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      Function of serine protease HtrA in the lifecycle of the foodborne pathogen Campylobacter jejuni

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          Abstract

          Campylobacter jejuni is a major food-borne zoonotic pathogen, responsible for a large proportion of bacterial gastroenteritis cases, as well as Guillian-Barré and Miller-Fisher syndromes. During infection, tissue damage is mainly caused by bacteria invading epithelial cells and traversing the intestinal barrier. C. jejuni is able to enter the lamina propria and the bloodstream and may move into other organs, such as spleen, liver, or mesenteric lymph nodes. However, the involved molecular mechanisms are not fully understood. C. jejuni can transmigrate effectively across polarized intestinal epithelial cells mainly by the paracellular route using the serine protease high-temperature requirement A (HtrA). However, it appears that HtrA has a dual function, as it also acts as a chaperone, interacting with denatured or misfolded periplasmic proteins under stress conditions. Here, we review recent progress on the role of HtrA in C. jejuni pathogenesis. HtrA can be transported into the extracellular space and cleaves cell-to-cell junction factors, such as E-cadherin and probably others, disrupting the epithelial barrier and enabling paracellular transmigration of the bacteria. The secretion of HtrA is a newly discovered strategy also utilized by other pathogens. Thus, secreted HtrA proteases represent highly attractive targets for anti-bacterial treatment and may provide a suitable candidate for vaccine development.

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          Most cited references 126

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          Food-borne diseases — The challenges of 20 years ago still persist while new ones continue to emerge

          The burden of diseases caused by food-borne pathogens remains largely unknown. Importantly data indicating trends in food-borne infectious intestinal disease is limited to a few industrialised countries, and even fewer pathogens. It has been predicted that the importance of diarrhoeal disease, mainly due to contaminated food and water, as a cause of death will decline worldwide. Evidence for such a downward trend is limited. This prediction presumes that improvements in the production and retail of microbiologically safe food will be sustained in the developed world and, moreover, will be rolled out to those countries of the developing world increasingly producing food for a global market. In this review evidence is presented to indicate that the microbiological safety of food remains a dynamic situation heavily influenced by multiple factors along the food chain from farm to fork. Sustaining food safety standards will depend on constant vigilance maintained by monitoring and surveillance but, with the rising importance of other food-related issues, such as food security, obesity and climate change, competition for resources in the future to enable this may be fierce. In addition the pathogen populations relevant to food safety are not static. Food is an excellent vehicle by which many pathogens (bacteria, viruses/prions and parasites) can reach an appropriate colonisation site in a new host. Although food production practices change, the well-recognised food-borne pathogens, such as Salmonella spp. and Escherichia coli, seem able to evolve to exploit novel opportunities, for example fresh produce, and even generate new public health challenges, for example antimicrobial resistance. In addition, previously unknown food-borne pathogens, many of which are zoonotic, are constantly emerging. Current understanding of the trends in food-borne diseases for bacterial, viral and parasitic pathogens has been reviewed. The bacterial pathogens are exemplified by those well-recognized by policy makers; i.e. Salmonella, Campylobacter, E. coli and Listeria monocytogenes. Antimicrobial resistance in several bacterial food-borne pathogens (Salmonella, Campylobacter, Shigella and Vibrio spp., methicillin resistant Staphylcoccus aureas, E. coli and Enterococci) has been discussed as a separate topic because of its relative importance to policy issues. Awareness and surveillance of viral food-borne pathogens is generally poor but emphasis is placed on Norovirus, Hepatitis A, rotaviruses and newly emerging viruses such as SARS. Many food-borne parasitic pathogens are known (for example Ascaris, Cryptosporidia and Trichinella) but few of these are effectively monitored in foods, livestock and wildlife and their epidemiology through the food-chain is poorly understood. The lessons learned and future challenges in each topic are debated. It is clear that one overall challenge is the generation and maintenance of constructive dialogue and collaboration between public health, veterinary and food safety experts, bringing together multidisciplinary skills and multi-pathogen expertise. Such collaboration is essential to monitor changing trends in the well-recognised diseases and detect emerging pathogens. It will also be necessary understand the multiple interactions these pathogens have with their environments during transmission along the food chain in order to develop effective prevention and control strategies.
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            Novel Murine Infection Models Provide Deep Insights into the “Ménage à Trois” of Campylobacter jejuni, Microbiota and Host Innate Immunity

            Background Although Campylobacter jejuni-infections have a high prevalence worldwide and represent a significant socioeconomic burden, it is still not well understood how C. jejuni causes intestinal inflammation. Detailed investigation of C. jejuni-mediated intestinal immunopathology is hampered by the lack of appropriate vertebrate models. In particular, mice display colonization resistance against this pathogen. Methodology/Principal Findings To overcome these limitations we developed a novel C. jejuni-infection model using gnotobiotic mice in which the intestinal flora was eradicated by antibiotic treatment. These animals could then be permanently associated with a complete human (hfa) or murine (mfa) microbiota. After peroral infection C. jejuni colonized the gastrointestinal tract of gnotobiotic and hfa mice for six weeks, whereas mfa mice cleared the pathogen within two days. Strikingly, stable C. jejuni colonization was accompanied by a pro-inflammatory immune response indicated by increased numbers of T- and B-lymphocytes, regulatory T-cells, neutrophils and apoptotic cells, as well as increased concentrations of TNF-α, IL-6, and MCP-1 in the colon mucosa of hfa mice. Analysis of MyD88−/−, TRIF−/−, TLR4−/−, and TLR9−/− mice revealed that TLR4- and TLR9-signaling was essential for immunopathology following C. jejuni-infection. Interestingly, C. jejuni-mutant strains deficient in formic acid metabolism and perception induced less intestinal immunopathology compared to the parental strain infection. In summary, the murine gut flora is essential for colonization resistance against C. jejuni and can be overcome by reconstitution of gnotobiotic mice with human flora. Detection of C. jejuni-LPS and -CpG-DNA by host TLR4 and TLR9, respectively, plays a key role in immunopathology. Finally, the host immune response is tightly coupled to bacterial formic acid metabolism and invasion fitness. Conclusion/Significance We conclude that gnotobiotic and “humanized” mice represent excellent novel C. jejuni-infection and -inflammation models and provide deep insights into the immunological and molecular interplays between C. jejuni, microbiota and innate immunity in human campylobacteriosis.
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              Campylobacter jejuni: a brief overview on pathogenicity-associated factors and disease-mediating mechanisms.

              Campylobacter jejuni has long been recognized as a cause of bacterial food-borne illness, and surprisingly, it remains the most prevalent bacterial food-borne pathogen in the industrial world to date. Natural reservoirs for this Gram-negative, spiral-shaped bacterium are wild birds, whose intestines offer a suitable biological niche for the survival and dissemination of C. jejuni Chickens become colonized shortly after birth and are the most important source for human infection. In the last decade, effective intervention strategies to limit infections caused by this elusive pathogen were hindered mainly because of a paucity in understanding the virulence mechanisms of C. jejuni and in part, unavailability of an adequate animal model for the disease. However, recent developments in deciphering molecular mechanisms of virulence of C. jejuni made it clear that C. jejuni is a unique pathogen, being able to execute N-linked glycosylation of more than 30 proteins related to colonization, adherence, and invasion. Moreover, the flagellum is not only depicted to facilitate motility but as well secretion of Campylobacter invasive antigens (Cia). The only toxin of C. jejuni, the so-called cytolethal distending toxin (CdtA,B,C), seems to be important for cell cycle control and induction of host cell apoptosis and has been recognized as a major pathogenicity-associated factor. In contrast to other diarrhoea-causing bacteria, no other classical virulence factors have yet been identified in C. jejuni. Instead, host factors seem to play a major role for pathogenesis of campylobacteriosis of man. Indeed, several lines of evidence suggest exploitation of different adaptation strategies by this pathogen depending on its requirement, whether to establish itself in the natural avian reservoir or during the course of human infection. (c) 2009 Elsevier GmbH. All rights reserved.
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                Author and article information

                Journal
                1886
                European Journal of Microbiology and Immunology
                EuJMI
                Akadémiai Kiadó
                2062-8633
                September 2018
                : 8
                : 3
                : 70-77
                Affiliations
                [1 ]Department of Biology, Institute for Microbiology, Friedrich Alexander University Erlangen/Nuremberg , Staudtstr. 5, D-91058 Erlangen, Germany
                [2 ]Department of Microbiology and Infection Immunology, Charité – University Medicine Berlin , Berlin, Germany
                Author notes
                [*]

                Corresponding author: Friedrich Alexander University Erlangen/Nuremberg, Department of Biology, Institute for Microbiology, Staudtstr. 5, D-91058 Erlangen, Germany; manja.boehm@ 123456fau.de ; +49 9131 8528588; +49 9131 8528082.

                Article
                10.1556/1886.2018.00011
                6186014
                © 2018 The Author(s)

                This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ( http://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

                Page count
                Pages: 8
                Categories
                Review Paper

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