Immunity against Helminths: Interactions with the Host and the Intercurrent Infections

Helminth parasites are of considerable medical and economic importance. Studies of the immune response against helminths are of great interest in understanding interactions between the host immune system and parasites. Effector immune mechanisms against tissue-dwelling helminths and helminths localized in the lumen of organs, and their regulation, are reviewed. Helminth infections are characterized by an association of Th2-like and Treg responses. Worms are able to persist in the host and are mainly responsible for chronic infection despite a strong immune response developed by the parasitized host. Two types of protection against the parasite, namely, premune and partial immunities, have been described. Immune responses against helminths can also participate in pathogenesis. Th2/Treg-like immunomodulation allows the survival of both host and parasite by controlling immunopathologic disorders and parasite persistence. Consequences of the modified Th2-like responses on co-infection, vaccination, and inflammatory diseases are discussed

Quand la recherche-action au doctorat devient possible place à l’artisan-chercheur

Le cheminement prévu pour le doctorat réseau amène certaines contraintes à l’étudiant-chercheur qui souhaiterait opter pour une recherche participative, notamment la recherche-action. Cet article fait état de la réflexion amorcée lors de mon cheminement doctoral concernant la méthodologie et m’ayant mené vers la création d’un modèle hybride. Ce modèle hybride s’inspire en partie du « proactive model research » proposé par Schmuck (2006) ainsi que du modèle proposé par Guay et Prud’homme (2011)

The invasion process of bovine erythrocyte by Babesia divergens: knowledge from an in vitro assay

Babesia divergens is a tick-transmitted apicomplexan parasite for which asexual multiplication in its vertebrate hosts is restricted to erythrocytes. Current knowledge of invasion of these target cells is limited. An efficient in vitro invasion assay was set up to gain access to this information. Parasites prepared from infected RBC, lysed by electroporation, and mixed with bovine RBC in a selected synthetic medium (RPMI 1640 supplemented with calcium) were able to establish subsequent cultures with parasitemia ranging from 6 to 14%. Free parasites remaining in the invasion medium could be eliminated by Percoll gradient and culture could be pursued with the freshly invaded erythrocytes. In this way, the invasion time window could be shortened to obtain a synchronised start of the culture or to study the kinetics of invasion. With this assay we demonstrate that 1) erythrocyte invasion by B. divergens is a rapid process since 70% of the invasion-competent parasites invaded the RBC in less than 45 s; 2) all invasion-competent parasites achieved invasion within 10 min of contact; 3) one erythrocyte could be invaded concomitantly by two merozoites; 4) despite a synchronous start, the parasite population evolved heterogeneously resulting in a progressive loss of synchronisation. Western blot analysis of proteins collected from invasion medium were performed with sera from animals experimentally infected with B. divergens and highlighted several proteins. The dose-dependent, inhibitory effects of these sera on B. divergens invasion suggest that these proteins might be involved in the invasion process. Further investigations are required for their characterisation

Individual heterogeneity in erythrocyte susceptibility to Babesia divergens is a critical factor for the outcome of experimental spleen-intact sheep infections

Susceptibility of sheep erythrocytes to Babesia divergens was investigated in vitro and a high inter-individual variability in their ability to support parasite population development was demonstrated, with some individuals having refractory red blood cells (RBC). As neither changes in growth conditions nor the use of different B. divergens strains influenced the level of susceptibility, the main factor postulated for this variability is the erythrocyte itself. Sheep therefore represent an excellent in vitro model to study the parasite-erythrocyte interaction. In addition, the existence of refractory RBC should help in the identification of the erythrocyte components required for B. divergens development. Experimental infections were carried out on spleen-intact sheep characterized by refractory or fully susceptible erythrocyte types. These differences translated into the successful infection of only those animals with susceptible erythrocytes: infected animals showed no clinical signs, but maintained an asymptomatic persistent infection, as usually observed in the natural bovine host. Sheep therefore represent model organisms that can allow us to study interactions between B. divergens and its vertebrate host at different levels of biological organisation, from the target cell to the intact animal, and represent an experimental infection model of concomitant immunity. Only a low percentage (13%) of the sheep population tested possessed susceptible erythrocytes and the potential role of sheep as a natural host or reservoir of B. divergens is discussed

Babesia and its hosts: adaptation to long-lasting interactions as a way to achieve efficient transmission

Babesia, the causal agent of babesiosis, are tick-borne apicomplexan protozoa. True babesiae (Babesia genus sensu stricto) are biologically characterized by direct development in erythrocytes and by transovarial transmission in the tick. A large number of true Babesia species have been described in various vertebrate and tick hosts. This review presents the genus then discusses specific adaptations of Babesia spp. to their hosts to achieve efficient transmission. The main adaptations lead to long-lasting interactions which result in the induction of two reservoirs: in the vertebrate host during low long-term parasitemia and throughout the life cycle of the tick host as a result of transovarial and transstadial transmission. The molecular bases of these adaptations in vertebrate hosts are partially known but few of the tick-host interaction mechanisms have been elucidated

Fasciolosis of ruminants : Immunity immunomodulation and control strategie

The first part of this article describes the differences in immune response against the liver fluke found in its various ruminant hosts. It shows that sensitivity to F. hepatica and F. gigantica infestation and the development of a resistance against these parasites vary widely from host to host. These host-specific responses of against the parasite, and especially the cellular response, are described. Lesions form around a necrotic area with inflammatory cells organised into a granuloma. These cells are mainly macrophages, lymphocytes and eosinophil granulocytes; the excretion-secretion products of F. hepatica or F. gigantica trigger early on a proliferative response from lymphocytes, as well as a secretion of cytokines, which vary depending on the ruminant host. The elimination of Fasciola spp. during its peritoneal or hepatic migration involves two mechanisms: destruction by macrophages activated by interferon gamma, which produces nitrogen monoxide (NO) toxic for the parasite, and antibody-dependent cell-mediated cytotoxicity (ADCC). These mechanisms are dependent on either Th1 cytokines, particularly IFNg for the induction of NO, or Th2 cytokines for ADCC. We describe how the parasites defeat these two mechanisms. This phenomenon could explain why ruminant resistance to reinfestation is only limited and why there is no premunition against flukes. Consequently, the anti-fasciolosis strategy is directed at the parasite, using agronomic measures to prevent animal infestation. Given the type of immunity animals develop against fasciolosis, the efficacy of vaccines is limited to reducing the parasite load.La première partie de cette revue décrit les manifestations de l'immunité anti-Fasciola chez les différents hôtes ruminants. Il en ressort que la sensibilité à l'infestation par F. hepatica et F. gigantica et l'acquisition d'une résistance contre ces parasites varient largement en fonction de l'hôte. La réponse antiparasitaire, et notamment cellulaire, est décrite en tenant compte des différents hôtes de Fasciola. Les lésions se forment autour d'une zone nécrotique et sont constituées de cellules inflammatoires s'organisant en granulome. Ces cellules sont principalement des macrophages, des lymphocytes et des granulocytes éosinophiles. Les produits d'excrétion-sécrétion de F. hepatica ou F. gigantica entraînent une réponse proliférative précoce de la part des lymphocytes; il en est de même pour la sécrétion des différentes cytokines, variables selon les ruminants infestés. Deux mécanismes peuvent être impliqués dans l'élimination de Fasciola spp. au cours de sa migration péritonéale ou hépatique : un mécanisme de destruction par des macrophages activés par l'interféron gamma et produisant alors du monoxyde d'azote (NO) toxique pour le parasite, et un mécanisme de cytotoxicité cellulaire dépendante des anticorps (ADCC). Ces mécanismes sont sous la dépendance, soit de cytokines Th1, notamment l'lFNγ pour l'induction de NO, soit de cytokines Th2 pour l'ADCC. Les modalités d'échappement à ces deux mécanismes, décrites ici, pourraient expliquer la résistance partielle à la réinfestation et l'absence de prémunition induite par la douve. En conséquence, la stratégie de lutte contre la fasciolose est une stratégie dirigée contre le parasite, visant à prévenir l'infestation des animaux par des mesures agronomiques. Étant donné le type d'immunité déclenchée par la présence de Fasciola, les vaccins ne permettent que de diminuer la charge parasitaire

αvβ3-dependent cross-presentation of matrix metalloproteinase–2 by melanoma cells gives rise to a new tumor antigen

A large array of antigens that are recognized by tumor-specific T cells has been identified and shown to be generated through various processes. We describe a new mechanism underlying T cell recognition of melanoma cells, which involves the generation of a major histocompatibility complex class I–restricted epitope after tumor-mediated uptake and processing of an extracellular protein—a process referred to as cross-presentation—which is believed to be restricted to immune cells. We show that melanoma cells cross-present, in an αvβ3-dependent manner, an antigen derived from secreted matrix metalloproteinase–2 (MMP-2) to human leukocyte antigen A*0201-restricted T cells. Because MMP-2 activity is critical for melanoma progression, the MMP-2 peptide should be cross-presented by most progressing melanomas and represents a unique antigen for vaccine therapy of these tumors

The genotype 3-specific hepatitis C virus core protein residue phenylalanine 164 increases steatosis in an in vitro cellular model.: HCV genotype 3-specific steatosis

International audienceBackground and aims: The prevalence and severity of liver steatosis are higher in patients infected with genotype 3 hepatitis C virus (HCV) than in patients infected with other genotypes. HCV core protein is known to affect lipid metabolism, inducing lipid droplet accumulation both in vitro and in vivo. We used an in vitro cellular model to investigate whether an HCV core protein with residues specific to genotype 3 increased this phenomenon. Methods: Sequence comparisons for HCV core protein domain II, which is known to interact with lipid droplets, identified the phenylalanine (F) residue at position 164 as the only residue specific to genotype 3. We compared the area covered by lipid droplets in sections of cells producing a wild-type genotype 1a HCV core protein with that in cells producing a Y164F mutant protein. Results: Cumulative lipid droplet area was significantly greater in sections of cells producing the Y164F mutant HCV core protein than in cells producing the wild-type protein (p<0.001). The frequency of cell sections containing more than 3 μm2 of lipid droplets, in particular, was higher for the mutant than for the wild-type protein. Conclusion: Our data provide a molecular explanation for HCV genotype 3-specific lipid accumulation. This difference between genotypes may be due to phenylalanine having a higher affinity for lipids than tyrosine (Y). These observations provide useful information for further studies of the mechanisms involved in HCV-induced steatosis

Viral sequence variation in chronic carriers of hepatitis C virus has a low impact on liver steatosis.: HCV variability and steatosis

International audienceMost clinical studies suggest that the prevalence and severity of liver steatosis are higher in patients infected with hepatitis C virus (HCV) genotype 3 than in patients infected with other genotypes. This may reflect the diversity and specific intrinsic properties of genotype 3 virus proteins. We analyzed the possible association of particular residues of the HCV core and NS5A proteins known to dysregulate lipid metabolism with steatosis severity in the livers of patients chronically infected with HCV. We used transmission electron microscopy to quantify liver steatosis precisely in a group of 27 patients, 12 of whom were infected with a genotype 3 virus, the other 15 being infected with viruses of other genotypes. We determined the area covered by lipid droplets in liver tissues and analyzed the diversity of the core and NS5A regions encoded by the viral variants circulating in these patients. The area covered by lipid droplets did not differ significantly between patients infected with genotype 3 viruses and those infected with other genotypes. The core and NS5A protein sequences of the viral variants circulating in patients with mild or severe steatosis were evenly distributed throughout the phylogenic trees established from all the collected sequences. Thus, individual host factors seem to play a much greater role than viral factors in the development of severe steatosis in patients chronically infected with HCV, including those infected with genotype 3 viruses

Galectin-4 and sulfatides in apical membrane trafficking in enterocyte-like cells

We have previously reported that 1-benzyl-2-acetamido-2-deoxy-α-d-galactopyranoside (GalNAcα-O-bn), an inhibitor of glycosylation, perturbed apical biosynthetic trafficking in polarized HT-29 cells suggesting an involvement of a lectin-based mechanism. Here, we have identified galectin-4 as one of the major components of detergent-resistant membranes (DRMs) isolated from HT-29 5M12 cells. Galectin-4 was also found in post-Golgi carrier vesicles. The functional role of galectin-4 in polarized trafficking in HT-29 5M12 cells was studied by using a retrovirus-mediated RNA interference. In galectin-4–depleted HT-29 5M12 cells apical membrane markers accumulated intracellularly. In contrast, basolateral membrane markers were not affected. Moreover, galectin-4 depletion altered the DRM association characteristics of apical proteins. Sulfatides with long chain-hydroxylated fatty acids, which were also enriched in DRMs, were identified as high-affinity ligands for galectin-4. Together, our data propose that interaction between galectin-4 and sulfatides plays a functional role in the clustering of lipid rafts for apical delivery