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      Flagellin-Deficient Legionella Mutants Evade Caspase-1- and Naip5-Mediated Macrophage Immunity

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          Abstract

          Macrophages from C57BL/6J (B6) mice restrict growth of the intracellular bacterial pathogen Legionella pneumophila. Restriction of bacterial growth requires caspase-1 and the leucine-rich repeat-containing protein Naip5 (Birc1e) . We identified mutants of L. pneumophila that evade macrophage innate immunity. All mutants were deficient in expression of flagellin, the primary flagellar subunit, and failed to induce caspase-1-mediated macrophage death. Interestingly, a previously isolated flagellar mutant (fliI) that expresses, but does not assemble, flagellin did not replicate in macrophages, and induced macrophage death. Thus, flagellin itself, not flagella or motility, is required to initiate macrophage innate immunity. Immunity to Legionella did not require MyD88, an essential adaptor for toll-like receptor 5 (TLR5) signaling. Moreover, flagellin of Legionella and Salmonella induced cytotoxicity when delivered to the macrophage cytosol using Escherichia coli as a heterologous host. It thus appears that macrophages sense cytosolic flagellin via a TLR5-independent pathway that leads to rapid caspase-1-dependent cell death and provides defense against intracellular bacterial pathogens.

          Synopsis

          Legionella pneumophila is a bacterial pathogen that is the cause of a severe form of pneumonia known as Legionnaires' disease. A crucial aspect of the propensity of Legionella to cause disease lies in its ability to survive and multiply inside host immune cells known as macrophages. The intracellular survival and replication of Legionella can be studied using isolated macrophages grown in culture. Macrophages isolated from different laboratory mouse strains are differentially permissive for intracellular Legionella growth. This difference in permissiveness is genetic, and is conferred by differences in a mouse protein known as Naip5. The authors determined that Legionella strains that are unable to produce a protein called flagellin are able to grow inside normally resistant mouse macrophages. In addition, these flagellin strains are defective in initiating a cell-death response on the part of infected macrophages. Based on these data, the authors suggest that there is an intracellular mechanism for detecting the presence of bacterial flagellin protein, and that a cell-death response is initiated upon the detection of flagellin.

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          Most cited references 41

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          Nod2 is a general sensor of peptidoglycan through muramyl dipeptide (MDP) detection.

          Nod2 activates the NF-kappaB pathway following intracellular stimulation by bacterial products. Recently, mutations in Nod2 have been shown to be associated with Crohn's disease, suggesting a role for bacteria-host interactions in the etiology of this disorder. We show here that Nod2 is a general sensor of peptidoglycan through the recognition of muramyl dipeptide (MDP), the minimal bioactive peptidoglycan motif common to all bacteria. Moreover, the 3020insC frameshift mutation, the most frequent Nod2 variant associated with Crohn's disease patients, fully abrogates Nod2-dependent detection of peptidoglycan and MDP. Together, these results impact on the understanding of Crohn's disease development. Additionally, the characterization of Nod2 as the first pathogen-recognition molecule that detects MDP will help to unravel the well known biological activities of this immunomodulatory compound.
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            Nod1 detects a unique muropeptide from gram-negative bacterial peptidoglycan.

            Although the role of Toll-like receptors in extracellular bacterial sensing has been investigated intensively, intracellular detection of bacteria through Nod molecules remains largely uncharacterized. Here, we show that human Nod1 specifically detects a unique diaminopimelate-containing N-acetylglucosamine-N-acetylmuramic acid (GlcNAc-MurNAc) tripeptide motif found in Gram-negative bacterial peptidoglycan, resulting in activation of the transcription factor NF-kappaB pathway. Moreover, we show that in epithelial cells (which represent the first line of defense against invasive pathogens), Nod1is indispensable for intracellular Gram-negative bacterial sensing.
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              Legionella and Legionnaires' disease: 25 years of investigation.

              There is still a low level of clinical awareness regarding Legionnaires' disease 25 years after it was first detected. The causative agents, legionellae, are freshwater bacteria with a fascinating ecology. These bacteria are intracellular pathogens of freshwater protozoa and utilize a similar mechanism to infect human phagocytic cells. There have been major advances in delineating the pathogenesis of legionellae through the identification of genes which allow the organism to bypass the endocytic pathways of both protozoan and human cells. Other bacteria that may share this novel infectious process are Coxiella burnetti and Brucella spp. More than 40 species and numerous serogroups of legionellae have been identified. Most diagnostic tests are directed at the species that causes most of the reported human cases of legionellosis, L. pneumophila serogroup 1. For this reason, information on the incidence of human respiratory disease attributable to other species and serogroups of legionellae is lacking. Improvements in diagnostic tests such as the urine antigen assay have inadvertently caused a decrease in the use of culture to detect infection, resulting in incomplete surveillance for legionellosis. Large, focal outbreaks of Legionnaires' disease continue to occur worldwide, and there is a critical need for surveillance for travel-related legionellosis in the United States. There is optimism that newly developed guidelines and water treatment practices can greatly reduce the incidence of this preventable illness.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS Pathog
                ppat
                PLoS Pathogens
                Public Library of Science (San Francisco, USA )
                1553-7366
                1553-7374
                March 2006
                17 March 2006
                : 2
                : 3
                Affiliations
                [1 ] Genetics Department, Harvard Medical School, Boston, Massachusetts, United States of America
                [2 ] Section of Microbial Pathogenesis, Yale University School of Medicine, New Haven, Connecticut, United States of America
                Tufts University School of Medicine, United States of America
                Author notes
                * To whom correspondence should be addressed. E-mail: dietrich@ 123456genetics.med.harvard.edu
                Article
                05-PLPA-RA-0254R2 plpa-02-03-04
                10.1371/journal.ppat.0020018
                1401497
                16552444
                Copyright: © 2006 Ren et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
                Page count
                Pages: 9
                Categories
                Research Article
                Immunology
                Infectious Diseases
                Microbiology
                Mus (Mouse)
                Eubacteria
                Custom metadata
                Ren T, Zamboni DS, Roy CR, Dietrich WF, Vance RE (2006) Flagellin-deficient Legionella mutants evade caspase-1- and Naip5-mediated macrophage immunity. PLoS Pathog 2(3): e18.

                Infectious disease & Microbiology

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