Six costs of immunity to gastrointestinal nematode infections

The strength of the immune response and the outcome of the interaction of a host with a parasite are influenced by genetic and phenotypic characteristics of both parties, and by environmental variables. Allocation of host resources to immune defence reduces resources available for other life-history traits. This review identifies six potential costs to the host from immune activation. The costs are likely to be broadly applicable to other immune responses in vertebrate species. Five phenotypic costs arise from: (i) increased metabolic activity; (ii) reduced nutrient availability due to anorexia; (iii) altered priorities for nutrient utilization; (iv) change in size and turnover of pools of immune cells and proteins; and (v) immunopathology from inappropriate or excessive immune activation. Subsumed by these costs is the cost of altered efficiency of nutrient use. A sixth cost is the genetic cost which arises from a change in the capacity of offspring to express production and life-history traits following selection for parasite resistance. The sensitivity of immune responses to the phenotypic status of the host, and the role the immune system shares with the neuroendocrine system in controlling use of resources underpin the importance of immunocompetence to the life-history of the host.     

Interleukin 6 is important for survival after partial hepatectomy in mice

The response to partial hepatectomy (PH) is impaired in interleukin 6 (IL-6)-deficient mice. IL-6 is well known for its role in the induction of the acute phase (AP) response, and the impairment of this response after surgery and hepatectomy could explain the defective hepatocyte regeneration. In addition, it was proposed that IL-6 has an important role in stimulating the reentry of quiescent cells into the cell cycle within the first 2 to 4 hours after PH. To further analyze the role for IL-6, we performed two third hepatectomies in wild-type mice, in IL-6 knockout (KO) mice, and in IL-6 KO mice that were treated 30 minutes before surgery with intravenous (IV) (short acting) or subcutaneous (SC) (long acting) injections of recombinant IL-6. The high postoperative mortality of IL-6-deficient mice could be completely prevented by SC, but not by IV IL-6 treatment, showing the requirement of a sustained action of IL-6. However, there is a subset of IL-6 KO mice that survives a PH in good health even without IL-6 treatment. When we analyzed these mice, we found an intact liver regeneration and no indication of a block in cell cycle reentry. We conclude that the major role of IL-6 is the induction of an adaptive response to PH that ensures body homeostasis and survival.     

The host immune response to gastrointestinal nematode infection in sheep

Gastrointestinal nematode infection represents a major threat to the health, welfare and productivity of sheep populations worldwide. Infected lambs have a reduced ability to absorb nutrients from the gastrointestinal tract, resulting in morbidity and occasional mortality. The current chemo‐dominant approach to nematode control is considered unsustainable due to the increasing incidence of anthelmintic resistance. In addition, there is growing consumer demand for food products from animals not subjected to chemical treatment. Future mechanisms of nematode control must rely on alternative, sustainable strategies such as vaccination or selective breeding of resistant animals. Such strategies take advantage of the host's natural immune response to nematodes. The ability to resist gastrointestinal nematode infection is considered to be dependent on the development of a protective acquired immune response, although the precise immune mechanisms involved in initiating this process remain to be fully elucidated. In this study, current knowledge on the innate and acquired host immune response to gastrointestinal nematode infection in sheep and the development of immunity is reviewed.     

The GroES homolog of Helicobacter pylori confers protective immunity against mucosal infection in mice.

Helicobacter pylori is an important etiologic agent of gastroduodenal disease. In common with other organisms, H. pylori bacteria express heat shock proteins that share homologies with the GroES-GroEL class of proteins from Escherichia coli. We have assessed the heat shock proteins of H. pylori as potential protective antigens in a murine model of gastric Helicobacter infection. Orogastric immunization of mice with recombinant H. pylori GroES- and GroEL-like proteins protected 80% (n = 20) and 70% (n = 10) of animals, respectively, from a challenge dose of 10(4) Helicobacter felis bacteria (compared to control mice, P = 0.0042 and P = 0.0904, respectively). All mice (n = 19) that were immunized with a dual antigen preparation, consisting of H. pylori GroES-like protein and the B subunit of H. pylori urease, were protected against infection. This represented a level of protection equivalent to that provided by a sonicated Helicobacter extract (P = 0.955). Antibodies directed against the recombinant H. pylori antigens were predominantly of the IgG1 class, suggesting that a type 2 T-helper cell response was involved in protection. This work reports a protein belonging to the GroES class of heat shock proteins that was shown to induce protective immunity. In conclusion, GroES-like and urease B-subunit proteins have been identified as potential components of a future H. pylori subunit vaccine.     

Complement-enhanced immunity to infection with Neisseria gonorrhoeae in mice.

Subcutaneous chambers were implanted in mice, injected with Neisseria gonorrhoeae, and supplemented with complement as a model for studying the immunogenicity and strain diversity of N. gonorrhoeae. Immunotypic resistance to N. gonorrhoeae in immunized mice was significantly (P less than 0.01) increased by injection of exogenous guinea pig complement into the host before challenge with gonococci. By using this model to test gonococcal isolates from various geographical areas, two highly immunogenic but immunotypically different gonococcal strains were identified. The piliated cells of these strains induced both complement-enhanced immunity and a degree of exogenous complement-independent immunity. The immunity in mice not treated with complement developed more slowly, was less effective, and waned earlier than that which was complement-dependent. Pretreatment with complement, although highly effective in preventing infection in immunized mice, was much less beneficial in terminating already established infections, even though bactericidal antibodies were present at the time of complement treatment. The mouse chamber model in which both complement-mediated and complement-independent mechanisms of protection can be evaluated may provide an additional tool for elucidating the immunology of gonococcal or other microbial infections.     

CD4~+T细胞与血吸虫感染的保护性免疫

血吸虫病仍是一个严重的世界性公共卫生问题,据WHO最近估计,全世界仍有6亿人口处于感染血吸虫的危险环境中,其中约2亿人受感染,每年死于血吸虫病者超过10万人,造成巨大的社会经济损失.虽然全球范围内,血吸虫病防治已持续数十年,全面控制血吸虫病传播的前景仍不容乐观.血吸虫病疫苗的研制与发展已被置于防治研究的重要地位.近年来,许多研究均集中于抗血吸虫感染的获得性免疫应答机制和寻找可能诱导保护免疫的相关寄生虫抗原分子等基础研究.     

Intranasal interleukin-12 is a powerful adjuvant for protective mucosal immunity.

The use of interleukin (IL)-12 as a new vaccine adjuvant for stimulating protective antiviral mucosal immunity has been examined. Mice were immunized intranasally (in) with an influenza vaccine consisting of soluble hemagglutinin (H1) and neuraminidase (N1) plus IL-12. This treatment resulted in elevated levels of lung and splenic interferon-gamma and IL-10 mRNA. Total and IgG2a anti-H1N1 antibody levels in serum were significantly elevated, as were total, IgG1, IgG2a, and secretory IgA antibody levels in bronchoalveolar lavage (BAL) fluids compared with animals receiving vaccine alone. Mice immunized in with vaccine and IL-12 also exhibited decreased weight loss and dramatically enhanced survival after lethal challenge with infectious influenza virus. Protection was dependent upon the presence of B cells and could be transferred to naive mice by inoculation of either serum or BAL fluid from IL-12-treated mice. These findings show for the first time that soluble IL-12 delivered in serves as a powerful respiratory adjuvant for protective antiviral immunity.     

Importance of immunoglobulin E (IgE) in the protective mechanism against gastrointestinal nematode infection: looking at the intestinal mucosae.

This review discusses experimental evidences that indicate the IgE participation on the effector mechanisms that leads to gastrointestinal nematode elimination. Data discussed here showed that, for most experimental models, the immune response involved in nematode elimination is regulated by Th-2 type cytokines (especially IL-4). However, the mechanism(s) that result in worm elimination is not clear and might be distinct in different nematode species. Parasite specific IgE production, especially the IgE produced by the intestinal mucosae or associated lymphoid organs could participate in the intestinal elimination of Trichinella spiralis from infected rats. Intestinal IgE may also be important to the protective mechanism developed against other gastrointestinal nematodes that penetrate the murine duodenum mucosa tissue, such as Strongyloides venezuelensis and Heligmosomoides polygyrus. At least in Trichinella spiralis infected rats, the results indicated that intestinal IgE might work independently from mast cell degranulation for worm elimination.     

Mapping of chromosomal regions influencing immunological responses to gastrointestinal nematode infections in mice

This paper reports the results of a genome-wide search for quantitative trait loci (QTL) influencing immunological responses to infection with the gastro-intestinal nematode parasite Heligmosomoides polygyrus in an F2 population created by crossing the resistant SWR and the susceptible CBA inbred mouse strains. Following infections, intestinal granuloma score at post mortem, mucosal mast cell protease 1, and IgE and IgG1 titres were recorded. The susceptible CBA mice had significantly higher IgG1, but significantly lower IgE, mucosal mast cell protease 1 and granuloma scores than SWR mice. Significant QTL were mapped to chromosomes 4, 11, 13 and 17 for granuloma score; chromosomes 12 and 17 for IgE; chromosome 10, 17 and 18 for IgG1 and chromosomes 1, 9, 10, 11, 17 and 18 for mucosal mast cell protease 1. Chromosomes 10, 11, 17 and 18 had QTL affecting more than one trait, and these are most likely to represent single QTL with multiple effects rather than multiple QTL. Some of these QTL map to regions known to harbour genes responsible for the induction of immunological responses to intestinal worms.     

Correlates of resistance to gastrointestinal nematode infection in Nigerian West African dwarf sheep

ObjectiveTo investigate correlates of resistance to GI nematode infection in Nigerian West African dwarf (WAD) sheep.MethodsThirty three sheep were randomly assigned to two groups, A (n=27) which were used for experimental infections, and B (n=6) which served as uninfected control. Each infected animal received weekly escalating infections with infective larvae (60% Haemonchus contortus (H. contortus) and 40% Trichostrongylus colubriformis (T. colubriformis) for 4 weeks. The responses of all the infected and control sheep were assessed by faecal egg count (FEC), worm burden (Wb), packed cell volume (PCV), body weight (Bwt), and body condition score (BCS). On the basis of their individual faecal egg output, Lambs in group A with epg ≤1 000 on any sampling day were classified as low faecal egg count (LFEC) phenotype (n = 16), those with epg between 1 000 and 10 000 as intermediate (n=5) and lambs with epg > 10 000 as high feacal egg count (HFEC) phenotype (n=6).ResultsThe difference between the FEC classes was highly significant (P=0.001). The BCS and weight gained at the end of the experiment by the control and LFEC sheep was significantly higher (P≤0.05) than those of the intermediate and HFEC phenotypes. There was a significant and negative correlation between the parasitological measures and the trio of BCS, PCV and Bwt of sheep.ConclusionThe result of the study indicated that the FEC, weight gain, PCV, and BCS are correlates and potential selection criteria of GI nematode resistant WAD sheep.     

卡介苗诱导小鼠产生保护性免疫的机制研究

目的　为了探索结核感染保护性免疫的产生机制及主要抗原成分。方法 我们调查了小鼠PEC细胞分别经活卡介苗和热杀死卡介苗刺激后,所产生的IL-12p40,IL-18和γ-干扰素的水平。调查卡介苗菌体裂解液和培养过滤液诱导细胞因子能力。结果 活的卡介苗可以激活巨噬细胞,诱导出IL-12p40和IL-18,而死的卡介苗却不能。活的和死的卡介苗菌体裂解物都可以诱导细胞产生IL-12p40。活的卡介苗的培养过滤液可以诱导出IL-12p40。而热杀死卡介苗过滤液却不能产生IL-12p40。结论 活的卡介苗分泌到培养上清液中的热稳定物质可以诱导细胞因子的大量产生。     

卡介苗诱导小鼠产生保护性免疫的机制研究

目的 为了探索结核感染保护性免疫的产生机制及主要抗原成分.方法 我们调查了小鼠PEC细胞分别经活卡介苗和热杀死卡介苗刺激后,所产生的IL-12p40,IL-18和γ-干扰素的水平.调查卡介苗菌体裂解液和培养过滤液诱导细胞因子能力.结果 活的卡介苗可以激活巨噬细胞,诱导出IL-12p40和IL-18,而死的卡介苗却不能.活的和死的卡介苗菌体裂解物都可以诱导细胞产生IL-12p40.活的卡介苗的培养过滤液可以诱导出IL-12p40.而热杀死卡介苗过滤液却不能产生IL-12p40.结论 活的卡介苗分泌到培养上清液中的热稳定物质可以诱导细胞因子的大量产生.     

Heterologously type IV pilus expressed protein of Burkholderia pseudomallei is immunogenic but fails to induce protective immunity in mice

Burkholderia pseudomallei is the causative agent of melioidosis, a severe disease of humans and animals. At present, no effective vaccine against melioidosis exists. Bacterial type IV pilin proteins have been used successfully as subunit vaccines. In this study, we evaluated a heterologously expressed and purified type IV pilus protein (PilV) of B. pseudomallei strain K96243 as a candidate subunit vaccine. PilV protein was assessed for its ability to protect BALB/c mice against B. pseudomallei strain G207 infection. Mice subcutaneously immunized with purified PilV protein produced high titers of IgG antibodies, which were strongly biased towards IgG1, with lower levels of IgG2a. Even though the PilV protein was highly immunogenic, it could not induce protection against a lethal B. pseudomallei challenge. Possible mechanisms of this non-protection phenomenon are discussed.     

The role of CD4 cells in protective immunity to Brugia pahangi

The BALB/c mouse immunized sub-cutaneously (s.c.) with 45 kRad attenuated third stage larvae (L₃) of the lymphatic filarial nematode Brugia pahangi is strongly immune to a challenge infection (75–100% reduction in recovery at day six post challenge). Analysis of spleen cell supernatants from immunized mice re-stimulated in vitro, with parasite antigen or the non specific T cell mitogen Con-A reveals a cytokine profile (IL-4, IL-5 and IL-9) which indicates that the Th2 subset of CD4 cells has been expanded. In an attempt to formally prove a critical role for CD4 cells in immunity in this model system, immunized mice were given either anti-CD4 or anti-CD8 neutralizing antibodies. Administration of anti-CD4 antibody had a significant and detrimental effect on the immune response whereas anti-CD8 antibody had a negligible effect on immunity. The efficacy of antibody in neutralizing their target cells was determined by fluorescence activated cell sorting analysis (FACS). Spleen cells from anti-CD4 treated immunized mice, when re-stimulated with parasite antigen had a significantly reduced potential to secrete IL-4, IL-5 and IL-9 in vitro and serum from these mice had reduced levels of parasite specific IgG and IgE. These results demonstrate a critical role for CD4 T cells in host protective immunity to B. pahangi in vivo and strongly suggest that some component of the Th2 response plays an important role in the immune response elicited in this model system.     

Genetic markers to gastrointestinal nematode resistance in sheep: a review

Summary  Nematode parasites are the major animal health constraint in sheep production on pasture and cause serious economic losses. Because of failure of anthelmintic drenches, a major research effort has been underway to examine alternatives to chemical control. One of them is selecting sheep which are genetically resistant to parasitic nematodes. However, this last is not widely practiced because of the difficulty of measuring parasite resistance which mostly relies on indirect criteria such as number of nematode eggs passed in the sheep faeces (FEC) packed cell volume (PCV) or enhanced number of eosinophils in peripheral blood. Despite the well known host immune reaction it has been impossible to standardize any immunological parameter and use it as an indicator of parasitic infection. The aim of finding some genetic markers associated with resistance/susceptibility to nematodes is to make diagnostic work easier and conduct an earlier selection of desirable genotypes. However, searching for reliable genetic markers is rather difficult due to different sheep’s manifestation of resistance to either the adult or larval stages of the same parasite species and against the same parasitic stage and various manifestations of the immune responses and antigens against parasites. This review summarizes findings reported in the literature relating to genetic markers to gastrointestinal nematodes resistance in sheep.