Cestode regulation of inflammation and inflammatory diseases

Helminth parasites are masters of immune regulation; a likely prerequisite for long-term survival by circumventing their hosts’ attempt to eradicate them. From a translational perspective, knowledge of immune events as a response to infection with a helminth parasite could be used to reduce the intensity of unwanted inflammatory reactions. Substantial data have accumulated showing that inflammatory reactions that promote a variety of auto-inflammatory diseases are dampened as a consequence of infection with helminth parasites, via either the mobilization of an anti-worm spectrum of immune events or by the direct effect of secretory/excretory bioactive immunomodulatory molecules released from the parasite. However, many issues are outstanding in the definition of the mechanism(s) by which infection with helminth parasites can affect the outcome, positively or negatively, of concomitant disease. We focus on a subgroup of this complex group of metazoan parasites, the cestodes, summarizing studies from rodent models that illustrate if, and by what mechanisms, infection with tapeworms ameliorate or exaggerate disease in their host. The ability of infection with cestodes, or other classes of helminth, to worsen a disease course or confer susceptibility to intracellular pathogens should be carefully considered in the context of ‘helminth therapy’. In addition, poorly characterised cestode extracts can regulate murine and human immunocyte function, yet the impact of these in the context of autoimmune or allergic diseases is poorly understood. Thus, studies with cestodes, as representative helminths, have helped cement the concept that infection with parasitic helminths can inhibit concomitant disease; however, issues relating to long-term effects, potential side-effects, mixed pathogen infections and purification of immunomodulatory molecules from the parasite remain as challenges that need to be addressed in order to achieve the use of helminths as anti-inflammatory agents for human diseases.     

Incorporating parasite systematics in comparative analyses of variation in spleen mass and testes sizes of rodents

Parasite diversity is hypothesized to act on host life-history traits through investment in immunity. In order to incorporate the diversity of the parasite community that an individual host or a host species may face, two indices can be used: Taxonomic Species Richness and Taxonomic Entropy, where the taxonomic information is incorporated with the taxonomic weight. We tested whether these indices correlate with several morphological traits potentially implicated in immune defence and in reproduction, using data on gastrointestinal helminths and their rodent hosts sampled in Southeast Asia. We found no relationship between parasite diversity indices and either spleen mass or testes size at the intraspecific level, i.e. at the level of individuals. At the interspecific level, we found no relationship between the parasite diversity indices and testes size. However, we found that female spleen mass is significantly influenced by the specific species richness of parasites, whereas male spleen mass is influenced by individual mean parasite diversity indices. We concluded that female spleen mass may have evolved in response to gastrointestinal helminth pressure acting at species levels, while in males, the individual spleen mass could be constrained by other factors, such as the blood storage function of the spleen.     

From individual heterogeneity to population-level overdispersion: quantifying the relative roles of host exposure and parasite establishment in driving aggregated helminth distributions

In most host-parasite systems, variation in parasite burden among hosts drives transmission dynamics. Heavily infected individuals introduce disproportionate numbers of infective stages into host populations or surrounding environments, causing sharp increases in frequency of infection. Parasite aggregation within host populations may result from variation among hosts in exposure to infective propagules and probability of subsequent establishment of parasites in the host. This is because individual host heterogeneities contribute to a pattern of parasite overdispersion that emerges at the population level. We quantified relative roles of host exposure and parasite establishment in producing variation in parasite burdens, to predict which hosts are more likely to bear heavy burdens, using big brown bats (Eptesicus fuscus) and their helminths as a model system. We captured bats from seven colonies in Michigan and Indiana, USA, assessed their helminth burdens, and collected data on intrinsic and extrinsic variables related to exposure, establishment, or both. Digenetic trematodes had the highest prevalence and mean abundance while cestodes and nematodes had much lower prevalence and mean abundance. Structural equation modeling revealed that best-fitting models to explain variations in parasite burden included genetic heterozygosity and immunocompetence as well as distance to the nearest water source and the year of host capture. Thus, both differential host exposure and differential parasite establishment significantly influence heterogeneous helminth burdens, thus driving population-level patterns of parasite aggregation.     

Seasonality, cohort-dependence and the development of immunity in a natural host-nematode system

Acquired immunity is known to be a key modulator of the dynamics of many helminth parasites in domestic and human host populations, but its relative importance in natural populations is more controversial. A detailed long-term dataset on the gastrointestinal nematode Trichostrongylus retortaeformis in a wild population of European rabbits (Oryctolagus cuniculus) shows clear evidence of seasonal acquired immunity in the age-structured infection profiles. By fitting a hierarchy of demographic infection-immunity models to the observed age-structured infection patterns, we are able to quantify the importance of different components (seasonality, immunity and host age structure) of the parasite dynamics. We find strong evidence that the hosts' immunocompetence waxes and wanes with the seasons, but also contains a lifelong cohort factor, possibly acting through a maternal effect dependent on the host's month of birth. These observations have important and broad implications for the ecology of parasite infection in seasonal natural herbivore systems.     

Evidence of MHC class I and II influencing viral and helminth infection via the microbiome in a non-human primate

Until recently, the study of major histocompability complex (MHC) mediated immunity has focused on the direct link between MHC diversity and susceptibility to parasite infection. However, MHC genes can also influence host health indirectly through the sculpting of the bacterial community that in turn shape immune responses. We investigated the links between MHC class I and II gene diversity gut microbiome diversity and micro- (adenovirus, AdV) and macro- (helminth) parasite infection probabilities in a wild population of non-human primates, mouse lemurs of Madagascar. This setup encompasses a plethora of underlying interactions between parasites, microbes and adaptive immunity in natural populations. Both MHC classes explained shifts in microbiome composition and the effect was driven by a few select microbial taxa. Among them were three taxa (Odoribacter, Campylobacter and Prevotellaceae-UCG-001) which were in turn linked to AdV and helminth infection status, correlative evidence of the indirect effect of the MHC via the microbiome. Our study provides support for the coupled role of MHC diversity and microbial flora as contributing factors of parasite infection.     

Immunity,antigenic heterogeneity,and aggregation of helminth parasites

Empirical studies of helminth parasites reveal that the distribution of parasite burdens in their host populations is highly aggregated. This aggregation is fundamental to the ecology and epidemiology of helminth parasites. Results from a stochastic model predict that aggregation of helminth parasites is inversely related to the intensity of host immunity. Aggregation also decreases with antigenic heterogeneity and increases with heterogeneity in transmissibility among parasite strains. It is also found that the degree of aggregation is greater when immunity affects parasite fecundity than when immunity acts on host susceptibility. Potential relevance of this result for assessing the influence of vaccines that target either host susceptibility or parasite fecundity on the level of aggregation and consequent effects on drug resistance and disease prevalence are discussed.     

Melanin‐based coloration is related to parasite intensity and cellular immune response in an urban free living bird: the feral pigeon Columba livia

Melanin‐based coloration is widespread among vertebrates, but the adaptive function of this trait remains poorly known. Recently, it has been shown that differently coloured individuals have different abilities to cope with parasites. This correlation between melanin‐based coloration and immunity could be explained by the pleiotropic effects of genes coding for melanin pigmentation on the immune system (‘genetic link’ hypothesis) but also because differently coloured individuals may exploit alternative habitats varying in parasite exposure, which leads to different development of the immune function (‘exposure’ hypothesis). As feral pigeons Columba livia are genetically polymorphic with respect to melanic coloration, they constitute an ideal model system to address such hypotheses. In this study, we showed that darker melanic individuals had a lower endoparasite intensity (reflecting host susceptibility) and had a greater cellular immune response to PHA injection than paler ones, whereas parasite prevalence (reflecting exposure to vectors) was similar between colorations. These results provide a correlative support of the ‘genetic link’ hypothesis: differently coloured individuals might be similarly exposed to parasites but darker ones might have a better ability to control the infection. This suggests that parasitism could play a crucial role in the maintenance of colour polymorphism in natural populations, which opens the interesting possibility that differently coloured individuals could be adapted to alternative environments varying in parasite diversity and exposure.     

Sexual ornamentation relates to immune function in male red grouse Lagopus lagopus scoticus

Sexual ornaments may enable females to discriminate amongst potential mates and choose those having either fewer parasites, or those which are more immunocompetent, or better able to cope with parasites. Tetraonid birds exhibit supra-orbital combs that function in both intra-sexual competition and mate choice. Through a correlative and experimental approach we investigated whether comb size of male red grouse Lagopus lagopus scoticus was related to infection intensity by their main parasite, the gastro intestinal nematode Trichostrongylus tenuis , and to immune function. We first looked at the relationships between immune function, parasite infection and condition. We found that spleen mass, an indirect measure of immune response, correlated positively with T. tenuis load, and negatively with condition. Cell-mediated immunity, a measure of immune defence, correlated positively with condition, and although not significantly related to T. tenuis load, increased when nematode parasites were experimentally reduced. Secondly, we investigated whether comb size was related to condition, T. tenuis load or immune function. Comb size was not significantly related to T. tenuis infection and did not change significantly after nematode parasite removal. However, males with bigger combs were in better condition, had a lighter spleen, a lighter spleen than expected from their T. tenuis load and had greater cell-mediated immunity. The findings suggest that comb size relates to immune function rather than T. tenuis parasite infection intensity. Males with bigger combs are likely to be of higher phenotypic quality because they are more immunocompetent and might be better able to cope with the detrimental effects of parasites.     

What makes a host profitable? Parasites balance host nutritive resources against immunity

Numerous host qualities can modulate parasite fitness, and among these, host nutritive resources and immunity are of prime importance. Indeed, parasite fitness increases with the amount of nutritive resources extracted from the host body and decreases with host immune response. To maximize fitness, parasites have therefore to balance these two host components. Yet, because host nutritive resources and immunity both increase with host body condition, it is unclear whether parasites perform better on hosts in prime, intermediate, or poor condition. We investigated blood meal size and survival of the ectoparasitic louse fly Crataerina melbae in relation to body condition and cutaneous immune response of their Alpine swift (Apus melba) nestling hosts. Louse flies took a smaller blood meal and lived a shorter period of time when feeding on nestlings that were experimentally food deprived or had their cutaneous immune response boosted with methionine. Consistent with these results, louse fly survival was the highest when feeding on nonexperimental nestlings in intermediate body condition. Our findings emphasize that although hosts in poor condition had a reduced immunocompetence, parasites may have avoided them because individuals in poor condition did not provide adequate resources. These findings highlight the fact that giving host immunocompetence primary consideration can result in a biased appraisal of host-parasite interactions.     

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.     

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.     

Helminthiasis, metabolic rates and cold resistance in the red-backed vole from a natural population

Estimation of the standard metabolic rate (SMR), maximal oxygen consumption (MOC) and thermoregulation ability in males of red-backed vole (Clethrionomys rutilus Pallas, 1779) have shown that individuals infected with nematodes Heligmosomum mixtum, regardless of intensity of worm infection, had an increased level of oxygen consumption in the cold exposition, while the individuals infected with the cestodes Arostrilepis horrida, had a lover oxygen consumption than non-invaded individuals. Worm burden of A. horrida correlated negatively with MOC value in the hosts. Thermo-conductance of individuals infected with A. horrida was significantly lower than in ones infected with H. mixtum. Opposite effects of these two helminthes seems to be determined by the specificity of pathogenesis and different body mass of parasites. Total body mass of nematodes are usually less than 0.2% of the host body mass whereas the total body mass of cestodes may exceed 5% of the host body mass.     

Specific versus nonspecific immune defense in the bumblebee,Bombus terrestris L

Abstract.— Hosts vary in both their strength of response to a general immunological insult and in their specific susceptibility to different parasite species or different strains of the same parasite. The variation in the general immune response is considered a result of the costs imposed by selection on defended individuals. The variation in the specific response may originate from variation in host and parasite genotypes and is a requirement for frequency-dependent selection. The relationship between these two fundamental aspects of defense has only rarely been studied. Using the bumblebee Bombus terrestris and its gut trypanosomal parasite Crithidia bombi we found that the host's specific response profile toward different strains correlates negatively with its level of response to a general insult. This is the opposite result one would expect if the level of general response were simply a measure of immunological quality (immunocompetence). Rather, it suggests that there is some form of a trade-off between these two fundamental aspects of the immune system. These results, therefore, shed an important light on the possible constraints that affect the evolution of the immune system and particularly the trade-off between different arms of the immune system.     

Handling ‘immunocompetence’ in ecological studies: do we operate with confused terms?

‘Immunocompetence’ is a term used in avian immunological ecology to refer to the ability of an individual to overcome potential parasite infections. However, there are multiple ecological definitions of this term currently used and all of them are rather liberal in immunological terms. This prevents much of the potential intellectual interchange between avian ecologists and immunologists, which decelerates the development of immunological ecology as a scientific discipline. We therefore highlight that the term should be handled with care. In any individual host‐parasite interrelationship the demands on host immunity are distinct and thus also the measurements of immunity in any particular case should be aimed differently. Although ornithologists often aspire to obtain a single variable for immunity in their research, due to the enormous diversity of parasites possessing the ability to infect the host, there is no single value for anti‐parasite resistance, i.e. no overall ‘immunocompetence’ per se exists. We propose to use more rigorous terminology, consistent with the one used in classical immunology. The term ‘immunocompetence’ (defined as the ability to produce anti‐parasite or anti‐antigen immune response) should be used as 0/1 character. The magnitude of a particular immune response (i.e. a continuous quantitative trait) should be referred to as ‘immune responsiveness’. Most importantly, both terms should always be used only with respect to a certain parasite taxon or antigen studied as otherwise they lose their explanatory value.     

Secondary sex traits,parasites, immunity and ejaculate quality in the Arctic charr

Ejaculate quality may limit male reproductive success. Sperm cells are immunologically perceived as non-self in the male reproductive tract and may therefore be attacked by the immune system. Males may consequently have to suppress their immune system in order to produce high-quality ejaculates. This suppression may be influenced by the current level of parasite infections, suggesting that only parasite-resistant males are able to produce high-quality ejaculates. In a study of naturally infected male Arctic charr sampled during their spawning period, we found that the density of circulating granulocytes, spleen mass and the intensity of infection by one nematode species located outside the testes were negatively associated with ejaculate quality. This suggests that a male''s extra-testicular immune environment may affect the production of high-quality ejaculates and that parasite infections located in the extra-testicular soma may influence ejaculate quality, a trait most likely under directional selection. Moreover, male fertilization potential was negatively correlated with their red spawning coloration. In conclusion, these results emphasize the importance of parasites and immunity as factors generating variability in sperm quality, suggesting that parasite resistance may be of importance for maintaining variance in reproductive success even after copulation.     

Interactions between immunocompetence,somatic condition and parasitism in the chub Leuciscus cephalus in early spring

Relationships between immunocompetence, somatic condition, parasitism and water temperature in a wild population of chub Leuciscus cephalus were investigated. The effects of a rapid temperature increase in early spring were studied for both sexes as water temperature affects immunocompetence. Investment in gonads and activity of mucus lysozyme were negatively correlated; lysozyme activity decreased as temperature increased. No correlations were found between lysozyme activity and parasitism or intensity of infection by monogeneans, the most abundant metazoan parasite group in L. cephalus. There was a positive correlation, however, between respiratory burst intensity and parasitism. Indices of investment in gonads and spleen were correlated, showing that energetic reserves allowed either investment in gonads and spleen, or that spleen investment, even if often used in other studies in immunoecology, was not always a significant indicator of immunocompetence during this period. This last proposition is supported by the lack of correlation between spleen investment and other factors linked to immunocompetence.     

The helminth community of the wood mouse, Apodemus sylvaticus, in the Sierra Espuna, Murcia, Spain

The helminth community of the wood mouse, Apodemus sylvaticus, in the Sierra Espuna was characterized after a complete analysis of its helminth community component and infracommunity structure relative to host age, sex and year of capture. The helminth community comprised 13 species: one trematode, four cestodes and eight nematodes. The cestode Pseudocatenotaenia matovi and the nematode Syphacia frederici were the most prevalent and abundant helminth species, respectively. Sixty four percent of mice analysed presented helminths with a direct cycle and 42% presented helminths with an indirect cycle. The helminth community presents a low diversity with infracommunities usually made up of only one or two helminth species. Host age and year of capture seem to play a major role in determining species richness and helminth diversity, but not in determining the abundance of helminths. Host sex does not seem to affect the infection rate nor the diversity. Further studies on more samples of wood mice and other small mammal species in this regional park are needed to explore any possible interactions between helminth communities in the host populations.     

The intra- and interspecific relationships between abundance and distribution in helminth parasites of birds

1. Positive correlations between local abundance and distribution on a larger spatial scale are commonly observed among related species.
2. Within parasite species, the same relationship may be expected between prevalence and intensity of infection across host species used. Across parasite species, a positive relationship is expected between average abundance in a host population and the number of host species that can be exploited based on the resource breadth hypothesis. Trade-offs between the ability to exploit many host species and the potential for heavy infections, however, could result in a negative relationship.
3. Intraspecifically, using data on 51 helminth species parasitic in birds, prevalence and intensity of infection among host species used are generally only weakly correlated. Only in nematodes is there an overall positive relationship between prevalence and intensity.
4. A comparative analysis was performed on data from 389 species of cestodes, trematodes and nematodes parasitic in birds to determine how host specificity covaries interspecifically with abundance, measured both as prevalence and intensity of infection.
5. After controlling for phylogenetic influences and sampling effort, the number of host species used correlated positively with prevalence in all three parasite taxa, and with intensity of infection in trematodes only.
6. These results do not support the existence of a trade-off between abundance and the use of many host species, as has been found for fish parasites. Instead, whatever makes helminth parasites of birds abundant within a host population may facilitate their successful colonization of new host species.     

捕食风险对越冬根田鼠肠道寄生物易感性的影响

在自然生态系统中,不同营养级物种可通过特征介导间接效应对生态系统的稳定及种群产生深刻的影响。但目前有关特征介导间接效应的实验研究多见于无脊椎动物、鱼类和两爬类。本研究以根田鼠为对象,在野外围栏内建立预防捕食者和未预防捕食者两种实验处理种群,并通过采用麦克马斯特法测定两种处理种群实验个体肠道寄生物感染种类及感染率和感染强度,采用PHA（phytohemagglutinin）反应和白细胞分类计数测定不同处理种群实验个体免疫能力,以分析捕食风险对根田鼠肠道寄生物的感染效应。结果表明,未预防捕食者处理组根田鼠PHA反应、白细胞计数和淋巴细胞计数较预防捕食者处理组实验个体显著降低,而球虫 E. wenrichi 的感染率和感染强度则显著增加,但绦虫和线虫以及其他3种球虫的感染率和感染强度无显著差异。结果表明,捕食者可通过介导猎物免疫力特征而间接影响猎物肠道寄生物的感染,验证了本项提出的捕食风险可通过降低根田鼠的免疫能力而增加其肠道寄生物感染的假设。     

Immuno-epidemiology of chronic bacterial and helminth co-infections: observations from the field and evidence from the laboratory

Co-infections can alter the host immune responses and modify the intensity and dynamics of concurrent parasitic species. The extent of this effect depends on the properties of the system and the mechanisms of host-parasite and parasite-parasite interactions. We examined the immuno-epidemiology of a chronic co-infection to reveal the immune mediated relationships between two parasites colonising independent organs, and the within-host molecular processes influencing the dynamics of infection at the host population level. The respiratory bacterium, Bordetella bronchiseptica, and the gastrointestinal helminth, Graphidium strigosum, were studied in the European rabbit (Oryctolagus cuniculus), using long-term field data and a laboratory experiment. We found that 65% of the rabbit population was co-infected with the two parasites; prevalence and intensity of co-infection increased with rabbit age and exhibited a strong seasonal pattern with the lowest values recorded during host breeding (from April to July) and the highest in the winter months. Laboratory infections showed no significant immune-mediated effects of the helminth on bacterial intensity in the lower respiratory tract but a higher abundance was observed in the nasal cavity during the chronic phase of the infection, compared with single bacterial infections. In contrast, B. bronchiseptica enhanced helminth intensity and this was consistent throughout the 4-month trial. These patterns were associated with changes in the immune profiles between singly and co-infected individuals for both parasites. This study confirmed the general observation that co-infections alter the host immune responses but also highlighted the often ignored role of bacterial infection in helminth dynamics. Additionally, we showed that G. strigosum had contrasting effects on B. bronchiseptica colonising different parts of the respiratory tract. At the host population level our findings suggest that B. bronchiseptica facilitates G. strigosum infection, and re-infection with G. strigosum assists in maintaining bacterial infection in the upper respiratory tract and thus long-term persistence.