Evasion of an immune response mounted by a host is fundamental to the survival of a parasite. Immune evasion can be mediated in many ways from the production of molecules by the parasite which mimic cytokines produced by the human immune system to hiding from the immune system by locating within host cells. The production of immune cell mediating molecules in excretory secretory products is another means by which the parasite can tailor its surroundings to facilitate prolonged survival. The hypothesis of immunosuppression by parasite products, in particular members of the Venom Allergen Like (VAL) family, is key to this thesis. VAL proteins are members of the much larger SCP/TAPS family, which covers proteins from parasitic helminths such as Heligmosomoides polygyrus (H.polygyrus)to the free-living nematode Caenorhabditis elegans. These nematodes may have one or more genes encoding proteins that contain the SCP/TAPS domains often choosing to express these proteins at critical points within the helminths lifecycle. Phylogenetic analysis of a selection of these proteins revealed that their classification could be determined based upon the number of SCP/TAPS domains. Alternatively the presence or absence of the signal sequence combined with conserved cysteine residue data could be used. Further investigations into possible functions of the VAL proteins from H.polygyrus were carried out using recombinant protein produced in an insect cell expression system. To further examine the function of VAL genes a system that allows the heterologous expression of a gene in the well-documented Leishmania infection setting was employed. In vitro and in vivo studies were carried out which examined various infection parameters. Parasite infectivity in bone marrow derived macrophages in vitro along with cytokine production was observed. In vivo the development of lesions and subsequent parasite recovery from infected mice gave indications of changes in virulence that could be attributed to the presence and expression of the HpVAL genes. The ability of parasites to ameliorate symptoms of allergic and autoimmune diseases is now well documented with the most extreme use of this knowledge resulting in administration of an active parasitic infection as a treatment regime. We hope to identify individual molecules from a parasite that is known to reduce allergic symptoms in the allergic airway inflammation (AAI) model and produce these in a more structured and regulated fashion. It is plausible that VAL proteins from H.polygyrus may possess these regulatory properties, as has been shown for the excretory secretory products (HES) of the parasite; to that end HpVAL-1 and HpVAL-4 were tested in the allergic airway inflammation model and were shown to reduce both cell numbers in the bronchioalveolar lavage fluid and eosinophilia. Finally, the position of the parasite and products secreted by the parasite was examined. Directly labelled HES and recombinant VAL proteins were used to identify binding sites inside the parasite and within the parasites’ locality in the host i.e. the gut. Confocal microscopy revealed binding of HES to the parasites surface and internal structures and of both HES and HpVAL-4 to goblet cells and Paneth cells inside the gut. Paneth cells may affect parasite survival by influencing the gut microbiota and goblet cells have been shown to influence parasite persistence by production of mucus. Thus HES and more specifically HpVAL proteins may, through their interactions with these cells, interfere with mechanisms employed by the host to expel the parasite.

The mammalian intestinal tract is highly colonised with a diverse bacterial microbiota. The importance of this bacterial presence is now recognised; these bacteria contribute both to the nutritional status of their hosts and are required for the development of a competent immune system. In addition, the composition of the microbiota is likely important in influencing how the immune system reacts to antigens, as the presence of specific bacterial species can promote differentiation of T cells towards specific effector or regulatory fates. Though the ability of the microbiota to influence infections with bacterial and viral agents has been reported, whether the microbiota can affect a parasitic infection has not yet been described. It is likely, due to millions of years of co-evolution within mammalian hosts, that helminths have co-opted mechanisms of the microbiota to manipulate the host’s immune system, in order to promote their own survival. In this thesis, the immune parameters required for expulsion of a primary infection with the murine gastrointestinal helminth parasite Heligmosomoides polygyrus are examined, and whether the microflora influence these parameters in order to modulate susceptibility is explored. Firstly, a multiparameter analysis of H. polygyrus infection was performed in two mouse strains which differ in susceptibility to a primary infection, to identify both immune factors and microbial populations which correlate with susceptibility to infection. BALB/c mice exhibited a stronger T helper (Th)2-type response to H. polygyrus excretory-secretory antigen (HES), produced high numbers of intestinal granulomas following infection and were better able to expel H. polygyrus, whereas the more susceptible C57BL/6 strain produced higher levels of inflammatory Th1 cytokines in response to HES. High levels of duodenal Lactobacillus/Lactococcus species positively correlated with H. polygyrus persistence within the BALB/c host, as did high levels of Enterobacteriaceae in the C57BL/6 host. Furthermore, the abundance of both of these bacterial groups was elevated in H. polygyrus-infected C57BL/6 mice compared to naïve controls, and mice given antibiotic treatment to diminish these groups were rendered more resistant to H. polygyrus. Infection persistence was prolonged in BALB/c mice which were administered the single species Lactobacillus taiwanensis, a normal component of the microbiota. Next, the impact of a loss of microbiota signalling by immune cells during H. polygyrus infection was examined, through the use of Toll-like receptor (TLR)- and TLR adaptor protein-deficient mice. MyD88-/- mice were more resistant to H. polygyrus than wildtype (Wt) C57BL/6 mice and exhibited increased granuloma formation: phenotypes which were not recapitulated by individual deficiencies in TLR2, TLR4, TLR5 or TLR9, and not seen in TRIF-/- mice. When MyD88-/- mice were additionally deficient in TRIF, the increased granuloma formation phenotype of MyD88-/- mice was lost. Whether MyD88 controls susceptibility to H. polygyrus infection via a TLR-independent mechanism, and how MyD88 and TRIF antagonistically contribute to granuloma formation remains to be resolved. Finally, the importance of TGF-β signalling during H. polygyrus infection was examined, using mice deficient in TGF-β signalling specifically in T cells (TGF-βRII DN mice). These mice were more susceptible to H. polygyrus than Wt C57BL/6 mice, which was explained by an attenuated Th2 response to infection accompanied by exuberant IFN-γ production. The increased susceptibility to H. polygyrus was lost in TGF-βRII DN IFN-γ-/-mice, in which Th2 responsiveness was partly restored. These data highlight the importance of both immune components, particularly IFN-γ, which promotes susceptibility, and the presence of specific intestinal bacterial populations in controlling the persistence of a primary H. polygyrus infection.

Solid organ transplantation is the gold standard treatment for a variety of conditions that result in organ failure. However, despite considerable advances in clinical transplantation in recent decades, the almost ubiquitous requirement of life-long immunosuppression of transplant recipients persists and is complicated by graft loss to rejection in the long term and multiple serious adverse effects that are frequently life limiting. Helminths currently infect more than one quarter of the world’s population and it is now well established that their success as parasites is the result of active immunomodulation of the host immune response. Whilst this primarily secures ongoing survival of the parasites, in some cases helminth-induced immunomodulation can be beneficial to the infected host and is not associated with the adverse sequelae of pharmacological immunosuppression. An emerging body of evidence suggests that harmful immune responses to alloantigens can be suppressed by helminths, but little mechanistic data exists and the active immunomodulators involved have remained hitherto unidentified. The hypothesis behind this thesis is that the model intestinal nematode, Heligmosomoides polygyrus, produces immunomodulatory molecules that can suppress responses to allo- and auto-antigens in animal models of transplantation and autoimmunity, and that some of these molecules could potentially be exploited as novel therapeutic agents. Full-thickness skin grafting was performed between fully-allogeneic mouse strains (BALB/c to C57BL/6). Recipient mice infected with H. polygyrus immediately prior to transplantation showed significantly prolonged allograft survival. Likewise, protection from allograft rejection could be replicated in recipient mice in which H. polygyrus excretory-secretory products (HES) (isolated from culture of adult worms) were delivered by continuous infusion via surgically implanted osmotic minipumps. A number of potential mechanisms underlying allograft protection were identified including induction of CD4+CD25+Foxp3+ regulatory T cells (Treg) and suppression of Th1 and Th17 effector CD4+ T cell phenotypes. H. polygyrus and HES were further shown to ameliorate disease in murine (pMOG) experimental autoimmune encephalomyelitis and colitis induced by T cell transfer. In addition to expansion of Treg, H. polygyrus-mediated protection against EAE was found to be almost completely lost in IL-4 receptor deficient mice, indicating a protective role of Th2 immune responses in this context. Finally, the mechanisms of action of the newly-identified TGF-β mimic, TGM, contained within HES were investigated. Despite bearing no sequence homology or structural resemblance to TGF-β, TGM was shown to act through the TGF-β receptor complex to induce Treg in human and mouse CD4+ T cells in vitro and to suppress murine allogeneic skin graft rejection in vivo. TGM may represent the origin of a safe, effective and long-overdue novel alternative to current immunosuppression therapy.

Infections with parasitic helminths are counted as neglected tropical diseases; they infect millions of people worldwide, causing high morbidity and economic loss. Many parasites establish long lasting infections in the host by blocking immune recognition, activation and effector pathways. To allow in depth research on their modes of immune evasion, several mouse models for parasitic helminth infections have been established. Heligmosomoides polygyrus for example is a gastrointestinal nematode of rodents exhibiting a wide spectrum of immunomodulatory effects, mediated in part by soluble molecules released by adult worms in vitro, the excretory/secretory products (HES). HES is a potent inhibitor of dendritic cell (DC) activation by Toll-like receptor (TLR) ligands, completely abolishing LPS induced IL-12 production and reducing the upregulation of cell surface activation markers. As of now, neither the modulatory molecule nor its mechanism of action are known. Here, the effect of HES on TLR ligand induced DC maturation was characterized in considerably more detail compared to previous publications. It could be shown to inhibit DC maturation induced by various TLR ligands, on both protein and mRNA levels. These effects were comparable in both C57BL/6 and BALB/c derived cells; in contrast to this HES differentially affected alternative activation of BMDC from these two mouse strains. Although for most of the experiments GM-CSF differentiated BMDC were used, HES also inhibited LPS induced activation of splenic CD11c+ cells as well as the activation of all three populations described in Flt3-L differentiated BMDC - pDCs, CD11b+ cDCs and CD24+ cDCs. Furthermore, it could be shown here that HES also inhibits LPS induced maturation in human monocyte derived DCs. In the search for the component in HES responsible for its inhibition of TLR ligand induced DC maturation, exosome depleted HES rather than exosomes was inhibitory, and the effect was heat labile. This lead to the conclusion that the modulatory molecule has a protein component which is indispensable for its effect; following this reasoning HES was subjected to fractionation, with subsequent analysis of the fraction protein contents by mass spectrometry. The top nine candidate proteins were expressed recombinantly; however, the recombinants were not able to inhibit LPS induced DC activation. In parallel, experiments to elucidate the mechanism by which HES inhibits TLR ligand induced DC maturation were performed. This led to the conclusion that HES induces changes in the cells that, while not affecting the induction of signalling downstream of TLRs, do impair its maintenance. As a complement to these experiments, the transcriptomes of LPS and LPS+HES treated cells eight hours after LPS stimulation were compared. This revealed that transcripts encoding a number of transcription factors inducing the expression of activation markers after TLR ligation were reduced upon treatment of cells with HES, as were the transcript levels of IRAK2, a kinase necessary for persistent signalling. In addition, HES increased the transcript levels for several factors known to negatively regulate DC maturation, including ATF3. Furthermore, this analysis revealed changes in transcript levels of factors like HIF-1a, indicating an even greater reliance on aerobic glycolysis if cells were treated with HES, in addition to hints at increased ER and oxidative stress. In conclusion, this work narrows down the list of potential DC modulators in HES, gives a first insight into changes in DC metabolism induced by HES and sheds light on the role of a number of signalling pathways with important roles in DC activation as targets of DC inhibition by HES.

RSV is the most common cause of infant bronchiolitis, leading to morbidity and mortality in both infants and the elderly. The relationship between RSV and asthma development further highlights the need to fully understand the immune responses involved in order to develop effective vaccines and therapeutics to aid prevention and treatment of RSV infection respectively. Helminths have long been studied both as a major pathogen of humans, infecting approximately 3 billion people worldwide, and also their ability to modulate the host immune response to allow survival and chronic infection to ensue. Specifically, helminth infections are thought to modulate the host immune response through regulatory mechanisms which are not fully understood. This not only confers protection and survival of the parasites themselves, but also modulates the immune response to unrelated antigens and pathogens. In this thesis, the potential role of a strictly enteric helminth infection, with Heligmosomoides polygyrus, in the modulation of respiratory syncytial virus (RSV) infection was investigated and the associated immune mechanisms were investigated. Firstly, the effects of prior H. polygyrus infection on RSV infection and immune responses in the lung were analysed. H. polygyrus significantly reduced the number of natural killer cells, CD8+ T cells, B cells and conventional dendritic cells in the lung following RSV infection. Co-infection also reduced the production of pro-inflammatory cytokines IL-6 and TNF-α in the lungs. All of these reductions were associated with significantly lower viral titres on day 4 of RSV infection. Interestingly, this attenuation of immune responses and viral titres, correlated with reduced severity of clinical disease, as assessed by weight loss and lung function. H. polygyrus excretory secretory product (HES) was not found to be the immune-modulatory factor in this system, as HES failed to suppress viral titres and reduce immune cell responses to RSV infection. However, irradiated larvae with stunted maturation to adult worms, revealed that larval stages were sufficient to suppress viral titres. Next, the role of type 2 signalling for H. polygyrus effects on RSV infection were examined, using IL-4Rα-/- mice. H. polygyrus infection maintained the ability to attenuate RSV infection and subsequent immune responses in IL-4Rα-/- mice. Furthermore, the presence of the adaptive immune response was not required for H. polygyrus-induced attenuation of RSV infection, as demonstrated in recombinase-activating gene (RAG-/-) deficient mice. H. polygyrus induces innate type 2 immune responses indicating the release of the innate alarmin, IL-33, in the lung and consequently an accumulation of group 2 innate lymphoid cells (ILC2). Their contribution to H. polygyrus effects remain to be fully elucidated. Finally, the role of antiviral responses was explored in H. polygyrus and RSV co-infection. H. polygyrus infection alone induced expression of antiviral genes, IFN-β, OAS1A, Viperin and the antimicrobial peptide CRAMP, in both the duodenum and the lung. Expression of these genes was still higher in the lung 1 hour after RSV in H. polygyrus co-infected mice compared to controls without co-infection. The importance of type I IFN signalling pathway was demonstrated using mice deficient in the type I IFN receptor in H. polygyrus co-infection, which failed to suppress RSV titres and subsequent lung immune cell infiltration. These data highlight the ability of the strictly enteric helminth H. polygyrus to attenuate RSV infection and subsequent immune responses in the lung through the potentiation of type I IFN signalling and consequent upregulation of antiviral immune responses in the lung.

Transmissible spongiform encephalopathies (TSEs) or prion diseases, are subacute neurodegenerative diseases that infect humans and animals. Many of these diseases are acquired by peripheral exposure (e.g. orally). After oral exposure prion replication within the Peyer's patches (PP) in the small intestine is necessary for the efficient spread of the disease to the brain. Within the intestine, bacteria and pathogenic microorganisms can affect the status of the gut associated lymphoid tissue (GALT). GALT consists of PP and isolated lymphoid follicles (ILF) that maintain homeostasis and protect from infections. Therefore, factors which modify GALT status, might dramatically affect oral prion disease pathogenesis by influencing the uptake of prions from the gut lumen or expanding their distribution within the host. Chronic intestinal helminth infections are common in animals and in man, and can cause significant pathology within the intestine. Little is known of the effects that intestinal helminth infections may have on oral prion diseases susceptibility. Therefore, in this study the influence that co-infection with Heligmosomoides polygyrus (a natural pathogen of the mouse small intestine) may have on oral prion disease pathogenesis and susceptibility was determined. The studies consisted of groups of 4 (for H. polygyrus characterization and for early prion detection) and 8 (for H. polygyrus-prion co-infection to terminal stage) mice infected with H. polygyrus (orally) alone or subsequently infected with ME7 scrapie prions (orally) at different time-points after parasitic infection. The effects of the H. polygyrus infection alone, and on oral prion disease pathogenesis and susceptibility were then determined. Initially the characterization of H. polygyrus infection on the host intestine revealed that this parasite caused significant pathology in the small intestine and affected the GALT microarchitecture. In the PP follicles, H. polygyrus infection increased the area of follicular dendritic cell expression, altered the positioning of mononuclear phagocytes and increased M cell density. H. polygyrus infection also reduced the number of ILF in both the small and large intestines. Additional studies in mice co-infected with a low dose of prions, revealed that these pathological changes affected the survival time and disease susceptibility. Data also show that the extent of the effects on prion disease pathogenesis and susceptibility were dependent on the stage of the helminth infection at which the mice were orally-exposed to prions. Data demonstrate that co-infection with the gastrointestinal helminth H. polygyrus can influence oral prion disease pathogenesis and susceptibility. Helminth infections can significantly modify the microarchitecture of the gut and the GALT. Data presented suggest the pathological changes that pathogens such as small intestinal helminths cause, may also influence the uptake of prions from the gut lumen after oral exposure.

Diss. (sammanfattning) Uppsala : Sveriges lantbruksuniv., 2004. / Härtill 4 uppsatser.

Parasitische Würmer gehören mit über 3,5 Milliarden Betroffenen zu den weltweit verbreitetesten Infektionskrankheiten. Der Erfolg dieser Parasiten beruht auf ihren ausgefeilten Mechanismen mit denen sie das Immunsystem ihrer Wirte manipulieren. Interessanter Weise gehen Wurminfektionen mit einer geringeren Wahrscheinlichkeit an Allergien zu erkranken einher. Wie genau die Parasiten das Immunsystem manipulieren ist weitgehend unbekannt. Um diese Mechanismen besser studieren zu können, wurde im Rahmen dieser Arbeit versucht RNA interference (RNAi), anhand des Modellmoleküls Tropomyosin zu etablieren. Wie sich am Beispiel des Strongyliden Heligmosomoides polygyrus bakeri zeigte, ist RNAi als Manipulationsmethode für Nematoden nicht oder nur in geringem Maße geeignet. Dies lässt sich auf das Fehlen von Aufnahme- und Verbreitungsmechanismen für Doppelstrang-RNA zurückführen. Desweiteren wurden die Auswirkungen von rekombinantem Tropomyosin der Filarie Acanthocheilonema viteae (rAv-TMY) auf die Entstehung allergischer Atemwegserkrankungen im Mausmodell untersucht. Eine viermalige Behandlung mit rAv-TMY in einem Zeitraum von vier Wochen führte zu verringerten entzündlichen Reaktionen in den Atemwegen. Die Analyse immunologischer Parameter ergab, dass rAv-TMY signifikant den Einstrom von Entzündungszellen in die Atemwege reduziert, allem voran den Einstrom von Eosinophilen. Dies lässt sich durch die verringerte Ausschüttung an IL-5, Eotaxin und MCP-5 zurückführen. Zudem wurde die Bildung von antigenspezifischen IgE verringert während sich die Produktion blockierender IgG1 Antikörper erhöhte. Diese Arbeit belegt somit die anti-allergischen Eigenschaften von rAv-TMY. Damit stellt rAv-TMY ein interessantes Kandidatenmolekül zur Behandlung allergischer Reaktionen dar. Desweiteren kann der Vergleich von allergenem, nicht allergenem und modulatorischem Tropomyosin wichtige Informationen über die allgemeinen Eigenschaften von Allergenen und ihrer molekularen Struktur geben. / Parasitic worms are among the world''s most prevalent infectious diseases with more than 3.5 billion. The success of these parasites is based on their sophisticated ways to manipulate the immune system of their hosts. Interestingly, worm infections abate the risk to develop allergic disorders. How exactly parasitic worms modulate the immune system is so far largely unknown. In order to be able to investigate parasite induced modulation, this work aimed to establish RNA interference (RNAi), a method of genetic manipulation, using tropomyosin as target gene. As shown for the example of Heligmosomoides polygyrus RNAi is not or only to a small extent useful as method to genetically manipulate nematodes. This can be explained with the lack of uptake and spreading mechanisms for double stranded RNA. Furthermore, this work examined the impact of the recombinant muscle protein tropomyosin of Acanthocheilonema viteae (rAv-TMY) on the course of a rodent model of allergic airway inflammation. A four-time treatment with rAv-TMY over a period of four weeks resulted in decreased inflammatory responses in the airways. The analysis of immunological parameters showed that rAv-TMY significantly reduces the influx of inflammatory cells into the airways, especially eosinophils. The reduced eosinophil influx can be attributed to the decreased expression of IL-5, eotaxin and MCP-5 in the airways. In addition, the formation of antigen-specific IgE was impaired whereas the production of the blocking antibody IgG1 was increased. These results demonstrate the anti-allergic properties of rAv-TMY. For this reason rAv-TMY becomes an interesting model molecule for the treatment of allergic diseases. Furthermore, the comparison of allergenic, non-allergenic and modulatory tropomyosin might put some light on the nature of allergens and their molecular patterns.

Les relations hôte-parasite sont complexes et soumettent les deux protagonistes à un ensemble de compromis aussi bien plastiques qu’évolutifs. D'un côté, bien que l’immunité soit indispensable pour la lutte contre les parasites, elle peut aussi causer de nombreux dégâts à l’hôte lors de la réponse et mener à des maladies inflammatoires. De l’autre côté, les parasites, bien que dotés de mécanismes d'évasion, vont être affectés par l'environnement inflammatoire de l'hôte. Cela pose la question des coûts et bénéfices que l'interaction entre ces deux protagonistes va avoir sur chacun d'eux lors de l'apparition de troubles inflammatoires chez l'hôte. Grâce à différentes approches expérimentales et bibliographiques nous avons pu montrer que l’immunopathologie est un trait qui perdure vraisemblablement grâce aux bénéfices de la réponse immunitaire dans la lutte contre les parasites. Par ailleurs, j’ai pu mettre en évidence qu’une inflammation altérait positivement les traits d’histoire de vie du parasite Heligmosomoides polygyrus aussi bien de façon plastique que lors de processus de sélection. Cependant, le parasite investit davantage dans l’immunomodulation et le camouflage lorsqu'il est confronté à cet environnement, laissant planer la question du coût de cette inflammation à long terme et sur plusieurs générations. / Host-parasite interactions are characterized by trade-offs that involve both plastic and microevolutionary responses. On one hand, while immunity is essential to fight parasites, it can also cause damage to the host, leading to autoimmunity and inflammatory diseases. On the other hand, parasites have to cope with the immune environnement provided by the host. This raises the question of the costs and benefits of the inflammatory response for the two partners of the interaction. With different experimental and literature-based approaches, I showed that immunopathology is a trait that likely persists because of the immediate benefits of the immune response in terms of protection against parasites. Furthermore, I was able to show that inflammation positively altered the life history traits of the gastrointestinal nematode Heligmosomoides polygyrus both plastically or after experimental evolution. However, the parasite invested more in immunomodulation and camouflage when facing an inflammatory environment, leaving open the question of the costs associated with an inflammatory environment over the entire lifespan of the parasite and/or across generations.

This thesis examines the parasite dynamics and the mechanisms affecting parasite load and transmission focalising on the role played by host and habitat heterogeneities. This study is based on the gastrointestinal nematode Heligmosomoides polygyrus and the small mammal yellow necked mouse and uses data gathered from experimental field manipulations of parasites intensities and data gathered from trapping monitoring. Initially the parasite community of yellow-necked mouse (Apodemus flavicollis) was explored in North-Eastern Italian Alps with the aim to describe the major patterns and identify the factors affecting parasite community structure. Despite the observed spatial variability it has been found that differences within the host population such age and secondly sex and breeding conditions, were the major factors acting on parasite occurrence and intensity. Habitat differences had a less apparent effect on parasite community structure. The consequences of H. polygyrus infection on other parasite species infections have been analysed, in specific the infestation of the tick Ixodes ricinus in populations of A. flavicollis. H. polygyrus load and tick infestation were monitored as well as were carried out field manipulations of H. polygyrus intensity and were monitored changes in tick infestation. It has been found that H. polygyrus load was negatively related to I. ricinus infestations. Host factors mediated the H. polygyrus-I. ricinus interaction such that young and non-breeding mice exhibited higher I. ricinus to H. polygyrus intensity respect breeding adults. The role of host sex on parasite abundance was then investigated carrying out a field experiment where the H. polygyrus intensity were manipulated in relation to mice gender. In specific, H. polygyrus was removed alternately from either sexes and the parasite load was analysed in the untreated sex. It was found that males mice were responsible to drive parasite transmission in the host population and this was observed in absence of sex-bias in parasite infection, suggesting that this pattern was not a mere consequence of quantitative differences in parasite loads between sexes. To disentangle the possible mechanism causing this sex bias in parasite transmission mathematical simulations based on parameters obtained for the field experiment were used. Two non mutually exclusive hypotheses causing sex bias in parasite transmission were tested: a- males immune response is less efficient and this causes the development of more successful parasite infective stages or b-males behaviours allow them to be more efficient is spreading in more exposed areas parasite infective stages. Multi-host models were developed and simulations were compared with field results. While it was not disentangled the most dominant mechanism causing sex bias in parasite transmission this study underlined the importance of host sexes in affecting parasite dynamics and host-parasite interaction. In conclusion this thesis highlighted the importance of considering host and environmental differences when investigating host parasite interactions. This finding could be extremely important when planning measured of disease control or to avoid disease outbreak. Controlling target group of individuals host could avoid economical losses and a more effective measure of intervention.