Reisediarrhö

Zusammenfassung: Reisediarrhö ist die häufigste Erkrankung beim Besuch tropischer Länder, wobei die Zahl der Reisenden in diese Destinationen stetig steigt. Reisediarrhö schränkt die Reisefreiheit ein, ist jedoch sehr selten lebensbedrohlich. In den meisten Fällen erfolgt eine spontane Heilung nach etwa 4 Tagen. Die Symptome können jedoch bei einer Minderheit über Wochen anhalten und es kann eine chronische Folgeerkrankung, z.B. ein Reizdarmsyndrom ausgelöst werden. Risikofaktoren betreffen sowohl das Individuum (z.B. Alter, Verhalten, Herkunft und genetische Disposition) als auch Umweltbedingungen (z.B. Destination und Hotel). Hauptsächlich sind bakterielle Erreger für eine Reisediarrhö verantwortlich vor allem Enterotoxin bildende Escherichiacoli (ETEC), Salmonellen, Shigellen und Campylobacter, zu nennen sind auch Rotaviren und Protozoen wie Giardia lamblia. Gezielt wird nach diesen bei Komplikationen und chronischem Verlauf gesucht. Therapeutisch greift man auf Ebenen an, die je nach Krankheitsverlauf und Erreger von der symptomatischen Blockierung der Darmmotilität, der oralen Rehydrierung bis zum Einsatz von Antibiotika reiche

Candida albicans hyphal form enhances tumor necrosis factor mRNA levels and protein secretion in murine ANA-1 macrophages.

We have demonstrated that Candida albicans in its hyphal form (H-Candida) acts as a stimulating agent in the cloned macrophage population ANA-1. Both tumor necrosis factor (TNF) mRNA levels and secreted biological activity augment in ANA-1 macrophages exposed to H-Candida. Such effects are observed at an effector-to-target cell ratio of 1:1 and occur after 1 and 3 hr of coincubation, respectively. The phenomenon is independent of the metabolic status of the fungus, since viable as well as heat-killed H-Candida are comparable in inducing TNF mRNA levels. The extent and kinetics of H-Candida-mediated effects are similar to those observed following exposure of ANA-1 macrophages to lipopolysaccharide (LPS). This implies that C. albicans in its hyphal form is a potent macrophage modulator; whether it acts through the same mechanism(s) as LPS remains to be elucidate

Up-regulation of Toll-like receptors 2, 3 and 4 in allergic rhinitis

BACKGROUND: Toll-like receptors enable the host to recognize a large number of pathogen-associated molecular patterns such as bacterial lipopolysaccharide, viral RNA, CpG-containing DNA and flagellin. Toll-like receptors have also been shown to play a pivotal role in both innate and adaptive immune responses. The role of Toll-like receptors as a primary part of our microbe defense system has been shown in several studies, but their possible function as mediators in allergy and asthma remains to be established. The present study was designed to examine the expression of Toll-like receptors 2, 3 and 4 in the nasal mucosa of patients with intermittent allergic rhinitis, focusing on changes induced by exposure to pollen. METHODS: 27 healthy controls and 42 patients with seasonal allergic rhinitis volunteered for the study. Nasal biopsies were obtained before and during pollen season as well as before and after allergen challenge. The seasonal material was used for mRNA quantification of Toll-like receptors 2, 3 and 4 with real-time polymerase chain reaction, whereas specimens achieved in conjunction with allergen challenge were used for immunohistochemical localization and quantification of corresponding proteins. RESULTS: mRNA and protein representing Toll-like receptors 2, 3 and 4 could be demonstrated in all specimens. An increase in protein expression for all three receptors could be seen following allergen challenge, whereas a significant increase of mRNA only could be obtained for Toll-like receptor 3 during pollen season. CONCLUSION: The up-regulation of Toll-like receptors 2, 3 and 4 in the nasal mucosa of patients with symptomatic allergic rhinitis supports the idea of a role for Toll-like receptors in allergic airway inflammation

The C Allele of rs5743836 Polymorphism in the Human TLR9 Promoter Links IL-6 and TLR9 Up-Regulation and Confers Increased B-Cell Proliferation

In humans, allelic variants in Toll-like receptors (TLRs) associate with several pathologies. However, the underlying cellular and molecular mechanisms of this association remain largely unknown. Analysis of the human TLR9 promoter revealed that the C allele of the rs5743836 polymorphism generates several regulatory sites, including an IL-6-responding element. Here, we show that, in mononuclear cells carrying the TC genotype of rs5743836, IL-6 up-regulates TLR9 expression, leading to exacerbated cellular responses to CpG, including IL-6 production and B-cell proliferation. Our study uncovers a role for the rs5743836 polymorphism in B-cell biology with implications on TLR9-mediated diseases and on the therapeutic usage of TLR9 agonists/antagonists

Diarrhoea in a large prospective cohort of European travellers to resource-limited destinations

BACKGROUND: Incidence rates of travellers' diarrhoea (TD) need to be updated and risk factors are insufficiently known. METHODS: Between July 2006 and January 2008 adult customers of our Centre for Travel Health travelling to a resource-limited country for the duration of 1 to 8 weeks were invited to participate in a prospective cohort study. They received one questionnaire pre-travel and a second one immediately post-travel. First two-week incidence rates were calculated for TD episodes and a risk assessment was made including demographic and travel-related variables, medical history and behavioural factors. RESULTS: Among the 3100 persons recruited, 2800 could be investigated, resulting in a participation rate of 89.2%. The first two-weeks incidence for classic TD was 26.2% (95%CI 24.5-27.8). The highest rates were found for Central Africa (29.6%, 95% CI 12.4-46.8), the Indian subcontinent (26.3%, 95%CI 2.3-30.2) and West Africa (21.5%, 95%CI 14.9-28.1). Median TD duration was 2 days (range 1-90). The majority treated TD with loperamide (57.6%), while a small proportion used probiotics (23.0%) and antibiotics (6.8%). Multiple logistic regression analysis on any TD to determine risk factors showed that a resolved diarrhoeal episode experienced in the 4 months pre-travel (OR 2.03, 95%CI 1.59-2.54), antidepressive comedication (OR 2.11, 95%CI 1.17-3.80), allergic asthma (OR 1.67, 95%CI 1.10-2.54), and reporting TD-independent fever (OR 6.56, 95%CI 3.06-14.04) were the most prominent risk factors of TD. CONCLUSIONS: TD remains a frequent travel disease, but there is a decreasing trend in the incidence rate. Patients with a history of allergic asthma, pre-travel diarrhoea, or of TD-independent fever were more likely to develop TD while abroad

The rs5743836 polymorphism in TLR9 confers a population-based increased risk of non-Hodgkin lymphoma

We are grateful to Paulo Vieira, Cecília Leão, Manuel T. Silva, Nuno Sousa, Jorge Correia- Pinto, Joana Palha, Margarida Correia-Neves, Margarida Lima and Matthew Berry for all their input throughout these studies and critical reading of the manuscript. We are grateful to the patients who joint this study as well as to all members of the Life and Health Sciences Research Institute and School of Health Sciences, University of Minho, who contributed in any way to the development of this workNon-Hodgkin lymphoma (NHL) has been associated with immunological defects, chronic inflammatory and autoimmune conditions. Given the link between immune dysfunction and NHL, genetic variants in toll-like receptors (TLRs) have been regarded as potential predictive factors of susceptibility to NHL. Adequate anti-tumoral responses are known to depend on TLR9 function, such that the use of its synthetic ligand is being targeted as a therapeutic strategy. We investigated the association between the functional rs5743836 polymorphism in the TLR9 promoter and risk for B-cell NHL and its major subtypes in three independent case-control association studies from Portugal (1160 controls, 797 patients), Italy (468 controls, 494 patients) and the US (972 controls, 868 patients). We found that the rs5743836 polymorphism was significantly overtransmitted in both Portuguese (odds ratio (OR), 1.85; P=7.3E-9) and Italian (OR, 1.84; P=6.0E-5) and not in the US cohort of NHL patients. Moreover, the increased transcriptional activity of TLR9 in mononuclear cells from patients harboring rs5743836 further supports a functional effect of this polymorphism on NHL susceptibility in a population-dependent manner.AC, NSO, MTC, and AJA were financially supported by a fellowship from Fundação para a Ciência e Tecnologia, Portugal. MS is a Ciência 2007 fellow. This study was supported by Fundação para a Ciência e Tecnologia, Portugal (PIC/IC/83313/2007) and by Fundação Calouste Gulbenkian, Serviço de Saúde e Desenvolvimento Humano, Portugal (Grant Number:Proc/60666-MM/734). CFS, PB and LC were supported by National Institutes of Health (NIH) grants CA122663 and CA104682, and PB also by NIH grants CA45614 and CA89745

A Novel Mechanism of Programmed Cell Death in Bacteria by Toxin–Antitoxin Systems Corrupts Peptidoglycan Synthesis

Most genomes of bacteria contain toxin–antitoxin (TA) systems. These gene systems encode a toxic protein and its cognate antitoxin. Upon antitoxin degradation, the toxin induces cell stasis or death. TA systems have been linked with numerous functions, including growth modulation, genome maintenance, and stress response. Members of the epsilon/zeta TA family are found throughout the genomes of pathogenic bacteria and were shown not only to stabilize resistance plasmids but also to promote virulence. The broad distribution of epsilon/zeta systems implies that zeta toxins utilize a ubiquitous bacteriotoxic mechanism. However, whereas all other TA families known to date poison macromolecules involved in translation or replication, the target of zeta toxins remained inscrutable. We used in vivo techniques such as microscropy and permeability assays to show that pneumococcal zeta toxin PezT impairs cell wall synthesis and triggers autolysis in Escherichia coli. Subsequently, we demonstrated in vitro that zeta toxins in general phosphorylate the ubiquitous peptidoglycan precursor uridine diphosphate-N-acetylglucosamine (UNAG) and that this activity is counteracted by binding of antitoxin. After identification of the product we verified the kinase activity in vivo by analyzing metabolite extracts of cells poisoned by PezT using high pressure liquid chromatograpy (HPLC). We further show that phosphorylated UNAG inhibitis MurA, the enzyme catalyzing the initial step in bacterial peptidoglycan biosynthesis. Additionally, we provide what is to our knowledge the first crystal structure of a zeta toxin bound to its substrate. We show that zeta toxins are novel kinases that poison bacteria through global inhibition of peptidoglycan synthesis. This provides a fundamental understanding of how epsilon/zeta TA systems stabilize mobile genetic elements. Additionally, our results imply a mechanism that connects activity of zeta toxin PezT to virulence of pneumococcal infections. Finally, we discuss how phosphorylated UNAG likely poisons additional pathways of bacterial cell wall synthesis, making it an attractive lead compound for development of new antibiotics