite. Recent publications have shed light on the human cellular immune responses to hookworms, as well as mechanisms that hookworms utilize to skew the immune response in its favour. Unlike most other human helminth infections, neither age- nor exposure-related immunity develops in the majority of infected people. A vaccine is therefore a highly desirable goal. To this end, gene sequencing efforts have resulted in the deposition of more than 10,000 hookworm cDNA sequences in the public domain, providing a molecular snapshot of this intriguing parasite and providing novel tools for the development of new control strategies. Significant progress has been made in the development of anti-hookworm recombinant vaccines, and clinical trials are expected to begin in the near future.     

Immune regulation of protection and pathogenesis in Plasmodium falciparum malaria

The immune mechanisms whereby malaria parasites are eliminated by the human host or how they may avoid the immune response are poorly understood. Individuals living in malaria-endemic areas gradually acquire immunity. It is well established that this immunity involves both cell-mediated and humoral mechanisms and that T cells are the major regulators in both these events. The existence of functionally distinct P. falciparum-specific CD4+ T-cell subsets in humans has been shown in several studies. However, in contrast to what is the case in murine models there is no definitive link between the activation of various T cells and the course of human P. falciparum blood-stage infection. In the present paper we will review recent findings which illustrate how the balance between functionally different T-cell subsets affects the development of malaria immunity but also may contribute to its pathogenicity. An example of the latter is the deposition of IgE-containing immune complexes in small vessels, probably leading to local overproduction of tumor-necrosis factor (TNF), a pathogenic factor in malaria.     

Blockade of B7-H1 (programmed death ligand 1) enhances humoral immunity by positively regulating the generation of T follicular helper cells

T follicular helper (T(FH)) cells are critical initiators in the development of T cell-dependent humoral immunity and the generation of protective immunity. We demonstrate that T(FH) cell accumulation and Ab production are negatively regulated by B7-H1 (programmed death ligand 1) in response to both helminth infection and active immunization. Following immunization of B7-H1(-/-) mice with keyhole limpet hemocyanin or helminth Ags, there is a profound increase in induction of T(FH) cells as a result of increased cell cycling and decreased apoptosis relative to wild-type mice. The increase in T(FH) cells in the absence of B7-H1 was associated with significant elevations in Ag-specific Ig response. Cotransfer experiments in vivo demonstrated that B7-H1 expression on B cells was required for negatively regulating T(FH) cell expansion and production of Ag-specific Ig. Treatment of immunized wild-type mice with anti-B7-H1 or anti-programmed death 1 mAbs, but not anti-B7-DC, led to a significant expansion of the T(FH) cell population and an enhanced Ag-specific Ig response. Our results demonstrate that the coinhibitory B7-H1/programmed death 1 pathway can limit the expansion of T(FH) cells and constrain Ag-specific Ig responses. This finding has direct implications for investigations examining the feasibility of therapeutically manipulating this pathway and reveals new insights into the regulation of the humoral immune response.     

Network model of immune responses reveals key effectors to single and co-infection dynamics by a respiratory bacterium and a gastrointestinal helminth

Co-infections alter the host immune response but how the systemic and local processes at the site of infection interact is still unclear. The majority of studies on co-infections concentrate on one of the infecting species, an immune function or group of cells and often focus on the initial phase of the infection. Here, we used a combination of experiments and mathematical modelling to investigate the network of immune responses against single and co-infections with the respiratory bacterium Bordetella bronchiseptica and the gastrointestinal helminth Trichostrongylus retortaeformis. Our goal was to identify representative mediators and functions that could capture the essence of the host immune response as a whole, and to assess how their relative contribution dynamically changed over time and between single and co-infected individuals. Network-based discrete dynamic models of single infections were built using current knowledge of bacterial and helminth immunology; the two single infection models were combined into a co-infection model that was then verified by our empirical findings. Simulations showed that a T helper cell mediated antibody and neutrophil response led to phagocytosis and clearance of B. bronchiseptica from the lungs. This was consistent in single and co-infection with no significant delay induced by the helminth. In contrast, T. retortaeformis intensity decreased faster when co-infected with the bacterium. Simulations suggested that the robust recruitment of neutrophils in the co-infection, added to the activation of IgG and eosinophil driven reduction of larvae, which also played an important role in single infection, contributed to this fast clearance. Perturbation analysis of the models, through the knockout of individual nodes (immune cells), identified the cells critical to parasite persistence and clearance both in single and co-infections. Our integrated approach captured the within-host immuno-dynamics of bacteria-helminth infection and identified key components that can be crucial for explaining individual variability between single and co-infections in natural populations.     

Complement Activation Products C3a and C4a as Endogenous Antimicrobial Peptides

All vertebrate species are constantly challenged by infectious agents and pathogens. In order to fight these infectious agents the human host has developed a sophisticated and powerful immune defense. The complement system, which represents the first defense line of innate immunity is activated immediately, within seconds. The activated immune system recognizes and damages an invading microbe, coordinates the host immune response and further orchestrates the adaptive immune response. Activation of the complement system leads to a rapid and amplified response which includes the generation of small peptides like C3a and C4a that display antimicrobial, anti-fungal and anaphylactic activity. Here we report how these antimicrobial peptides are generated during the immune response and summarize the functional mechanisms of these intrinsically generated anti microbial peptides.     

Protective immune mechanisms in helminth infection

Important insights have recently been gained in our understanding of how host immune responses mediate resistance to parasitic helminths and control associated pathological responses. Although similar cells and cytokines are evoked in response to infection by helminths as diverse as nematodes and schistosomes, the components of the response that mediate protection are dependent on the particular parasite. In this Review, we examine recent findings regarding the mechanisms of protection in helminth infections that have been elucidated in murine models and discuss the implications of these findings in terms of future therapies.     

Immunity to Haemonchus contortus and the cellular response to helminth antigens in the mammary gland of non-lactating sheep.

Cellular exudates induced by infusion with helminth antigens were examined in non-lactating mammary glands of ewes immune to infection with the abomasal nematode, Haemonchus contortus. Secondary immunological responsiveness was expressed in two ways. Firstly, antigens from adult H. contortus elicited larger eosinophil-rich cellular exudates in immune compared to non-immune ewes. In this situation, secondary responsiveness in the mammary gland must have been generated through abomasal infection with the parasite. Secondly, repeated infusion with the antigens from adult H. contortus increased the size of cellular exudates in both immune and non-immune ewes. Eosinophils predominated but numbers of macrophages and lymphocytes were also increased. In this second situation, secondary responsiveness must have been either supplemented in immune ewes or derived completely in non-immune ewes by contact with helminth antigens through the mammary gland. The helminth antigens which induce eosinophil exudates in the mammary gland may not be potently protective against H. contortus. Furthermore, eosinophil exudation may not be an in vivo correlate of immunity which is directly useful for discriminating protective antigens and applicable to vaccine development. Infusion with antigens from adult forms of either H. contortus or Trichostrongylus colubriformis elicited cellular exudates equally well in immune ewes primed by infusion with H. contortus adult antigens 7 days beforehand. In addition, antigens from infective larvae of H. contortus elicited cellular exudates more potently than antigens from adult worms. However, vaccination with irradiated larvae has shown that species-specific protective immunity for H. contortus is stronger than cross-protective immunity conferred by T. colubriformis.(ABSTRACT TRUNCATED AT 250 WORDS)     

Th2-mediated host protective immunity to intestinal nematode infections.

Despite many years of study, relatively little is known about the effector mechanisms that operate against intestine-dwelling nematodes. Most of the current understanding comes from studies of laboratory model systems in rodents. It is clear that when an intestinal helminth infection takes place the immune system generates a strong Th2-mediated response, which regulates a variety of responses characteristic of helminth infections such as eosinophilia, intestinal mastocytosis and elevated IgE production. The ability to modulate the host''s immune response in vivo with cytokine-specific monoclonal antibodies and recombinant cytokines, together with the use of animals with disruption of key genes involved in the immune response, have provided powerful tools with which to dissect the potential effector mechanisms operating. In the absence of a T-cell compartment the host is unable to expel the parasite. If a Th1-dominated response is generated, protective immunity is almost universally compromised. Thus, it it would appear that some aspect of a Th2-mediated response controls effector mechanisms. Although it is clear that for some infections the mast cell appears to be involved in protection, probably through the generation of a non-specific inflammatory response, how these cells become activated remains unclear. Data from infections in transgenic animals suggest that activation is not through the high-affinity receptor for IgE. Such studies also call into doubt the importance of conventional interactions between effector leucocytes and antibody. There is little evidence to support a protective role for eosinophilia in any system. New data also imply that, although interleukin 4 (IL-4) is generally important (and can exert effects independent of an adaptive immune response), it is not always sufficient to mediate protection; other Th2 cytokines (e.g. IL-13) may warrant closer investigation. It is apparent that a number of potential Th2-controlled effector mechanisms (some of which may be particularly important at mucosal surfaces) remain to be explored. Overall, it is likely that worm expulsion is the result of a combination of multiple mechanisms, some of which are more critical to some species of parasite than to others.