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.     

Parasite co-infection and interaction as drivers of host heterogeneity

We examined the hypothesis that the interaction between concomitant infecting parasites modifies host susceptibility, parasite intensity and the pattern of parasite distribution within the host population. We used a 26 year time series of three common parasites in a natural population of rabbits: two gastrointestinal nematodes (Trichostrongylus retortaeformis and Graphidium strigosum) and the immunosuppressive myxoma virus. The frequency distribution of nematodes in the host population and the relationship between host age and nematode intensity were explored in rabbits with either single or dual nematode infections and rabbits infected with the nematodes and myxoma virus. The aggregation of T. retortaeformis and G. strigosum among the rabbits varied with the nature of the co-infection both in male and female hosts. The two nematodes exhibited different age-intensity profiles: G. strigosum intensity increased exponentially with host age while T. retortaeformis intensity exhibited a convex shape. The presence of a secondary infection did not change the age-intensity profile for G. strigosum but for T. retortaeformis co-infection (either both nematodes or myxoma-nematodes) resulted in significantly greater intensities in adult hosts. Results suggest that multi-species infections contributed to aggregation of parasites in the host population and to seasonal variation in intensity, but also enhanced differences in parasitism between sexes. This effect was apparent for T. retortaeformis, which appears to elicit a strong acquired immune response but not for G. strigosum which does not produce any evident immune reaction. We concluded that concomitant infections mediated by host immunity are important in modifying host susceptibility and influencing heterogeneity amongst individual hosts.     

Helminth parasites of the wild rabbit Oryctolagus cuniculus near Malham Tarn, Yorkshire, UK

Between 1992 and 1996, 95 rabbits from the immediate locality of Malham Tarn, North Yorkshire, UK were examined for the presence of helminth parasites. All the examinations took place in late September or October. Three species of nematodes, Graphidium strigosum, Passalurus ambiguus and Trichostrongylus retortaeformis and two species of cestodes, Taenia pisiformis and Cittotaenia pectinata were identified. There were no associations between helminth species richness and year of sampling, host weight or sex. A logistic model was fitted to the prevalence data from these helminths as was an over-dispersed Poisson model to the worm burden data. Graphidium strigosum was the most frequently identified species with an average prevalence of 78%. The mean prevalence and intensity of Graphidium infection were significantly effected by sampling year. The lower than normal rainfall recorded at the Tarn during the years 1995 and 1996 may have be one reason for this pattern. The worm burden of G. strigosum was significantly positively associated with rabbit body weight. The intensity of infection with P. ambiguus was significantly higher in female rabbits. There was a significant non-linear relationship between P. ambiguus worm burden and rabbit weight (P = 0.002) with worm burdens being highest in the 1000 g to 1499 g weight cohort. Trichostrongylus retortaeformis was only identified in 1994 and male rabbits harboured significantly higher worm burdens than females (48 vs. 7, P = 0.022). Over the five years, the average Taenia pisiformis prevalence was 31% and there was a significant positive association between worm burden and rabbit weight (P = 0.001). Cittotaenia pectinata had a prevalence of 37% over the whole study period with no interactions between prevalence or intensity and body weight, year of sampling or rabbit sex. All five helminths showed an overdispersed distribution with k values less than 1.     

Bordetella type III secretion modulates dendritic cell migration resulting in immunosuppression and bacterial persistence

Chronic bacterial infection reflects a balance between the host immune response and bacterial factors that promote colonization and immune evasion. Bordetella bronchiseptica uses a type III secretion system (TTSS) to persist in the lower respiratory tract of mice. We hypothesize that colonization is facilitated by bacteria-driven modulation of dendritic cells (DCs), which leads to an immunosuppressive adaptive host response. Migration of DCs to the draining lymph nodes of the respiratory tract was significantly increased in mice infected with wild-type B. bronchiseptica compared with mice infected with TTSS mutant bacteria. Reduced colonization by TTSS-deficient bacteria was evident by 7 days after infection, whereas colonization by wild-type bacteria remained high. This decrease in colonization correlated with peak IFN-gamma production by restimulated splenocytes from infected animals. Wild-type bacteria also elicited peak IFN-gamma production on day 7, but the quantity was significantly lower than that elicited by TTSS mutant bacteria. Additionally, wild-type bacteria elicited higher levels of the immunosuppressive cytokine IL-10 compared with the TTSS mutant bacteria. B. bronchiseptica colonization in IL-10(-/-) mice was significantly reduced compared with infections in wild-type mice. These findings suggest that B. bronchiseptica use the TTSS to rapidly drive respiratory DCs to secondary lymphoid tissues where these APCs stimulate an immunosuppressive response characterized by increased IL-10 and decreased IFN-gamma production that favors bacterial persistence.     

The helminth parasites of the wild rabbit Oryctolagus cuniculus and their effect on host condition in Dunas de Mira, Portugal

The present study focuses on the helminth parasite community of the wild rabbit in a sand dune area in Portugal over a 5-year period. The influence of host sex and year on the composition of the helminth community is assessed, along with the potential effect of the detected helminths on host body condition. The basic structure of the helminth community comprises Mosgovoyia ctenoides, Graphidium strigosum, Trichostrongylus retortaeformis, Nematodiroides zembrae and Passalurus ambiguus. Mean intensities of G. strigosum varied between years. General G. strigosum intensities were also found to vary according to both year and host sex, but not according to the interaction of both factors. When assessing the effect of helminths on rabbit body condition (expressed by the kidney fat index), higher burdens of M. ctenoides, a cestode that presents a relatively large body mass, were found to induce a reduction in rabbit condition.     

Prevalence, intensity and aggregation of intestinal parasites in mountain hares and their potential impact on population dynamics

Mountain hare Lepus timidus populations show unstable dynamics and since hares carry a significant helminth infection and host-parasite interactions are known to be destabilising, they have been proposed as a possible causal mechanism for the observed instability. We assessed the prevalence, intensity of infection and aggregation of the helminth parasites Graphidium strigosum and Trichostrongylus retortaeformis recovered from 589 mountain hares culled from 30 Scottish sporting estates in 1999 and 2000. Graphidium strigosum showed low prevalence and intensity of infection and was highly aggregated. In contrast, T. retortaeformis showed high prevalence and intensity of infection and a low degree of aggregation. Differences in body condition of the hares were best explained by a model including sex and month of collection and interaction terms for sex-month and intensity of infection of T. retortaeformis-month. The low degree of aggregation of T. retortaeformis and the significant negative effect of intensity of infection on body condition are in accordance with the hypothesis that the host-parasite interaction is the causative destabilising mechanism for mountain hare dynamics.     

The effect of helminth co-infection on malaria in mice: a meta-analysis

The question of how helminths may alter the course of concurrent malaria infection has attracted much interest in recent years. In particular, it has been suggested that by creating an anti-inflammatory immune environment, helminth co-infection may dampen both protective and immunopathological responses to malaria parasites, thus altering malaria infection dynamics and disease severity. Both synergistic and antagonistic interactions are reported in the literature, and the causes of variation among studies are not well understood. Here, meta-analysis of 42 mouse co-infection experiments was used to address how helminths influence malaria parasite replication and host mortality, and explore the factors explaining variation in findings. Most notably, this analysis revealed contrasting effects of helminth co-infection in lethal and resolving malaria models. Whilst co-infection exacerbated mortality and increased peak parasitaemia in ordinarily resolving malaria infections (Plasmodium chabaudi and Plasmodium yoelii), effects among lethal malaria infections (Plasmodium berghei) tended to be in the opposite direction with no change in parasitaemia. In the subset of experiments on cerebral malaria models (P. berghei ANKA strain in a susceptible host), helminth co-infection significantly delayed death. These findings are consistent with the hypothesis that depending on the existing balance of pro- and anti-inflammatory responses mounted against malaria parasites in a given host, immune responses elicited by helminth co-infection may either promote or inhibit malarial disease. However, despite such broad patterns, a prominent feature of this dataset was great heterogeneity in effects across studies. A key future challenge therefore lies in explaining the biological causes of this variation, including a more thorough exploration of non-immunological mechanisms of helminth-malaria interaction.     

Concomitant helminth infection downmodulates the Vaccinia virus-specific immune response and potentiates virus-associated pathology

The aim of this work was to elucidate the immunopathological mechanisms of how helminths may influence the course of a viral infection, using a murine model. Severe virulence, a relevant increase in the virus titres in the lung and a higher mortality rate were observed in Ascaris and Vaccinia virus (VACV) co-infected mice, compared with VACV mono-infected mice. Immunopathological analysis suggested that the ablation of CD8⁺ T cells, the marked reduction of circulating CD4⁺ T cells producing IFN-γ, and the robust pulmonary inflammation were associated with the increase of morbidity/mortality in co-infection and subsequently with the negative impact of concomitant pulmonary ascariasis and respiratory VACV infection for the host. On the other hand, when evaluating the impact of the co-infection on the parasitic burden, co-infected mice presented a marked decrease in the total number of migrating Ascaris lung-stage larvae in comparison with Ascaris mono-infection. Taken together, our major findings suggest that Ascaris and VACV co-infection may potentiate the virus-associated pathology by the downmodulation of the VACV-specific immune response. Moreover, this study provides new evidence of how helminth parasites may influence the course of a coincident viral infection.     

Interactions among bacterial strains and fluke genotypes shape virulence of co-infection

Most studies of virulence of infection focus on pairwise host–parasite interactions. However, hosts are almost universally co-infected by several parasite strains and/or genotypes of the same or different species. While theory predicts that co-infection favours more virulent parasite genotypes through intensified competition for host resources, knowledge of the effects of genotype by genotype (G × G) interactions between unrelated parasite species on virulence of co-infection is limited. Here, we tested such a relationship by challenging rainbow trout with replicated bacterial strains and fluke genotypes both singly and in all possible pairwise combinations. We found that virulence (host mortality) was higher in co-infections compared with single infections. Importantly, we also found that the overall virulence was dependent on the genetic identity of the co-infecting partners so that the outcome of co-infection could not be predicted from the respective virulence of single infections. Our results imply that G × G interactions among co-infecting parasites may significantly affect host health, add to variance in parasite fitness and thus influence evolutionary dynamics and ecology of disease in unexpected ways.     

Influence of host weight, sex and reproductive status on helminth parasites of the wild rabbit, Oryctolagus cuniculus, in Navarra, Spain.

A study was carried out in Navarra (northern Spain) on the influence of the weight, sex and reproductive status (lactant, pregnant or lactant + pregnant females and testicular weight for males) of the wild rabbit (Oryctolagus cuniculus) on two cestodes species: Andrya cuniculi and Mosgovoyia ctenoides and four intestinal nematodes: Graphidium strigosum, Trichostrongylus retortaeformis, Nematodiroides zembrae and Dermatoxys hispaniensis. A significantly higher prevalence of A. cuniculi was detected in lactant + pregnant females compared with non-breeding females. Trichostrongylus retortaeformis and N. zembrae showed a significantly higher mean intensity in lactant and lactant + pregnant females than in non-reproductive females. Trichostrongylus retortaeformis presented a higher mean intensity in females than in males, and the mean intensity of the same parasite species was significantly lower in active and inactive males compared with lactant and lactant + pregnant females. There were no significant differences between sexes in the prevalence of helminth parasites. No significant correlation was detected between host weight and the intensity (of infection) of helminths studied. No significant differences in the prevalence and mean intensity of the two cestode species were observed in the three weight categories studied (kittens, juveniles and adults). The prevalence of G. strigosum and mean intensity of T. retortaeformis were significantly higher in older heavier animals than in juveniles.     

Necator americanus and helminth co-infections: further down-modulation of hookworm-specific type 1 immune responses

Background

Helminth co-infection in humans is common in tropical regions of the world where transmission of soil-transmitted helminths such as Ascaris lumbricoides, Trichuris trichiura, and the hookworms Necator americanus and Ancylostoma duodenale as well as other helminths such as Schistosoma mansoni often occur simultaneously.

Methodology

We investigated whether co-infection with another helminth(s) altered the human immune response to crude antigen extracts from either different stages of N. americanus infection (infective third stage or adult) or different crude antigen extract preparations (adult somatic and adult excretory/secretory). Using these antigens, we compared the cellular and humoral immune responses of individuals mono-infected with hookworm (N. americanus) and individuals co-infected with hookworm and other helminth infections, namely co-infection with either A. lumbricoides, Schistosoma mansoni, or both. Immunological variables were compared between hookworm infection group (mono- versus co-infected) by bootstrap, and principal component analysis (PCA) was used as a data reduction method.

Conclusions

Contrary to several animal studies of helminth co-infection, we found that co-infected individuals had a further downmodulated Th1 cytokine response (e.g., reduced INF-γ), accompanied by a significant increase in the hookworm-specific humoral immune response (e.g. higher levels of IgE or IgG4 to crude antigen extracts) compared with mono- infected individuals. Neither of these changes was associated with a reduction of hookworm infection intensity in helminth co-infected individuals. From the standpoint of hookworm vaccine development, these results are relevant; i.e., the specific immune response to hookworm vaccine antigens might be altered by infection with another helminth.     

Helminths of the wild rabbit (Oryctolagus cuniculus) in Macaronesia

Two hundred and four rabbits from 8 Macaronesian islands (Pico, San Jorge, San Miguel, Terceira, and Flores from Azores Archipelago; Tenerife and Alegranza from Canary Islands; and Madeira from Madeira Archipelago) were examined for helminth parasites between 1995 and 2000. Three species of cestodes, Taenia pisiformis (larvae), Andrya cuniculi, and Mosgovoyia ctenoides, and 5 species of nematodes, Trichuris leporis, Graphidium strigosum, Trichostrongylus retortaeformis, Passalurus ambiguus, and Dermatoxys hispaniensis, were identified. Only 3 species (M. ctenoides, T. retortaeformis, and P. ambiguus) were regularly distributed over the 3 archipelagos. Taenia pisiformis was not collected in Madeira, nor was A. cuniculi in the Azores and G. strigosum in the Canary Islands. Trichuris leporis and D. hispaniensis were only found in Madeira. Significant differences in the general prevalence of the nematodes G. strigosum and T. retortaeformis were detected between Azores and Madeira. The prevalence of T. retortaeformis differs significantly between the Azores and the Canaries and that of P. ambiguus was higher in Madeira than in Azores and Canaries. The helminth richness found in the wild rabbit in these Macaronesian archipelagos was very low compared with the Palearctic helminth fauna of this host. The wild rabbit was introduced from the Iberian Peninsula into different Macaronesian islands. Helminths introduced with Oryctolagus cuniculus into these islands also are commonly found in Iberian wild rabbits, which are excellent colonizers, as demonstrated in this study.     

Bordetella bronchiseptica responses to physiological reactive nitrogen and oxygen stresses

Bordetella bronchiseptica can establish prolonged airway infection consistent with a highly developed ability to evade mammalian host immune responses. Upon initial interaction with the host upper respiratory tract mucosa, B. bronchiseptica are subjected to antimicrobial reactive nitrogen species (RNS) and reactive oxygen species (ROS), effector molecules of the innate immune system. However, the responses of B. bronchiseptica to redox species at physiologically relevant concentrations (nM-microM) have not been investigated. Using predicted physiological concentrations of nitric oxide (NO), superoxide and hydrogen peroxide (H2O2) on low numbers of CFU of B. bronchiseptica, all redox active species displayed dose-dependent antimicrobial activity. Susceptibility to individual redox active species was significantly increased upon introduction of a second species at subantimicrobial concentrations. An increased bacteriostatic activity of NO was observed relative to H2O2. The understanding of Bordetella responses to physiologically relevant levels of exogenous RNS and ROS will aid in defining the role of endogenous production of these molecules in host innate immunity against Bordetella and other respiratory pathogens.     

Bordetella type III secretion and adenylate cyclase toxin synergize to drive dendritic cells into a semimature state

Bordetella bronchiseptica establishes persistent infection of the murine respiratory tract. We hypothesize that long-term colonization is mediated in part by bacteria-driven modulation of dendritic cells (DCs) leading to altered adaptive immune responses. Bone marrow-derived DCs (BMDCs) from C57BL/6 mice infected with live B. bronchiseptica exhibited high surface expression of MHCII, CD86, and CD80. However, B. bronchiseptica-infected BMDCs did not exhibit significant increases in CD40 surface expression and IL-12 secretion compared with BMDCs treated with heat-killed B. bronchiseptica. The B. bronchiseptica type III secretion system (TTSS) mediated the increase in MHCII, CD86, and CD80 surface expression, while the inhibition of CD40 and IL-12 expression was mediated by adenylate cyclase toxin (ACT). IL-6 secretion was independent of the TTSS and ACT. These phenotypic changes may result from differential regulation of MAPK signaling in DCs. Wild-type B. bronchiseptica activated the ERK 1/2 signaling pathway in a TTSS-dependent manner. Additionally, ACT was found to inhibit p38 signaling. These data suggest that B. bronchiseptica drive DC into a semimature phenotype by altering MAPK signaling. These semimature DCs may induce tolerogenic immune responses that allow the persistent colonization of B. bronchiseptica in the host respiratory tract.     

Modulation of host immune responses, induction of apoptosis and inhibition of NF-kappaB activation by the Bordetella type III secretion system

Bordetella bronchiseptica establishes respiratory tract infections in laboratory animals with high efficiency. Colonization persists for the life of the animal and infection is usually asymptomatic in immunocompetent hosts. We hypothesize that this reflects a balance between immunostimulatory events associated with infection and immunomodulatory events mediated by the bacteria. We have identified 15 loci that are part of a type III secretion apparatus in B. bronchiseptica and three secreted proteins. The functions of the type III secretion system were investigated by comparing the phenotypes of wild-type bacteria with two strains that are defective in type III secretion using in vivo and in vitro infection models. Type III secretion mutants were defective in long-term colonization of the trachea in immunocompetent mice. The mutants also elicited higher titres of anti- Bordetella antibodies upon infection compared with wild-type bacteria. Type III secretion mutants also showed increased lethal virulence in immunodeficient SCID-beige mice. These observations suggest that type III-secreted products of B. bronchiseptica interact with components of both innate and adaptive immune systems of the host. B. bronchiseptica induced apoptosis in macrophages in vitro and inflammatory cells in vivo and type III secretion was required for this process. Infection of an epithelial cell line with high numbers of wild type, but not type III deficient B. bronchiseptica resulted in rapid aggregation of NF-κB into large complexes in the cytoplasm. NF-κB aggregation was dependent on type III secretion and aggregated NF-κB did not respond to TNFα activation, suggesting B. bronchiseptica may modulate host immunity by inactivating NF-κB. Based on these in vivo and in vitro results, we hypothesize that the Bordetella type III secretion system functions to modulate host immune responses during infection.     

Filarial infection induces protection against P. berghei liver stages in mice

Chronic helminth infections such as filariasis in human hosts can be life long, since parasites are equipped with a repertoire of immune evasion strategies. In many areas where helminths are prevalent, other infections such as malaria are co-endemic. It is still an ongoing debate, how one parasite alters immune responses against another. To dissect the relationships between two different parasites residing in the same host, we established a murine model of co-infection with the filarial nematode Litomosoides sigmodontis and the malaria parasite Plasmodium berghei (ANKA strain). We found that filarial infection of BALB/c mice leads to protection against a subsequent P. berghei sporozoite infection in one-third of co-infected mice, which did not develop blood-stage malaria. This finding did not correlate with adult worm loads, however it did correlate with the presence of microfilariae in blood. Interestingly, protection was abrogated in IL-10-deficient mice. Thus, murine filariasis, in particular when it is a patent infection, is able to modify the immunological balance to induce protection against an otherwise deadly Plasmodium infection and is therefore able to influence the course of malaria in favour of the host.     

Development of Fatal Intestinal Inflammation in MyD88 Deficient Mice Co-infected with Helminth and Bacterial Enteropathogens

Infections with intestinal helminth and bacterial pathogens, such as enteropathogenic Escherichia coli, continue to be a major global health threat for children. To determine whether and how an intestinal helminth parasite, Heligomosomoides polygyrus, might impact the TLR signaling pathway during the response to a bacterial enteropathogen, MyD88 knockout and wild-type C57BL/6 mice were infected with H. polygyrus, the bacterial enteropathogen Citrobacter rodentium, or both. We found that MyD88 knockout mice co-infected with H. polygyrus and C. rodentium developed more severe intestinal inflammation and elevated mortality compared to the wild-type mice. The enhanced susceptibility to C. rodentium, intestinal injury and mortality of the co-infected MyD88 knockout mice were found to be associated with markedly reduced intestinal phagocyte recruitment, decreased expression of the chemoattractant KC, and a significant increase in bacterial translocation. Moreover, the increase in bacterial infection and disease severity were found to be correlated with a significant downregulation of antimicrobial peptide expression in the intestinal tissue in co-infected MyD88 knockout mice. Our results suggest that the MyD88 signaling pathway plays a critical role for host defense and survival during helminth and enteric bacterial co-infection.     

CD11b is required for the resolution of inflammation induced by Bordetella bronchiseptica respiratory infection

CD11b is a cell surface receptor that contributes to many cellular processes which are involved in the generation of a protective immune response against pathogenic organisms. In this work, the natural host-pathogen model of murine Bordetella bronchiseptica infection was used to explore the role of CD11b in respiratory immunity. Following intranasal inoculation, CD11b-/- mice rapidly succumb to B. bronchiseptica respiratory infection, highlighting the prominent role of CD11b in the generation of a protective immune response in this model. CD11b appears to be required for both the control of bacterial numbers and the regulation of cellular responses in the lungs. An increased accumulation of neutrophils in the lungs of CD11b-/- mice as compared with wild-type mice suggests that CD11b contributes to the regulation of cellular responses to respiratory infection. This accumulation may be explained by a decrease in apoptosis that is observed in the absence of CD11b following cellular interactions with B. bronchiseptica. Interestingly, this role for CD11b in the regulation of cellular accumulation appears to be critically important for the resolution of damage associated with the type III secretion system (TTSS) of B. bronchiseptica. These data provide new insight into the key role CD11b plays in the resolution of damage in the lower respiratory tract, as well as the B. bronchiseptica virulence determinant that induces it.     

Bordetella bronchiseptica modulates macrophage phenotype leading to the inhibition of CD4+ T cell proliferation and the initiation of a Th17 immune response

Bordetella bronchiseptica is a Gram-negative bacterium equipped with several colonization factors that allow it to establish a persistent infection of the murine respiratory tract. Previous studies indicate that B. bronchiseptica adenylate cyclase toxin (ACT) and the type III secretion system (TTSS) synergize to drive dendritic cells into an altered phenotype to down-regulate the host immune response. In this study, we examined the effects of B. bronchiseptica ACT and TTSS on murine bone marrow-derived macrophages. We demonstrate that ACT and TTSS are required for the inhibition of Ag-driven CD4+ T cell proliferation by bacteria-infected macrophages. We identify PGE2 as the mediator of this inhibition, and we show that ACT and the TTSS synergize to increase macrophage production of PGE2. We further demonstrate that B. bronchiseptica can modulate normal macrophage function and drive the immune response toward a Th17 phenotype classified by the significant production of IL-17. In this study, we show that B. bronchiseptica-infected macrophages can induce IL-17 production from naive CD4+ splenocytes, and that lung tissues from B. bronchiseptica-infected mice exhibit a strong Th17 immune response. ACT inhibited surface expression of CD40 and CD86, suppressed TNF-alpha production, and up-regulated IL-6 production. TTSS also synergized with ACT to up-regulate IL-10 and PGE2 secretion. These findings indicate that persistent colonization by B. bronchiseptica may rely on the ability of the bacteria to differentially modulate both macrophage and dendritic cell function leading to an altered adaptive immune response and subsequent bacterial colonization.     

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.