Vaccine strategies against schistosomiasis

In this review the authors analyze the effector and regulatory mechanisms in the immune response to schistosomiasis. To study these mechanisms two animal models were used, mouse and rat. The mouse totaly permissive host like human, show prominent-T cell control in the acquisition of resistance. But other mechanisms like antibody mediated cytotoxity (ADCC) involving eosinophils and IgG antibodies described in humans, are observed in rats. Also in this animal, it is observed specific IgE antibody high production and blood and tisssue eosinophilia. Using the rat model and schistosomula as target, some ADCC features have emerged: the cellular population involved are bone marrow derived inflammatory cell (mononuclear phagocytes, eosinophils and platelets), interacting with IgE through IgE Fc receptors. Immunization has been attempted using the recombinant protein Sm28/GST. Protection has been observed in rodents with significant decrease of parasite fecundity and egg viability affecting the number, size and volume of liver egg granulomas. The association of praziquantel and immunization with with Sm28/GST increases the resistance to infection and decreases egg viability. The authors suggest the possibility of the stablishment of a future vaccine against Schistosoma mansoni.

Vaccine strategies against schistosomiasis

Schistosomiasis, the second major parasitic disease in the world after malaria affects at least 200 million people, 500 million being exposed to the risk of infection. It is widely agreed that a vaccine strategy wich could lead to the induction of effector mechanisms reducing the level of reinfection and ideally parasite fecundity would deeply affect the incidence of pathological manifestations as well as the parasite transmission potentialities. Extensive studies performed in the rat model have allowed the identification of novel effector mechanisms involving IgE antibodies and various inflammatory cell populations (eosinophils, macrophages and platelets) whereas regulation of immune response by blocking antibodies has been evidencial. Recent epidemiological studies have now entirely confirmed in human populations the the role of IgE antibodies in the acquisition of resistance and the association of IgG4 blocking antibodies with increased susceptibility. On the basis of these concepts, several schistosome glutathion S-transferase (Sm 28 GST) appears as a pronising vaccine candidate. Immunization experiments have shown that two complementary goals can be achieved: (a) a partial but significant reduction of the worm population (up to 60//in rats); (b) a significant reduction of parasite fecundity (up in the mice and 85//in cattle) and egg viability (up to 80//). At least two distinct immunological mechanisms account for these two effects. IgE antibodies appear as a major humoral component of acquired resistance whereas IgA antibodies appear as a major humoral factor affecting parasite fecundity. These studies seem to represent a parasite diseases through the identification of potentially protective antigens and of the components of the immune response which vaccination should aim at inducing.

Development of a vaccine strategy against human and bovine schistosomiasis: background and update

Schistosomiasis is a chronic and debilitating parasitic disease that affects over 200 million people throughout the world and causes about 500,000 deaths annually. Two specific characteristics of schistosome infection are of primordial importance to the development of a vaccine: schistosomes do not multiply within the tissues of their definitive hosts (unlike protozoan parasites) and a partial non-sterilizing immunity can have a marked effect on the incidence of pathology and on disease transmission. Since viable eggs are the cause of disease pathology, a reduction in worm fecundity whether or not accompanied by a reduction in parasite burden is a sufficient goal for vaccine induced immunity. We originally showed that IgE antibodies played in experimental models a pivotal role for the development of protective immunity. These laboratory findings have been now confirmed in human populations. Following the molecular cloning and expression of a protein 28 kDa protein of Schistosoma mansoni and its identification as a glutathion S-transferase, immunization experiments have been undertaken in several animal species (rats, mice, baboons). Together with a significant reduction in parasite burden, vaccination with Sm28 GST was recently shown to reduce significantly parasite fecundity and egg viability leading to a decrease in liver pathology. Whereas IgE antibodies were shown to be correlated with protection against infection, IgA antibodies have been identified as one of the factors affecting egg laying and viability. In human populations, a close association was found between IgA antibody production to Sm28 GST and the decrease of egg output. The use of appropriate monoclonal antibody probes has allowed the demonstration that the inhibition of parasite fecundity following immunization was related to the inhibition of enzymatic activity of the molecule. Epitope mapping of Sm28 GST has indicated the prominent role of the N and C terminal domains. Immunization with the corresponding synthetic peptides was followed by a decrease of 70% of parasite fecundity and egg viability. As a preliminary step towards phase I human trials, vaccination experiments have been performed in cattle, a natural model for Schistosoma bovis. Vaccination of calves with the S. bovis GST has led to a reduction of ever 80% of egg output and tissue egg count. Significant levels of protection were also observed in goats after immunization with the recombinant S. bovis GST. Increasing evidence of the participation of IgA antibodies in protective immunity has prompted us toward the development of mucosal immunization. Preliminary results indicate that significant levels of protection can be achieved following oral immunization with live attenuated vectors or liposomes. These studies seem to represent a promising approach towards the future development of a vaccine strategy against one of major human parasitic diseases.

Epizootiology: [Chapter 9 in Biology of the Acanthocephala]

In practice, epizootiology deals with how parasites spread through host populations, how rapidly the spread occurs and whether or not epizootics result. Prevalence, incidence, factors that permit establishment of infection, host response to infection, parasite fecundity and methods of transfer are, therefore, aspects of epizootiology. Indeed, most aspects of a parasite could be related in sorne way to epizootiology, but many of these topics are best considered in other contexts. General patterns of transmission, adaptations that facilitate transmission, establishment of infection and occurrence of epizootics are discussed in this chapter. When life cycles are unknown, little progress can be made in understanding the epizootiological aspects of any group of parasites. At the time Meyer's monograph was completed (1933), intermediate hosts were known for only 17 species of Acanthocephala, and existing descriptions are not sufficient to permit identification of two of those. Laboratory infections of intermediate hosts had apparently been produced for only two species. Study at that time was primarily devoted to species descriptions, host and geographical distribution, structure and ontogeny. Little or nothing was known about adaptations that promote transmission and the concept of paratenic hosts was unclear. In spite of the paucity of information, Meyer (1932) summarized pathways of transmission among principal groups of hosts, visualized the relationships among life cycle patterns for the major groups of Acanthocephala, and devised models for the hypothetical origin of terrestrial life cycles from aquatic ones. Nevertheless, most of our knowledge regarding epizootiology has been recently acquired.

Polyclonal and specific antibodies mediate protective immunity against enteric helminth infection

Anti-helminth immunity involves CD4+ T cells, yet the precise effector mechanisms responsible for parasite killing or expulsion remain elusive. We now report an essential role for antibodies in mediating immunity against the enteric helminth Heligmosomoides polygyrus (Hp), a natural murine parasite that establishes chronic infection. Polyclonal IgG antibodies, present in naive mice and produced following Hp infection, functioned to limit egg production by adult parasites. Comparatively, affinity-matured parasite-specific IgG and IgA antibodies that developed only after multiple infections were required to prevent adult worm development. These data reveal complementary roles for polyclonal and affinity-matured parasite-specific antibodies in preventing enteric helminth infection by limiting parasite fecundity and providing immune protection against reinfection, respectively. We propose that parasite-induced polyclonal antibodies play a dual role, whereby the parasite is allowed to establish chronicity, while parasite load and spread are limited, likely reflecting the long coevolution of helminth parasites with their hosts.

Lysosome-associated membrane glycoprotein (LAMP)--preliminary study on a hidden antigen target for vaccination against schistosomiasis

Our previously reported gene atlasing of schistosome tissues revealed transcripts that were highly enriched in the digestive tract of Schistosoma mansoni. From these, we selected two candidates, Sm-LAMP and Sm-NPC2 for testing as vaccine targets. The two molecules were selected on the basis of relatively high expression in the gastrodermis, their potentially important biological function, divergence from homologous molecules of the host and possible apical membrane expression in the gastrodermis. Bacterially expressed recombinant peptides corresponding to regions excluding trans-membrane domains of the selected vaccine targets were used in blinded vaccine trials in CBA mice using alum-CpG as adjuvant. Vaccine trials using the recombinant insoluble Sm-LAMP protein showed 16-25% significant reduction in total worm burden. Faecal egg count reduction was 52% and 60% in two trials, respectively, with similar results for the solubly expressed protein. Liver egg burden was reduced significantly (20% and 38%) with an insoluble recombinant Sm-LAMP in two trials, but not with the soluble recombinant form. Parasite fecundity was not affected by either Sm-LAMP protein preparations in the trials. It is concluded that Sm-LAMP may provide limited protection towards S. mansoni infections but could be used in combination with other vaccine candidates, to provide more comprehensive protection.

Female plumage spottiness and parasite resistance in the barn owl (Tyto alba)

The hypothesis that extravagant ornaments signal parasite resistance has received support in several species for ornamented males but more rarely for ornamented females. However, recent theories have proposed that females should often be under sexual selection, and therefore females may signal the heritable capacity to resist parasites. We investigated this hypothesis in the socially monogamous barn owl, Tyto alba, in which females exhibit on average more and larger black spots on the plumage than males, and in which males were suggested to choose a mate with respect to female plumage spottiness. We hypothesized that the proportion of the plumage surface covered by black spots signals parasite resistance. In line with this hypothesis, we found that the ectoparasitic fly, Carnus hemapterus, was less abundant on young raised by more heavily spotted females and those flies were less fecund. In an experiment, where entire clutches were cross-fostered between nests, we found that the fecundity of the flies collected on nestlings was negatively correlated with the genetic mother's plumage spottiness. These results suggest that the ability to resist parasites covaries with the extent of female plumage spottiness. Among females collected dead along roads, those with a lot of black spots had a small bursa of Fabricius. Given that parasites bigger the development of this immune organ, this observation further suggests that more spotted females are usually less parasitized. The same analyses performed on male plumage spottiness all provided non-significant results. To our knowledge, this study is the first one showing that a heritable secondary sexual characteristics displayed by females reflects parasite resistance.

Effect of temperature on different stages of Romanomermis iyengari, a mermithid nematode parasite of mosquitoes

The effect of temperature (20 degrees-35 degrees C) on different stages of Romanomermis iyengari was studied. In embryonic development, the single-cell stage eggs developed into mature eggs in 4.5-6.5 days at 25-35 degrees C but, required 9.5 days at 20 degrees C. Complete hatching occurred in 7 and 9 days after egg-laying at 35 and 30 degrees C, respectively. At 25 and 20 degrees C, 85-96 of the eggs did not hatch even by 30th day. Loss of infectivity and death of the preparasites occurred faster at higher temperatures. The 50 survival durations of preparasites at 20 and 35 degrees C were 105.8 and 10.6 hr respectively. They retained 50 infectivity up to 69.7 and 30.3 hr. The duration of the parasitic phase increased as temperature decreased. Low temperature favoured production of a higher proportion of females which were also larger in size. The maximum time taken for the juveniles to become adults was 14 days at 20 degrees C and the minimum was 9 days at 35 degrees C. Oviposition began earlier at higher temperature than at lower temperature. However, its fecundic period was shorter at 20 degrees C than at 35 degrees C indicating enhanced rate of oviposition at 20 degrees C. Fecundity was adversely affected at 20 degrees C and 35 degrees C. It is shown that the temperature range of 25 degrees-30 degrees C favours optimum development of R. iyengari.

Host-parasite relationships during a biologic invasion: 75 years postinvasion, cane toads and sympatric Australian frogs retain separate lungworm faunas.

Invasive species may carry with them parasites from their native range, differing from parasite taxa found in the invaded range. Host switching by parasites (either from the invader to native fauna or from native fauna to the invader) may have important consequences for the viability of either type of host (e.g., their survivorship, fecundity, dispersal ability, or geographic distribution). Rhabdias pseudosphaerocephala (Nematoda) is a common parasite of cane toads (Rhinella marina) in the toad's native range (South and Central America) and also in its introduced Australian range. This lungworm can depress host viability and is capable of infecting Australian frogs in laboratory trials. Despite syntopy between toads and frogs for up to 75 yr, our analyses, based on DNA sequence data of lungworms from 80 frogs and 56 toads, collected from 2008 to 2011, did not reveal any cases of host switching in nature: toads and native frogs retain entirely different lungworm faunas. All lungworms in cane toads were the South and Central American species Rhabdias pseudosphaerocephala, whereas Australian frogs contained at least four taxa (mostly undescribed and currently lumped under the name Rhabdias cf. hylae). General patterns of prevalence and intensity, based on the dissection of 1,315 frogs collected between 1989 and 2011 across the toads' Australian range, show that these Australian endemic Rhabdias spp. are widely distributed geographically and across host taxa but are more common in some frog species (especially, large-bodied species) than they are in others.

Effects of Plasmodium gallinaceum on hemolymph physiology of Aedes aegypti during parasite development

Insect disease vectors show diminished fecundity when infected with Plasmodium. This phenomenon has already been demonstrated in laboratory models such as Aedes aegypti, Anopheles gambiae and Anopheles stephensi. This study demonstrates several changes in physiological processes of A. aegypti occurring upon infection with Plasmodium gallinaceum, such as reduced ecdysteroid levels in hemolymph as well as altered expression patterns for genes involved in vitellogenesis, lipid transport and immune response. Furthermore, we could show that P. gallinaceum infected A. aegypti presented a reduction in reproductive fitness, accompanied by an activated innate immune response and increase in lipophorin expression, with the latter possibly representing a nutritional resource for Plasmodium sporozoites. (C) 2010 Elsevier Ltd. All rights reserved.

Relationship of abomasal histology and parasite-specific immunoglobulin A with the resistance to Haemonchus contortus infection in three breeds of sheep

This study was carried out to evaluate the relationship of abomasal inflammatory cells and parasite-specific immunoglobulin A (IgA) in mucus, with the resistance to Haemonchus contortus infection in three breeds of sheep naturally infected with gastrointestinal nematodes. The breeds were the native Santa Ines sheep, and the European Suffolk and Ile de France breeds. Mast cells, eosinophils and globule leucocytes were enumerated in abomasal mucosa. Eosinophils within the sub-mucosa also were counted separately. Histamine concentration was estimated in abomasal tissue samples. Enzyme-linked immunosorbent assay was carried out in mucus samples to determine the level of IgA anti-H. contortus third and fifth instar. There were no significant differences among group means of these variables (P > 0.05). The correlation coefficients between fecal egg counts (FEC) x mast cells (r = -0.490; P < 0.05) and FEC x eosinophils in sub-mucosa (r = -0.714; P < 0.01) was significant in the Santa Ines sheep. In the Ile de France group, the correlation coefficients between globule leucocytes x FEC (r = -0.879; P < 0.001) and histamine x worm burden (r = -0.833; P < 0.01) were also significant. In the Santa Ines and Ile de France sheep, correlation coefficients between IgA anti-L3 x worm burden and IgA anti-L3 x FEC were negative. In general, inflammatory cells and IgA-parasite-specific in abomasum were inversely associated with H. contortus worm burden and FEC indicating that they may impair parasite development or fecundity in the three breeds of sheep. However, similar mean values of inflammatory cells and IgA were found in the resistant (Santa Ines) and in the susceptible (Suffolk and Ile de France) breeds of sheep. The enumeration of cells by histological assessment does not provide information on their functional activity, which may be different among breeds. Thus, the effect of breed on the functional activity of these and other inflammatory cells is an important area for further study. (c) 2004 Elsevier B.V. All rights reserved.

Host condition and host immunity affect parasite fitness in a bird-ectoparasite system

1. Parasites might preferentially feed on hosts in good nutritional condition as such hosts provide better resources for the parasites' own growth, survival and reproduction. However, hosts in prime condition are also better able to develop costly immunological or physiological defence mechanisms, which in turn reduce the parasites' reproductive success. The interplay between host condition, host defence and parasite fitness will thus play an important part in the dynamics of host-parasite systems.;2. In a 2 x 2 design, we manipulated both the access to food in great tit Parus major broods and the exposure of the nestlings to hen fleas Ceratophyllus gallinae, a common ectoparasite of hole-breeding birds. We subsequently investigated the role of manipulated host condition, host immunocompetence, and experimentally induced host defence in nestlings on the reproductive success of individual hen flea females.;3. The food supplementation of the nestlings significantly influenced the parasites' reproductive success. Female fleas laid significantly more eggs when feeding on food-supplemented hosts.;4. Previous parasite exposure of the birds affected the reproductive success of fleas. However, the impact of this induced host response on flea reproduction depended on the birds' natural level of immunocompetence, assessed by the phytohaemagglutinin (PHA) skin test. Flea fecundity significantly decreased with increasing PHA response of the nestlings in previously parasite-exposed broods. No relationship between flea fitness and host immunocompetence was, however, found in previously unexposed broods. The PHA response thus correlates with the nestlings' ability to mount immunological or physiological defence mechanisms against hen fleas. No significant interaction effect between early flea exposure and food supplementation on the parasites' reproductive success was found.;5. Our study shows that the reproductive success of hen fleas is linked to the hosts' food supply early in life and their ability to mount induced immunological or physiological defence mechanisms. These interactions between host quality and parasite fitness are likely to influence host preference, host choice and parasite virulence and thus the evolutionary dynamics in host-parasite systems.

Anti-mosquito midgut antibodies block development of Plasmodium falciparum and Plasmodium vivax in multiple species of Anopheles mosquitoes and reduce vector fecundity and survivorship

The mosquito midgut plays a central role in the sporogonic development of malaria parasites. We have found that polyclonal sera, produced against mosquito midguts, blocked the passage of Plasmodium falciparum ookinetes across the midgut, leading to a significant reduction of infections in mosquitoes. Anti-midgut mAbs were produced that display broad-spectrum activity, blocking parasite development of both P. falciparum and Plasmodium vivax parasites in five different species of mosquitoes. In addition to their parasite transmission-blocking activity, these mAbs also reduced mosquito survivorship and fecundity. These results reveal that mosquito midgut-based antibodies have the potential to reduce malaria transmission in a synergistic manner by lowering both vector competence, through transmission-blocking effects on parasite development, and vector abundance, by decreasing mosquito survivorship and egg laying capacity. Because the intervention can block transmission of different malaria parasite species in various species of mosquitoes, vaccines against such midgut receptors may block malaria transmission worldwide.

Suppression of the Insulin Receptors in Adult Schistosoma japonicum Impacts on Parasite Growth and Development: Further Evidence of Vaccine Potential

To further investigate the importance of insulin signaling in the growth, development, sexual maturation and egg production of adult schistosomes, we have focused attention on the insulin receptors (SjIRs) of Schistosoma japonicum, which we have previously cloned and partially characterised. We now show, by Biolayer Interferometry, that human insulin can bind the L1 subdomain (insulin binding domain) of recombinant (r)SjIR1 and rSjIR2 (designated SjLD1 and SjLD2) produced using the Drosophila S2 protein expression system. We have then used RNA interference (RNAi) to knock down the expression of the SjIRs in adult S. japonicum in vitro and show that, in addition to their reduced transcription, the transcript levels of other important downstream genes within the insulin pathway, associated with glucose metabolism and schistosome fecundity, were also impacted substantially. Further, a significant decrease in glucose uptake was observed in the SjIR-knockdown worms compared with luciferase controls. In vaccine/challenge experiments, we found that rSjLD1 and rSjLD2 depressed female growth, intestinal granuloma density and faecal egg production in S. japonicum in mice presented with a low dose challenge infection. These data re-emphasize the potential of the SjIRs as veterinary transmission blocking vaccine candidates against zoonotic schistosomiasis japonica in China and the Philippines.