Measles virus infection – Interplay between virus and host cells

Measles, caused by measles virus (MV), is a highly contagious viral disease causing severe respiratory infection and a typical rash. Despite the availability of a protective vaccine, measles is still the leading vaccine-preventable cause of childhood mortality worldwide. The high mortality associated with the disease is mainly due to an increased susceptibility to secondary infections during the period of immunosuppression that continues for several weeks after recovery. The present study was undertaken to elucidate the role of cytoskeletal components in the regulation of MV infection. The most interesting finding was that MV replication was activated in unstimulated peripheral blood mononuclear cells (PBMC) when globular actin was converted into the filamentous form with jasplakinolide. This provides a new aspect in our understanding of MV infection in PBMC. In the second part of the thesis we investigated MV-induced structural changes of cellular nuclear matrix, which is a proteinaceous framework of the nucleus similar to the cytoskeleton in the cytoplasm. We showed that cleavage of nuclear markers was virusspecific and a general caspase inhibitor rescued MV-infected cells from cell death. Furthermore, we studied MV-induced innate immune mechanisms in lung epithelial and endothelial cells. Our results showed that MV infection resulted in activation of the double stranded RNA (dsRNA) binding molecules melanoma differentiation-associated gene 5 (mda-5), retinoic acid inducible gene I (RIG-I), and toll-like receptor 3 (TLR3) gene expression, followed by high expression of antiviral cytokine mRNA.

Consultations infectiologiques ambutatoires non VIH: analyse d'un centre universitaire sur cinq ans [Non-HIV infectious disease outpatient consultations: a 5-year study in a Swiss University Hospital].

Few studies have examined the workload or clinical spectrum of non-HIV infectious diseases outpatient consultations (IDOC). This retrospective study aims to describe IDOC referrals over the past 5 years. In total, 483 patients were referred (with an increase of 63% between 2009 and 2013). Most referrals were received from primary care clinicians (45%). Median patient age was 47 years, 57% of patients were men and 17% were immunosuppressed. Of the diagnoses retained, 74% were infectious, 20% were non-infectious and 6% were of unknown aetiology. Two community outbreaks were identified (tattoo-related mycobacterial infection and Q fever). In conclusion, the infectious diseases outpatient clinic, which has expanded progressively in the past 5 years, provides a specialised service for primary health clinicians and for public health.

Genomic insights into the Ixodes scapularis tick vector of Lyme disease.

Ticks transmit more pathogens to humans and animals than any other arthropod. We describe the 2.1 Gbp nuclear genome of the tick, Ixodes scapularis (Say), which vectors pathogens that cause Lyme disease, human granulocytic anaplasmosis, babesiosis and other diseases. The large genome reflects accumulation of repetitive DNA, new lineages of retro-transposons, and gene architecture patterns resembling ancient metazoans rather than pancrustaceans. Annotation of scaffolds representing ∼57% of the genome, reveals 20,486 protein-coding genes and expansions of gene families associated with tick-host interactions. We report insights from genome analyses into parasitic processes unique to ticks, including host 'questing', prolonged feeding, cuticle synthesis, blood meal concentration, novel methods of haemoglobin digestion, haem detoxification, vitellogenesis and prolonged off-host survival. We identify proteins associated with the agent of human granulocytic anaplasmosis, an emerging disease, and the encephalitis-causing Langat virus, and a population structure correlated to life-history traits and transmission of the Lyme disease agent.

Host Genetics of Response to Hepatitis B Vaccine: A Systematic Review

Background. Hepatitis B virus (HBV) is an important cause of chronic viral disease worldwide and can be life threatening. While a safe and effective vaccine is widely available, 5 to 10% of healthy vaccinees fail to achieve a protective anti-hepatitis B surface antigen antibody (anti-HBs) titer (>10mIU/ml). A limited number of studies investigated host genetics of the response to HBV vaccine. To our knowledge, no comprehensive overview of genetic polymorphisms both within and outside the HLA system has been done so far. Aim. The aim of this study was to perform a systematic review of the literature of human genetics influencing immune response after hepatitis B vaccination. Methods. Literature searches using keywords were conducted in the electronic databases Medline, Embase and ISI Web of Science the cut-off date being March 2014. After selection of papers according to stringent inclusion criteria, relevant information was systematically collected from the remaining articles, including demographic data, number of patients, schedule and type of vaccine, phenotypes, genes and single nucleotide polymorphisms (SNPs) genotyping results and their association with immune response to hepatitis B vaccine. Results. The literature search produced a total of 1968 articles from which 46 studies were kept for further analyses. From these studies, data was extracted for 19 alleles from the human leukocyte antigen (HLA) region that were reported as significant at least twice. Among those alleles, 9 were firmly associated with vaccine response outcome (DQ2 [DQB1*02 and DQB1*0201], DR3 [DRB1*03 and DRB1*0301], DR7 [DRB1*07 and DRB1*0701], C4AQ0, DPB1*0401, DQ3, DQB1*06, DRB1*01 and DRB1*13 [DRB1*1301]). In addition, data was extracted for 55 different genes from which 13 extra-HLA genes had polymorphisms that were studied by different group of investigators or by the same group with a replication study. Among the 13 genes allowing comparison, 4 genes (IL-1B, IL-2, IL-4R and IL- 6) revealed no significant data, 6 genes (IL-4, IL-10, IL-12B, IL-13, TNFA, IFNG and TLR2) were explored with inconsistent results and 2 genes (CD3Z and ITGAL) yielded promising results as their association with vaccine response was confirmed by a replication approach. Furthermore, this review produced a list of 46 SNPs from 26 genes that were associated with immune response to vaccine only once, providing novel candidates to be tested in datasets from existing genome-wide association studies (GWAS). Conclusion. To the best of our knowledge, this is the first systematic review of immunogenetic studies of response to hepatitis B vaccine. While this work reassesses the role of several HLA alleles on vaccine response outcome, the associations with polymorphisms in genes outside the HLA region were rather inconsistent. Moreover, this work produced a list of 46 significant SNPs that were reported by a single group of investigators, opening up some interesting possibilities for further research.

Silicon and rice disease management

The element silicon (Si) is not considered an essential nutrient for plant function. Nevertheless, Si is absorbed from soil in large amounts that are several fold higher than those of other essential macronutrients in certain plant species. Its beneficial effects have been reported in various situations, especially under biotic and abiotic stress conditions. The most significant effect of Si on plants, besides improving their fitness in nature and increasing agricultural productivity, is the restriction of parasitism. There has been a considerable amount of research showing the positive effect of Si in controlling diseases in important crops. Rice (Oryza sativa), in particular, is affected by the presence of Si, with diseases such as blast, brown spot and sheath blight becoming more severe on rice plants grown in Si-depleted soils. The hypothesis underlying the control of some diseases in both mono- and di-cots by Si has been confined to that of a mechanical barrier resulting from its polymerization in planta. However, some studies show that Si-mediated resistance against pathogens is associated with the accumulation of phenolics and phytoalexins as well as with the activation of some PR-genes. These findings strongly suggest that Si plays an active role in the resistance of some plants to diseases rather than forming a physical barrier that impedes penetration by fungal pathogens.

Annona squamosa, a new host of Ceratocystis fimbriata

Mango branch blight disease, caused by Ceratocystis fimbriata, is endemic to the municipality of São Fidelis in northern Rio de Janeiro State. In addition to mango, C. fimbriata was found associated with sugar apple trees (Annona squamosa) showing symptoms of branch blight in São Fidelis. Sugar apple and mango isolates from the same region had the same morphology and showed similar ITS-rDNA sequences. These sequences were also similar to other Brazilian isolates of C. fimbriata sensu stricto. Cross inoculation of such isolates obtained from diseased sugar apple and mango resulted in diseased symptoms on both plant species. This is the first record of A. squamosa as a host for C. fimbriata.

Heartworm (Dirofilaria immitis) disease in a Brazilian oncilla (Leopardus tigrinus)

Heartworm disease is caused by the intravascular nematode Dirofilaria immitis, a pathogen of public health importance usually associated to domestic dogs and cats, and to a lesser extend to other mammal species. The oncilla (Leopardus tigrinus) is a threatened neotropic felid species that naturally occurs in Brazil. Here, we report the encounter of adult and larval stages of heartworms in a female specimen of L. tigrinus, probable of free-ranging origin, from Ubatuba, São Paulo, Brazil, which died showing clinical signals compatible with heartworm disease. This was the first reported case of D. immitis infection and associated disease in L. tigrinus, also suggesting that the oncilla acted as a definitive host for this parasite. The present findings confirmed D. immitis as a pathogenic agent for this felid species, thus supporting the recommendation for the inclusion of diagnostic testing for this pathogen in routine health screening procedures for captive and free-ranging oncillas in Brazil, especially in those localities where climate conditions support the occurrence of the parasite. Potential reservoirs as oncillas are established beyond the reach of veterinary care, thus representing a continuing risk for domestic animals and humans acquiring heartworm infection. We encourage further serologic and molecular studies aiming to establish D. immitis prevalences in L. tigrinus and other wild carnivores in the region of Ubatuba, as well as ecological and veterinary studies to access the role of this pathogen for the survival of this threatened felid species.

Cytokines as determinants of disease and disease interactions

The immune response to pathogens results in both host resistance and immunopathology. Cytokines and in particular those lymphokines produced by Th1 and Th2 cells play a key role in determining the balance between these two immunologic outcomes. Recent data suggest that interleukin-10, a product of both Th2 cells and macrophages, protects the host against excessive immunopathology. The cytokine environment generated by different pathogens may also influence the course and outcome of infections with unrelated organisms. This relationship may be particularly important in the case of HIV-1 where prior Th1 or Th2 biases established by helminth or intracellular infections may influence either initial viral susceptibility or drive progression to AIDS through immune activation

Apoptosis in parasites and parasite-induced apoptosis in the host immune system: a new approach to parasitic diseases

Apoptosis, a form of programmed cell death (PCD), has been described as essential for normal organogenesis and tissue development, as well as for the proper function of cell-renewal systems in adult organisms. Apoptosis is also pivotal in the pathogenesis of several different diseases. In this paper we discuss, from two different points of view, the role of apoptosis in parasitic diseases. The description of apoptotic death in three different species of heteroxenic trypanosomatids is reviewed, and considerations on the phylogenesis of apoptosis and on the eventual role of PCD on their mechanism of pathogenesis are made. From a different perspective, an increasing body of evidence is making clear that regulation of host cell apoptosis is an important factor on the definition of a host-pathogen interaction. As an example, the molecular mechanisms by which Trypanosoma cruzi is able to induce apoptosis in immunocompetent cells, in a murine model of Chagas' disease, and the consequences of this phenomenon on the outcome of the experimental disease are discussed.

RNA and DNA aptamers as potential tools to prevent cell adhesion in disease

Recent research has shown that receptor-ligand interactions between surfaces of communicating cells are necessary prerequisites for cell proliferation, cell differentiation and immune defense. Cell-adhesion events have also been proposed for pathological conditions such as cancer growth, metastasis, and host-cell invasion by parasites such as Trypanosoma cruzi. RNA and DNA aptamers (aptus = Latin, fit) that have been selected from combinatorial nucleic acid libraries are capable of binding to cell-adhesion receptors leading to a halt in cellular processes induced by outside signals as a consequence of blockage of receptor-ligand interactions. We outline here a novel approach using RNA aptamers that bind to T. cruzi receptors and interrupt host-cell invasion in analogy to existing procedures of blocking selectin adhesion and function in vitro and in vivo.

Evasion of immune responses by Trypanosoma cruzi, the etiological agent of Chagas disease

Infection with the protozoan parasite Trypanosoma cruzi leads to Chagas disease, which affects millions of people in Latin America. Infection with T. cruzi cannot be eliminated by the immune system. A better understanding of immune evasion mechanisms is required in order to develop more effective vaccines. During the acute phase, parasites replicate extensively and release immunomodulatory molecules that delay parasite-specific responses mediated by T cells. This immune evasion allows the parasite to spread in the host. In the chronic phase, parasite evasion relies on its replication strategy of hijacking the TGF-β signaling pathway involved in inflammation and tissue regeneration. In this article, the mechanisms of immune evasion described for T. cruzi are reviewed.

Characterization of the chitinolytic system during the mycoparasitic interaction between Trichoderma aggressivum f. aggressivum and different host strains of Agaricus bisporus /

Green mould is a serious disease of commercially grown mushrooms, the causal agent being attributed to the filamentous soil fungus Triclzodenna aggressivum f. aggressivu11l and T. aggressivum f. ellropaellm. Found worldwide, and capable of devastating crops, this disease has caused millions of dollars in lost revenue within the mushroom industry. One mechanism used by TricllOdenlla spp. in the antagonism of other fungi, is the secretion of lytic enzymes such as chitinases, which actively degrade a host's cell wall. Therefore, the intent of this study was to examine the production of chitinase enzymes during the host-parasite interaction of Agaricus bisporus (commercial mushroom) and Triclzodemza aggressivum, focusing specifically on chitinase involvement in the differential resistance of white, off-white, and brown commercial mushroom strains. Chitinases isolated from cultures of A. bisporus and T. aggressivu11l grown together and separately, were identified following native PAGE, and analysis of fluorescence based on specific enzymatic cleavage of 4-methylumbelliferyl glucoside substrates. Results indicate that the interaction between T. aggressivulll and A. bisporus involves a complex enzyme battle. It was determined that T. aggressivum produces a number of chitinases that appear to correlate to those isolated in previous studies using biocontrol strains of T. Izarziallilm. A 122 kDa N-acetylglucosaminidase of T. aggressivu11l revealed the highest and most variable activity, and is therefore believed to be an important predictor of antifungal activity. Furthermore, results indicate that brown strain resistance of mushrooms may be related to high levels of a 96 kDa N-acetylglucosaminidase, which showed elevated activity in both solitary and dual cultures with T. aggressivum. Overall, each host-parasite combination produced unique enzyme profiles, with the majority of the differences seen between day 0 and day 6 for the extracellular chitinases. Therefore, it was concluded that the antagonistic behaviour of T. aggressivli1ll does not involve a typical response, always producing the same types and levels of enzymes, but that mycoparasitism, specifically in the form of chitinase production, may be induced and regulated based on the host presented.

Genes involved in the metabolism of fatty acids and risk for Crohn's disease in children: a candidate gene study

Contexte - La prévalence de la maladie de Crohn (MC), une maladie inflammatoire chronique du tube digestif, chez les enfants canadiens se situe parmi les plus élevées au monde. Les interactions entre les réponses immunes innées et acquises aux microbes de l'hôte pourraient être à la base de la transition de l’inflammation physiologique à une inflammation pathologique. Le leucotriène B4 (LTB4) est un modulateur clé de l'inflammation et a été associé à la MC. Nous avons postulé que les principaux gènes impliqués dans la voie métabolique du LTB4 pourrait conférer une susceptibilité accrue à l'apparition précoce de la MC. Dans cette étude, nous avons exploré les associations potentielles entre les variantes de l'ADN des gènes ALOX5 et CYP4F2 et la survenue précoce de la MC. Nous avons également examiné si les gènes sélectionnés montraient des effets parent-d'origine, influençaient les phénotypes cliniques de la MC et s'il existait des interactions gène-gène qui modifieraient la susceptibilité à développer la MC chez l’enfant. Méthodes – Dans le cadre d’une étude de cas-parents et de cas-témoins, des cas confirmés, leurs parents et des contrôles ont été recrutés à partir de trois cliniques de gastro-entérologie à travers le Canada. Les associations entre les polymorphismes de remplacement d'un nucléotide simple (SNP) dans les gènes CYP4F2 et ALOX5 ont été examinées. Les associations allélique et génotypiques ont été examinées à partir d’une analyse du génotype conditionnel à la parenté (CPG) pour le résultats cas-parents et à l’aide de table de contingence et de régression logistique pour les données de cas-contrôles. Les interactions gène-gène ont été explorées à l'aide de méthodes de réduction multi-factorielles de dimensionnalité (MDR). Résultats – L’étude de cas-parents a été menée sur 160 trios. L’analyse CPG pour 14 tag-SNP (10 dans la CYP4F2 et 4 dans le gène ALOX5) a révélé la présence d’associations alléliques ou génotypique significatives entre 3 tag-SNP dans le gène CYP4F2 (rs1272, p = 0,04, rs3093158, p = 0.00003, et rs3093145, p = 0,02). Aucune association avec les SNPs de ALOX5 n’a pu être démontrée. L’analyse de l’haplotype de CYP4F2 a montré d'importantes associations avec la MC (test omnibus p = 0,035). Deux haplotypes (GAGTTCGTAA, p = 0,05; GGCCTCGTCG, p = 0,001) montraient des signes d'association avec la MC. Aucun effet parent-d'origine n’a été observé. Les tentatives de réplication pour trois SNPs du gene CYP4F2 dans l'étude cas-témoins comportant 225 cas de MC et 330 contrôles suggèrent l’association dans un de ceux-ci (rs3093158, valeur non-corrigée de p du test unilatéral = 0,03 ; valeur corrigée de p = 0.09). La combinaison des ces deux études a révélé des interactions significatives entre les gènes CYP4F2, ALOX et NOD2. Nous n’avons pu mettre en évidence aucune interaction gène-sexe, de même qu’aucun gène associé aux phénotypes cliniques de la MC n’a pu être identifié. Conclusions - Notre étude suggère que la CYP4F2, un membre clé de la voie métabolique LTB4 est un gène candidat potentiel pour MC. Nous avons également pu mettre en évidence que les interactions entre les gènes de l'immunité adaptative (CYP4F2 et ALOX5) et les gènes de l'immunité innée (NOD2) modifient les risques de MC chez les enfants. D'autres études sur des cohortes plus importantes sont nécessaires pour confirmer ces conclusions.

Intestinal microbiology in Crohn's disease: a study of Escherichia coli as a potential etiologic agent

La malaltia de Crohn és una malaltia inflamatòria intestinal crònica d'etiologia encara desconeguda. Actualment es pensa que hi participen factors genètics i immunològics que confereixen una susceptibilitat a l'hoste, i factors externs o ambientals, com serien els microorganismes i/o l'estil de vida. L'objectiu principal d'aquest treball ha estat descriure les poblacions bacterianes associades especialment als malalts de Crohn, amb la intenció d'identificar possibles agents etiològics. Els resultats d'aquest treball coincideixen amb investigacions prèvies que descriuen l'alteració bacteriana present en els malalts de Crohn (disbiosi) i recolzen la hipòtesi que implica el recentment descrit patovar "Adherent- Invasive Escherichia coli" (AIEC) en l'etiologia d'aquesta malaltia inflamatòria intestinal. A més, contribuïm a la descripció de les poblacions d'E. coli associades a la mucosa intestinal aportant dades sobre aspectes ecològics i patogènics. Finalment, descrivim nous aspectes fenotípics d'AIEC que podrien estar relacionats amb la seva patogènia, com seria la capacitat de formar biofilms.

A qualitative host-pathogen interaction in the Theobroma cacao-Moniliophthora perniciosa pathosystem

The aim of this study was to test whether resistance of clones of Theobroma cacao ( cocoa) varied between isolates of Moniliophthora (formerly Crinipellis) perniciosa, the cause of witches' broom disease. Developing buds of vegetatively propagated T. cacao grown in greenhouses in the UK were inoculated with 16 000 spores of M. perniciosa per meristem in water, under conditions where water condensed on the inoculated shoot for at least 12 h after inoculation. The proportion of successful inoculations varied between clones and was inversely correlated with time to symptom production or broom formation. A specific interaction was demonstrated among three single-spore isolates of M. perniciosa and the clone Scavina 6 (SCA 6) and a variety of susceptible clones. Isolates Castenhal-I and APC3 were equally likely to infect SCA 6 and the other clones, but isolate Gran Couva A9 never infected SCA 6, although it was as virulent on the other clones. The interaction was maintained when the wetness period was extended to 70 h. Offspring of SCA 6 x Amelonado matings were all susceptible to both Castenhal-I and GC-A5, with no evidence of greater variability in susceptibility to GC-A5 than Castanhal-I. This suggests recessive inheritance of a single homozygous factor conferring resistance to GC-A5, from SCA 6. The progenies were slightly more susceptible to Castanhal-I than GC-A5. The implications for managing the disease are discussed.