Cysteine protease B of Leishmania mexicana inhibits host Th1 responses and protective immunity

C3H mice infected with Leishmania mexicana fail to develop a protective Th1 response, and are unable to cure. In this study, we show that L. mexicana cysteine proteases suppress the antileishmanial immune response. Previous studies demonstrated that deletion of the entire multicopy cysteine protease B (CPB) gene array in L. mexicana is associated with decreased parasite virulence, potentially attributable to factors related to parasite fitness rather than to direct effects on the host immune response. We now show that C3H mice infected with the L. mexicana deletion mutant (Deltacpb) initially develop lesions that grow at rates comparable to those of wild-type L. mexicana-infected mice. However, in contrast to controls, Deltacpb-induced lesions heal with an accompanying Th1 immune response. Lesion resolution was Th1 dependent, as Deltacpb-infected IL-12p40(-/-) and STAT4(-/-) mice developed high parasite burdens and progressive disease. Moreover, when L. major was transfected with a cosmid expressing multiple L. mexicana CPB genes, this parasite induced a significantly lower IFN-gamma response compared with wild-type L. major. These data indicate that cysteine proteases of L. mexicana are critical in suppressing protective immune responses and that inhibition of CPB may prove to be a valuable immunomodulatory strategy for chronic forms of leishmaniasis.     

Plasmodium yoelii: the effect of second blood meal and anti-sporozoite antibodies on development and gene expression in the mosquito vector, Anopheles stephensi

The sporogonic development of the malaria parasite takes place in the mosquito and a wide range of factors modulates it. Among those, the contents of the blood meal can influence the parasite development directly or indirectly through the mosquito response to the infection. We have studied the effect of a second blood meal in previously infected mosquitoes and the effect of anti-sporozoite immune serum on parasite development and mosquito response to the infection. The prevalence and intensity of infection and gene expression of both Plasmodium yoelii and Anopheles stephensi was analyzed. We verified that a second blood meal and its immune status interfere with parasite development and with Plasmodium and mosquito gene expression.     

Immune response to Leishmania (Leishmania) chagasi infection is reduced in malnourished BALB/c mice

Protein-energy malnutrition and micronutrient deficiencies may down-regulate immune response and increase morbidity and mortality due to infection. In this study, a murine model was used to study the effects of protein, iron and zinc deficiencies on the immune response to Leishmania (Leishmania) chagasi infection. Mice were initially fed a standard diet or with a diet containing 3% casein but deficient in zinc and iron. After malnutrition was established, mice were inoculated with L. chagasi and sacrificed four weeks later in order to evaluate liver and spleen parasite loads and serum biochemical parameters. Significant decreases in liver and spleen weight, an increase in the parasite loads in these organs and decreases in serum protein and glucose concentrations in malnourished animals were observed. Furthermore, the production of interferon-gamma by spleen cells from infected malnourished mice stimulated by Leishmania antigen was significantly lower compared with that in control diet mice. These data suggest that malnutrition alters the immune response to L. chagasi infection in the BALB/c model and, in association with the effects on biochemical and anatomical parameters of the host, favored increases in the parasite loads in the spleens and livers of these animals.     

Effects of dexamethasone on host innate and adaptive immune responses and parasite development in rainbow trout Oncorhynchus mykiss infected with Loma salmonae

The effects of dexamethasone (dex) treatment on infections with the microsporidian parasite, Loma salmonae and the effects of dex on initiation of the adaptive immune response were investigated in rainbow trout, Oncorhynchus mykiss experimentally infected with the parasite. Dex treatment resulted in significantly higher infections with the parasite in the gills and other internal organs, suggesting that dex inhibits aspects of the innate immune response to L. salmonae; the heavier infections in the gills and organs of rainbow trout resembled infections seen in Chinook salmon. Mean xenoma counts per microscope field in the gills of fish infected with L. salmonae treated with dex or left untreated were 169 and 30, respectively. Although higher numbers of xenomas were observed in dex treated fish, the xenomas were generally smaller in size than in infected control fish. The xenomas in dex treated fish showed morphological signs of degeneration including loss and degeneration of early parasite stages, accumulation of amorphous material in xenomas, and infiltration with phagocytic cells containing degenerated parasites. The xenomas in infected untreated fish had larger xenomas with a more uniform size and contained identifiable parasite stages in the cytoplasm. According to this study, once fish have developed an adaptive immune response to the parasite by previous exposure, then fish have 100% protection to reinfection even when treated with heavy doses of dex. L. salmonae immune fish treated or untreated with dex during reinfection with the parasite developed no xenomas in the gills 6 weeks post reinfection. These results indicate that once the cellular response is primed to L. salmonae, then dex related immunosuppression does not reduce the effectiveness of the adaptive immune response.     

Adaptive social immunity in leaf-cutting ants

Social insects have evolved a suite of sophisticated defences against parasites. In addition to the individual physiological immune response, social insects also express ‘social immunity’ consisting of group-level defences and behaviours that include allogrooming. Here we investigate whether the social immune response of the leaf-cutting ant Acromyrmex echinatior reacts adaptively to the virulent fungal parasite, Metarhizium anisopliae. We ‘immunized’ mini-nests of the ants by exposing them twice to the parasite and then compared their social immune response with that of naive mini-nests that had not been experimentally exposed to the parasite. Ants allogroomed individuals exposed to the parasite, doing this both for those freshly treated with the parasite, which were infectious but not yet infected, and for those treated 2 days previously, which were already infected but no longer infectious. We found that ants exposed to the parasite received more allogrooming in immunized mini-nests than in naive mini-nests. This increased the survival of the freshly treated ants, but not those that were already infected. The results thus indicate that the social immune response of this leaf-cutting ant is adaptive, with the group exhibiting a greater and more effective response to a parasite that it has previously been exposed to.     

Direct and indirect immunosuppression by a malaria parasite in its mosquito vector

Malaria parasites develop as oocysts within the haemocoel of their mosquito vector during a period that is longer than the average lifespan of many of their vectors. How can they escape from the mosquito''s immune responses during their long development? Whereas older oocysts might camouflage themselves by incorporating mosquito-derived proteins into their surface capsule, younger stages are susceptible to the mosquito''s immune response and must rely on other methods of immune evasion. We show that the malaria parasite Plasmodium gallinaceum suppresses the encapsulation immune response of its mosquito vector, Aedes aegypti, and in particular that the parasite uses both an indirect and a direct strategy for immunosuppression. Thus, when we fed mosquitoes with the plasma of infected chickens, the efficacy of the mosquitoes to encapsulate negatively charged Sephadex beads was considerably reduced, whether the parasite was present in the blood meal or not. In addition, zygotes that were created ex vivo and added to the blood of uninfected chickens reduced the efficacy of the encapsulation response. As dead zygotes had no effect on encapsulation, this result demonstrates active suppression of the mosquito''s immune response by malaria parasites.     

Chitinase Dependent Control of Protozoan Cyst Burden in the Brain

Chronic infections represent a continuous battle between the host''s immune system and pathogen replication. Many protozoan parasites have evolved a cyst lifecycle stage that provides it with increased protection from environmental degradation as well as endogenous host mechanisms of attack. In the case of Toxoplasma gondii, these cysts are predominantly found in the immune protected brain making clearance of the parasite more difficult and resulting in a lifelong infection. Currently, little is known about the nature of the immune response stimulated by the presence of these cysts or how they are able to propagate. Here we establish a novel chitinase-dependent mechanism of cyst control in the infected brain. Despite a dominant Th1 immune response during Toxoplasma infection there exists a population of alternatively activated macrophages (AAMØ) in the infected CNS. These cells are capable of cyst lysis via the production of AMCase as revealed by live imaging, and this chitinase is necessary for protective immunity within the CNS. These data demonstrate chitinase activity in the brain in response to a protozoan pathogen and provide a novel mechanism to facilitate cyst clearance during chronic infections.     

Leishmania infantum: soluble proteins released by the parasite exert differential effects on host immune response

The objective of this study was to analyse the modulatory effect of proteins released by cultured Leishmania infantum promastigotes on the cellular immune response of infected susceptible (BALB/c) and more resistant (C57BL/6) mice strains after 30 and 45 days of infection. One month after parasite inoculation, L. infantum released protein fractions (High, Inter, and Low according to molecular weight) stimulated C57BL/6 mice spleen cells to proliferate and to express cytokines. Following the decrease of parasite load only the Low protein fraction induced a considerable release of IL-4. In BALB/c mice, specific immune response to protein fractions was only observed at the higher parasitic level, with the fraction Inter promoting the production of IL-4 and fractions High and Low inducing high levels of IL-12. These results point out to a role of these proteins fractions in the modulation of host immunity, that depending on the host genetic background and parasite magnitude, seem to be critical in the control of parasite replication levels, thus avoiding premature host death.     

Analysis of immune response patterns in naïve and Plasmodium berghei-infected young rats following a ferroquine treatment

The direct antimalarial activity of ferroquine (FQ, SSR97193), a chloroquine (CQ) derivative, is well established. To determine whether the FQ anti-parasite activity affects the host immune properties, we have investigated its effect on several immunological parameters in young rats infected with Plasmodium berghei and compared it with that of CQ. In uninfected young rats, treatment with either drug did not show any impairment in the cellular distribution of spleen cells in their response to mitogens and did not induce the production of IL-10 in vivo. After infection, rats treated with CQ or FQ showed no parasitemia and survived with no recrudescence, in comparison with placebo. Nevertheless, FQ cured young rats more rapidly than its parent drug. Analysis of cellular distribution including CD4+TCR+, CD8+TCR+, NK and NKT cells in blood and spleen and the production of specific antibodies did not reveal any alteration of these parameters in infected young rats treated either with CQ or FQ. However, we observed a persistence of CD4+CD25+T-cells in infected CQ-treated rats when compared with infected FQ-treated rats, very likely related to the delay of blood parasite clearance by CQ-treatment. Another significant difference is that the CQ treatment dramatically inhibited the lymphoproliferative response of young infected rats when compared with FQ. Collectively, the absence of any observable immunotoxic effects due to FQ in naïve and infected young rats, together with previous results indicating the susceptibility to FQ of all Plasmodium falciparum field isolates and CQ-resistant strains make it a promising drug for malarial treatment.     

Top-down or bottom-up regulation of intra-host blood-stage malaria: do malaria parasites most resemble the dynamics of prey or predator?

Knowledge of the factors that limit parasite numbers offers hope of improved intervention strategies as well as exposing the selective forces that have shaped parasite life-history strategies. We develop a theoretical framework with which to consider the intra-host regulation of malaria parasite density. We analyse a general model that relates timing and magnitude of peak parasite density to initial dose under three different regulatory processes. The dynamics can be regulated either by top-down processes (upgradable immune regulation), bottom-up processes (fixed immune response and red blood cell (RBC) limitation) or a mixture of the two. We define and estimate the following key parameters: (i) the rate of RBC replenishment; (ii) the rate of destruction of uninfected RBCs; and (iii) the maximum parasite growth rate. Comparing predictions of this model with experimental results for rodent malaria in laboratory mice allowed us to reject functional forms of immune upregulation and/or effects of RBC limitation that were inconsistent with the data. Bottom-up regulation alone was insufficient to account for observed patterns without invoking either localized depletion of RBC density or merozoite interference. By contrast, an immune function upregulated in proportion to either merozoite or infected RBC density was consistent with observed dynamics. An immune response directed solely at merozoites required twice the level of activation of one directed at infected RBCs.     

Mucosal immunity in Toxoplasma gondii infection

Toxoplasma gondii is an intracellular parasite that frequently infects a large spectrum of warm-blooded animals. This parasite induces abortion and establishes both chronic and silent infections, particularly in the brain. Parasite penetration into the host activates a strong anti-parasite immune response. In the present paper, we will discuss the interplay between innate and adaptive immunity that occurs within the infected intestine to clear the parasite and to maintain intestinal homeostasis despite the exacerbation of an inflammatory immune response.     

Effect ofDaucus carota var.boissieri extracts on immune response ofSchistosoma mansoni infected mice

Isolation and structure elucidation was carried out of flavonoid constituents found in fractionated extracts of the seeds and green leaves of Daucus carota L. var. boissieri (Apiaceae). The flavonoids are mainly apigenin, luteolin, their glycosidic precursors and 2,4,5-trimethoxybenzaldehyde. Fatty acids, hydrocarbons and sterols were identified by GLC. The effect of various carrot extracts on the immune responses of Schistosoma mansoni infected mice was studied. The rate of reduction in worm infestation in mice injected with some fractions indicated a strong protection. Some extracts induced humoral immune response through raising the IgG level at 2, 4 and 6 weeks post-infection as compared with infected control. The phenotypic analysis of the cellular immune response in spleen and mesenteric lymph nodes was accomplished by direct immunofluorescence. The data showed that some extracts stimulated the blastogenesis of CD4(+)-T splenocytes and mesenteric lymph node cells.     

Oxidative responses during bacterial phagocytosis of polymorphonuclear leucocytes in primarily and secondarily Fasciola hepatica infected goats

The polymorphonuclear leukocyte (PMN) function, in terms of oxidative response during bacterial phagocytosis, was studied using a Luminol-Dependant Chemiluminiscence (LDCL) assay in primarily and secondarily Fasciola hepatica infected goats. Polymorphonuclear leukocytes of F. hepatica infected goats displayed lower LDCL responses than naive goats. The lowest responses were observed in secondarily infected animals that had higher parasitic burdens and more prominent hepatic lesions. The reduced responses were induced by a functional defect of the circulating PMN but also by a direct involvement of serum factors. Both circulating parasite products and the non protective immune response that occurred during secondary F. hepatica infection of goats could be implied in the alteration of PMN function. These findings suggest the existence of an important mechanism for impairment of the host immune system during goat fasciolosis.     

Effects of dietary protein types on immune responses and levels of infection with Eimeria vermiformis in mice

The present study reports the dietary effects of bovine alpha whey fraction, bovine casein and soy protein isolate on the immune responsiveness of C57BL/6J mice infected with Eimeria vermiformis. During the patent period, mice fed alpha whey fraction had significantly higher blood total white cell, CD4+ and CD8+ lymphocyte counts and higher Con A-stimulated IFN-gamma production by spleen cells than those fed other protein sources, but there was no significant difference in output of faecal oocysts. Casein-fed mice had significantly higher levels of Con A- stimulated IFN-gamma production and a lower output of faecal oocysts than soy-fed mice. The study demonstrated that dietary proteins have different impacts on immune responsiveness and level of parasitic infection in the gut; however, the mechanisms affecting level of infection are not clear. These effects appeared not to be solely related to nutritional properties of the diets. Further research into the underlying immune mechanisms and possible direct interactions between bioactive proteins and the parasite E. vermiformis should be fruitful.     

Costs of parasite resistance for female survival and parental care in a freshwater isopod

Parasite resistance is expected to be costly because activation and maintenance of immune system requires energy that will not be available for other fitness related functions. Here, we experimentally exposed gravid female isopods from two lake populations to trophically transmitted acanthocephalan parasite. Successful establishment of the parasite requires penetration to body cavity; therefore, it is likely to induce an immune response. Resistant females from a lake where the parasite occurs as well as from a lake without the parasite experienced higher mortality than susceptible or control females. Parasite exposure reduced the offspring size at birth in both susceptible, but especially, in resistant females, suggesting that resistant females had less resource to direct for parental care. Parasite exposure had no effect on brood dumping, time to release of offspring or offspring growth rate after birth. Hence, our results reveal costs of resistance in parental survival and parental care of offspring.     

Cytokine Interaction and Immune Responses during Schistosoma mansoni Infection

Of the estimated 200 million people infected with Schistosoma, a subset develop severe life-threatening disease. Adult Schistosoma mansoni are refractory to the immune response and are long-lived, causing chronic exposure to parasite antigen. Although the adult worms themselves are not antigenically inert, it is the parasite eggs that, by accumulating in the liver and traversing the intestinal wall, place a complex series of often-conflicting demands on the host's immune system. In this article, Laura Rosa Brunet, David Dunne and Edward Pearce discuss data from experimental studies in the mouse and field studies in endemic areas that combine to suggest that it is a failure to juggle this immunological conflict that results in severe disease.     

A general model for the influence of immune priming on disease prevalence

Invertebrate immune priming, and other forms of innate immune memory in bacteria, plants, and mammals, modulate the post‐infection resistance, tolerance, and survival phenotypes of individuals previously exposed to microbes. By influencing the probability of both transmission and disease‐induced mortality, priming is likely to have a significant impact on disease dynamics. Two alternative models have been proposed as frameworks for the role of priming in infected populations, but the differences in their underlying key assumptions yield very different predictions for the effect of priming on disease dynamics. By examining these assumptions from the lens of within‐host dynamics, the model presented in this paper demonstrates that priming systems can be characterized along a continuous dose‐response gradient that unites these disparate frameworks. Moreover, it facilitates the incorporation of different kinds of immunological plasticity mechanisms, as well as the exposure probability and transmission characteristics of parasites. Simulating the interaction of these thresholds with the diversity of parasite life history strategies and distributions predicts that priming may actually inflate disease prevalence under certain conditions. Thus, priming of innate immune systems may act analogously to leaky vaccines and drive parasite virulence evolution. The results underscore the need for experimental studies that determine dose response curves for the both the probability of becoming primed following primary parasite exposure and shifts in resistance and tolerance in infected primed hosts. This framework is applicable to a variety of systems that show immunological memory.     

Treatment with dehydroepiandrosterone in vivo and in vitro inhibits reproduction, growth and viability of Taenia crassiceps metacestodes

The aim of this work was to explore the effect of dehydroepiandrosterone (DHEA) on the establishment, growth and reproduction of the metacestode stage of the tapeworm Taenia crassiceps, both in vivo and in vitro. Administration of DHEA prior to infection in mice of both sexes reduced the parasite load by 50% compared with untreated mice. This protective effect was not associated with the immune response, since there was no effect of DHEA treatment on mRNA levels of IL-2, IFN-γ, IL-4 or IL-10. DHEA treatment of infected mice increased androgen receptor expression in splenocytes of both sexes. Moreover, in vitro treatment of T. crassiceps with DHEA reduced reproduction, motility and viability in a dose- and time-dependent fashion. Results indicate that DHEA has strong negative direct modulatory effects on murine cysticercosis. We suggest the use of hormonal-analogues for protective purposes as a therapeutic approach to prevent murine cysticercosis.     

Changes in the haemocyte population of the mosquito, Culex quinquefasciatus, following infection with the filarial parasite, Wuchereria bancrofti

The mosquito Culex quinquefasciatus Say (Diptera: Culicidae) is the vector of the filarial parasite Wuchereria bancrofti (Cobbold) (Spirurida: Onchocercidae), which causes human bancroftian filariasis. Information on the mosquito humoral response against the filarial parasite during the process of its infection and development is important, as it decides the vector competence of the mosquito. Visible changes in the haemocyte population of mosquito, if any, will be an indicator of the possible humoral factors. The present study was aimed at investigating changes in the populations of various types of haemocytes of Cx. quinquefasciatus following infection with W. bancrofti. On day 2 post-feeding on microfilaraemic blood, the haemolymph perfusate of infected mosquitoes with L1 stage of the parasite showed 44.1% granulocytes, 42% prohaemocytes and 13.9% plasmatocytes, whereas that of the control mosquitoes fed on amicrofilaraemic blood showed 63.4% plasmatocytes, 22.2% prohaemocytes and 14.4% granulocytes. Differences in the population numbers of haemocyte types between the infected and control were significant (P > 0.05). However, the mosquitoes examined on day 6 post-feeding, when the parasite was in L2 stage, did not show any such changes. But, similar changes reappeared on day 12 in mosquitoes with L3 stage of the parasite. The observed haemocyte population changes indicate the possibility of some amount of humoral immune response, through the production of certain immune molecules, in Cx. quinquefasciatus infected with W. bancrofti. The nature and exact role of such a response on the filarial parasite development need further investigation.