BCG: a modifier of immune responses to parasites

The use of BCG (Bacille Calmette-Guerin) as an adjuvant is well-established for vaccination against leprosy and tuberculosis. Dominique Frommel and Phillippe Lagrange discuss the effects of BCG in the control of parasite infections, particularly leishmaniasis, and the possibility of the development of anti-parasite recombinant BCG vaccines.     

Sex-dependent genetic effects on immune responses to a parasitic nematode

Background

Many disease aetiologies have sex specific effects, which have important implications for disease management. It is now becoming increasingly evident that such effects are the result of the differential expression of autosomal genes rather than sex-specific genes. Such sex-specific variation in the response to Trichuris muris, a murine parasitic nematode infection and model for the human parasitic nematode T. trichiura, has been well documented, however, the underlying genetic causes of these differences have been largely neglected. We used the BXD mouse set of recombinant inbred strains to identify sex-specific loci that contribute to immune phenotypes in T. muris infection.

Results

Response phenotypes to T. muris infection were found to be highly variable between different lines of BXD mice. A significant QTL on chromosome 5 (TM5) associated with IFN-γ production was found in male mice but not in female mice. This QTL was in the same location as a suggestive QTL for TNF-α and IL-6 production in male mice suggesting a common control of these pro-inflammatory cytokines. A second QTL was identified on chromosome 4 (TM4) affecting worm burden in both male and female cohorts. We have identified several genes as potential candidates for modifying responses to T. muris infection.

Conclusions

We have used the largest mammalian genetic model system, the BXD mouse population, to identify candidate genes with sex-specific effects in immune responses to T. muris infection. Some of these genes may be differentially expressed in male and female mice leading to the difference in immune response between the sexes reported in previous studies. Our study further highlights the importance of considering sex as an important factor in investigations of immune response at the genome-wide level, in particular the bias that can be introduced when generalizing results obtained from only one sex or a mixed sex population. Rather, analyses of interaction effects between sex and genotype should be part of future studies.

Electronic supplementary material

The online version of this article (doi:10.1186/1471-2164-15-193) contains supplementary material, which is available to authorized users.     

Fish immune responses to experimental and natural infection with helminth parasites

Selected features of the responses by fish to helminth parasites are discussed and comparison is made where appropriate with mammals. These include: (i) Factors influencing host specificity and consideration of the mechanisms that underpin the restriction of some parasites in their host spectrum, (ii) How fish leucocytes kill helminth larvae, with emphasis on the role of released oxygen (ROS) and nitrogen (RNS) free radicals from macrophages, (iii) Immune evasion strategies used by fish helminths, including invasion of immunologically privileged sites, encystment, adsorption of host proteins on the parasite surface, and high surface membrane turnover, (iv) Potential immunogens for vaccination and use for immunodiagnosis of infection, and (v) Natural and induced protection against helminths, with emphasis on the potential for future vaccination strategies.     

Modulation of host immune responses by nematode cystatins

Parasitic nematodes, living in the intestinal tract or within tissues of theirs hosts, are constantly exposed to an array of immune effector mechanisms. One strategy to cope with the immune response is the release of immunomodulatory components that block effector mechanisms or interact with the cytokine network. Among the secreted nematode immunomodulators, cysteine protease inhibitors (cystatins) are shown to be of major importance. Nematode cystatins inhibit, among others, proteases involved in antigen processing and presentation, which leads to a reduction of T cell responses. At the same time nematode cystatins modulate cytokine responses, the most prominent trait being the upregulation of IL-10, a Th2 cytokine, by macrophages. In this situation, IL-10 leads among others to downregulation of costimulatory surface molecules of macrophages. These properties contribute to induction of an anti-inflammatory environment, concomitant with a strong inhibition of cellular proliferation. This setting is believed to favour the survival of worms. An opposite activity of nematode cystatins is the upregulation of production of inducible nitric oxide by IFN-gamma activated macrophages, an intrinsic property of natural cysteine protease inhibitors. This shows that these proteins can act as proinflammatory molecules under certain circumstances. A comparison of the immunomodulatory effects of cystatins of filarial nematodes with homologous proteins of the free-living nematode Caenorhabditis elegans revealed distinct differences. Caenorhabditis elegans cystatins induce the production of the Th1 cytokine IL-12, in contrast to filarial cystatins that upregulate IL-10. Caenorhabditis elegans cystatins hardly inhibit cellular proliferation. These data suggest that cystatins of parasitic nematodes have multiple, specific capacities for immunomodulation, acting in parallel on different immune effector mechanisms. Elucidation of the mechanisms involved might be useful in the development of immunotherapeutic reagents in the future.     

Density-dependent immune responses against the gastrointestinal nematode Strongyloides ratti

Negative density-dependent effects on the fitness of parasite populations are an important force in their population dynamics. For the parasitic nematode Strongyloides ratti, density-dependent fitness effects require the rat host immune response. By analysis of both measurements of components of parasite fitness and of the host immune response to different doses of S. ratti infection, we have identified specific parts of the host immune response underlying the negative density-dependent effects on the fitness of S. ratti. The host immune response changes both qualitatively from an inflammatory Th1- to a Th2-type immune profile and the Th2-type response increases quantitatively, as the density of S. ratti infection increases. Parasite survivorship was significantly negatively related to the concentration of parasite-specific IgG(1) and IgA, whereas parasite fecundity was significantly negatively related to the concentration of IgA only.     

Insect immune resistance to parasitoids

Insect host-parasitoid interactions involve complex physiological, biochemical and genetic interactions. Against endoparasitoids, immune-competent hosts initiate a blood cell-mediated response that quickly destroys the intruders and envelops them in a multilayered melanotic capsule. During the past decade, considerable progress has been made in identifying some of the critical components of the host response, mainly because of the use of efficient molecular tools. This review examines some of the components of the innate immune response of Drosophila, an insect that has served as an exceptionally good experimental model for studying non-self recognition processes and immune cell signaling mechanisms. Topics considered in this review include hematopoiesis, proliferation and adhesion of hemocytes, melanogenesis and associated cytotoxic molecules, and the genetic aspects of the host-parasitoid interaction.     

Fish immune response to Myxozoan parasites

Myxozoan parasites are responsible for important economic losses among fisheries and aquaculture industries, and hence the high interest in studying the immune response of fish against them. The most important data available concerning the immune response of fish against myxosporeans are reviewed, with emphasis on the different innate and adaptive immune mechanisms, their relationship with natural and acquired resistance and the strategies to control and prevent myxosporoses. Cellular effectors (lymphocytes, granulocytes, phagocytes, non-specific cytotoxic cells, rodlet cells) and humoral factors (lysozyme, peroxidades, antiproteases, complement, specific antibodies) have been examined for several myxosporoses, and some immune relevant genes have been studied. This information will be crucial for the future development of vaccines and other preventive strategies such as immunomodulation and selection of disease-resistant strains     

Mosquito immune responses and compatibility between Plasmodium parasites and anopheline mosquitoes

Background  

Functional screens based on dsRNA-mediated gene silencing identified several Anopheles gambiae genes that limit Plasmodium berghei infection. However, some of the genes identified in these screens have no effect on the human malaria parasite Plasmodium falciparum; raising the question of whether different mosquito effector genes mediate anti-parasitic responses to different Plasmodium species.     

Characterisation of effector mechanisms at the host:parasite interface during the immune response to tissue-dwelling intestinal nematode parasites

The protective immune response that develops following infection with many tissue-dwelling intestinal nematode parasites is characterised by elevations in IL-4 and IL-13 and increased numbers of CD4+ T cells, granulocytes and macrophages. These cells accumulate at the site of infection and in many cases can mediate resistance to these large multicellular pathogens. Recent studies suggest novel potential mechanisms mediated by these immune cell populations through their differential activation and ability to stimulate production of novel effector molecules. These newly discovered protective mechanisms may provide novel strategies to develop immunotherapies and vaccines against this group of pathogens. In this review, we will examine recent studies elucidating mechanisms of host protection against three widely-used experimental murine models of tissue-dwelling intestinal nematode parasites: Heligmosomoides polygyrus, Trichuris muris and Trichinella spiralis.     

Resistance in nematode parasites of livestock to the benzimidazole anthelmintics

The benzimidazoles have served humans well in the continual battle to control nematode parasites among livestock. However, the value of these drugs has been seriously undermined in various countries, particularly in the southern hemisphere, by the development of resistance in the target parasite species. Scientists in many countries are trying to come to grips with this problem, with studies both in the laboratory and the field. However, there are shortcomings with both approaches, particularly the former, which need to be recognized. In this article, Peter Waller discusses these in relation to research into the experimental and epidemiological aspects of benzimidazole resistance.     

Insect baculoviruses strongly potentiate adaptive immune responses by inducing type I IFN

Baculoviruses (BVs) are dsDNA viruses that are pathogenic for insects. They have been used worldwide as selective bioinsecticides and for producing recombinant proteins in insect cells. Surprisingly, despite their widespread use in research and industry and their dissemination in the environment, the potential effects of these insect viruses on the immune responses of mammals remain totally unknown. We show in this study that BVs have strong adjuvant properties in mice, promoting potent humoral and CD8(+) T cell adaptive responses against coadministered Ag. BVs also induce the in vivo maturation of dendritic cells and the production of inflammatory cytokines. We demonstrate that BVs play a major role in the strong immunogenicity of virus-like particles produced in the BV-insect cell expression system. The presence of even small numbers of BVs among the recombinant proteins produced in the BV expression system may therefore strengthen the immunological properties of these proteins. This adjuvant behavior of BVs is mediated primarily by IFN-alphabeta, although mechanisms independent of type I IFN signaling are also involved. This study demonstrates that nonpathogenic insect viruses may have a strong effect on the mammalian immune system.     

Nematode parasites of animals are more prone to develop xenobiotic resistance than nematode parasites of plants

In this paper, we concentrate on a comparison of plant and animal-parasitic nematodes, to gain insight into the factors that influence the acquisition of the drug resistance by nematodes. Comparing nematode parasite of domestic animals and cultivated plants, it appears that drug resistance threatens only domestic animal production. Does the paucity of report on nematicide field resistance reflect reality or, is nematicide resistance bypassed by other management practices, specific to cultivated plants (i.e. agricultural control)? First, it seems that selection pressure by treatments in plants is not as efficient as selection pressure in ruminants. Agronomic practices (i.e. sanitation, early planting, usage of nematodes resistant cultivar and crop rotation) are frequently used to control parasitic-plant nematodes. Although the efficiency of such measures is generally moderate to high, integrated approaches are developing successfully in parasitic-plant nematode models. Secondly, the majority of anthelmintic resistance cases recorded in animal-parasitic nematodes concern drug families that are not used in plant-parasitic nematodes control (i.e. benzimidazoles, avermectines and levamisole). Thirdly, particular life traits of parasitic-plant nematodes (low to moderate fecundity and reproductive strategy) are expected to reduce probability of appearance and transmission of drug resistance genes. It has been demonstrated that, for a large number of nematodes such as Meloidogyne spp., the mode of reproduction by mitotic parthenogenesis reduced genetic diversity of populations which may prevent a rapid drug resistance development. In conclusion, anthelmintic resistance develops in nematode parasite of animals as a consequence of an efficient selection pressure. Early detection of anthelmintic resistance is then crucial: it is not possible to avoid it, but only to delay its development in farm animal industry.     

Vaccines against gastrointestinal nematode parasites of ruminants

A consequence of intensive livestock production is an increase in the incidence and impact of gastrointestinal (GI) parasites. Farmers have sought to redress this shift in the natural host-parasite relationship by chemotherapy. However, with the widespread development of resistance to anthelmintics and the current impetus for sustainable agricultural practices, alternatives such as vaccines are being sought to maintain animal productivity. In this article, David Emery and Barry Wagland discuss recent advances in immunity to nematode infections of ruminants and the development of vaccines made possible by the dogged persistence and ingenuity of cadres of parasitologists who have done more than 'go through the motions'.     

An eye on RNAi in nematode parasites

RNA interference (RNAi) has revolutionised approaches to gene function determination. From a parasitology perspective, gene function studies have the added dimension of providing validation data, increasingly deemed essential to the initial phases of drug target selection, pre-screen development. Notionally advantageous to those working on nematode parasites is the fact that Caenorhabditis elegans research spawned RNAi discovery and continues to seed our understanding of its fundamentals. Unfortunately, RNAi data for nematode parasites illustrate variable and inconsistent susceptibilities which undermine confidence and exploitation. Now well-ensconced in an era of nematode parasite genomics, we can begin to unscramble this variation.     

Cellular immune responses in mice infected with the intestinal nematode Trichuris muris.

CBA and B10.BR mice show variation in immune response to the intestinal nematode Trichuris muris. CBA mice develop strong resistance, eliminating worms from the intestine; B10BR mice are permissive and develop chronic infections. It is already known that resistance and permissiveness reflect differential T helper responses. The data reported here show that resistant CBA mice express good antigen-specific lymphocyte proliferative responses to infection, whereas cells from B10.BR mice are relatively anergic, although still responsive to Concanavalin A (ConA). The possibility that the altered proliferative responsiveness seen in infected B10.BR mice reflected quantitative or qualitative changes in T helper cells was examined by comparing cytokine production and expression of cell surface markers (CD4, CD8, and CD28) in mesenteric lymph node cells and spleen cells from both strains and comparing these with the characteristics of cells from resistant CBA mice and from CBA mice that had been rendered permissive to infection by a combination of irradiation and corticosteroid treatment. As expected, cells from B10.BR mice produced high levels of interferon-gamma (IFN-gamma), whereas those from CBA mice released high levels of IL-5, whether stimulated with adult worm somatic antigens, excretory/secretory antigens, or ConA. Immunosuppressed CBA mice produced high levels of both IFN-gamma and IL-5 throughout the experiment. FACS analysis revealed a decrease of CD4+ and an initial increase in CD8+ cells in all infected mice. No major changes occurred in the relative proportion of CD28(+) cells. Further evaluation of the CD28 costimulatory molecule, measured as mean fluorescence intensity, displayed down-regulation in permissive and immunosuppressed mice. The data obtained suggest that lymphocyte unresponsiveness and permissiveness to T. muris infection may be associated with a down-regulation or an initially reduced expression of costimulatory CD28 molecules.     

Immune responses to asexual blood-stages of malaria parasites

The blood stage of the malaria parasite's life cycle is responsible for all the clinical symptoms of malaria. The development of clinical disease is dependent on the interplay of the infecting parasite with the immune status and genetic background of the host. Following repeated exposure to malaria parasites, individuals residing in endemic areas develop immunity. Naturally acquired immunity provides protection against clinical disease, especially severe malaria and death from malaria, although sterilizing immunity is never achieved. Given the absence of antigen processing in erythrocytes, immunity to blood stage malaria parasites is primarily conferred by humoral immune responses. Cellular and innate immune responses play a role in controlling parasite growth but may also contribute to malaria pathology. Here, we analyze the natural humoral immune responses acquired by individuals residing in P. falciparum endemic areas and review their role in providing protection against malaria. In addition, we review the dual potential of cellular and innate immune responses to control parasite multiplication and promote pathology.