Article

Manipulation of host-cell pathways by bacterial pathogens

University of British Columbia - Vancouver, Vancouver, British Columbia, Canada
Nature (Impact Factor: 41.46). 11/2007; 449(7164):827-34. DOI: 10.1038/nature06247
Source: PubMed

ABSTRACT

Bacterial pathogens operate by attacking crucial intracellular pathways in their hosts. These pathogens usually target more than one intracellular pathway and often interact at several points in each of these pathways to commandeer them fully. Although different bacterial pathogens tend to exploit similar pathway components in the host, the way in which they 'hijack' host cells usually differs. Knowledge of how pathogens target distinct cytoskeletal components and immune-cell signalling pathways is rapidly advancing, together with the understanding of bacterial virulence at a molecular level. Studying how these bacterial pathogens subvert host-cell pathways is central to understanding infectious disease.

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Available from: Amit P Bhavsar
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    • "These pathways then work collectively to recognize, take up, and ultimately kill invading pathogens. However, pathogens have evolved diverse strategies for survival and replication under hostile host environments123. Pathogens usually counteract host immune defense and even acquire host nutrition through physical protein–protein interactions (PPIs). "
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    ABSTRACT: Pathogens usually evade and manipulate host-immune pathways through pathogen-host protein-protein interactions (PPIs) to avoid being killed by the host immune system. Therefore, uncovering pathogen-host PPIs is critical for determining the mechanisms underlying pathogen infection and survival. In this study, we developed a computational method, which we named pairwise structure similarity (PSS)-PPI, to predict pathogen-host PPIs. First, a high-quality and non-redundant structure-structure interaction (SSI) template library was constructed by exhaustively exploring heteromeric protein complex structures in the PDB database. New interactions were then predicted by searching for PSS with complex structures in the SSI template library. A quantitative score named the PSS score, which integrated structure similarity and residue-residue contact-coverage information, was used to describe the overall similarity of each predicted interaction with the corresponding SSI template. Notably, PSS-PPI yielded experimentally confirmed pathogen-host PPIs of human immunodeficiency virus type 1 (HIV-1) with performance close to that of in vitro high-throughput screening approaches. Finally, a pathogen-host PPI network of human pathogen Mycobacterium tuberculosis, the causative agent of tuberculosis, was constructed using PSS-PPI and refined using filtration steps based on cellular localization information. Analysis of the resulting network indicated that secreted proteins of the STPK, ESX-1, and PE/PPE family in M. tuberculosis targeted human proteins involved in immune response and phagocytosis. M. tuberculosis also targeted host factors known to regulate HIV replication. Taken together, our findings provide insights into the survival mechanisms of M. tuberculosis in human hosts, as well as co-infection of tuberculosis and HIV. With the rapid pace of three-dimensional protein structure discovery, the SSI template library we constructed and the PSS-PPI method we devised can be used to uncover new pathogen-host PPIs in the future.
    Full-text · Article · Jan 2016 · PLoS ONE
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    • "Microbial pathogens during interaction with their hosts develop various strategies for invasion and adaptation to manipulate environmental signals of host cells (Bhavsar et al., 2007). One of these strategies is DNA damage or perturbation of the cell cycle machinery of the host to create a better environment for bacterial replication (Mattoo et al., 2007). "
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    DESCRIPTION: Detection and functionality of CdtB, PltA and PltB from Salmonella enterica serovar Javiana
    Full-text · Research · Jan 2016
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    • "Such phenotypic shifts would be indicative of fundamental changes to tissue metabolism and local inflammatory/immune cell functions in response to infection. Further, cell intrinsic metabolic programs orchestrated by multiple metabolic sensors, including mTOR, PPARγ, and AMPK, can be manipulated by pathogens for metabolites that support pathogen survival/replication (Bhavsar et al., 2007; Delgoffe et al., 2009; Terry et al., 2012; Eisele et al., 2013; Eisenreich et al., 2013; Ivanov and Roy, 2013; Keating et al., 2013; Xavier et al., 2013). "
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    ABSTRACT: Non-typhoidal Salmonella enterica induce an early pro-inflammatory response in chickens, but the response is short-lived, asymptomatic of clinical disease, results in a persistent colonization of the gastrointestinal (GI) tract, and can transmit infections to naïve hosts via fecal shedding of bacteria. The underlying mechanisms that facilitate this persistent colonization of the ceca of chickens by Salmonella are unknown. We have begun to concentrate on the convergence of metabolism and immune function as playing a major role in regulating the host responsiveness to infection. It is now recognized that the immune system monitors the metabolic state of tissues and responds by modulating metabolic function. The aim in this review is to summarize the literature that has defined a series of genotypic and phenotypic alterations in the regulatory host immune-metabolic signaling pathways in the local cecal microenvironment during the first 4 d following infection with Salmonella enterica serovar Enteritidis. Using chicken-specific kinomic immune-metabolism peptide arrays and quantitative real-time-PCR of cecal tissue during the early (4 to 48 h) and late stages (4 to 17 d) of a Salmonella infection in young broiler chickens, the local immunometabolic microenvironment has been ascertained. Distinct immune and metabolic pathways are altered between 2 to 4 d post-infection that dramatically changed the local immunometabolic environment. Thus, the tissue immunometabolic phenotype of the cecum plays a major role in the ability of the bacterium to establish a persistent cecal colonization. In general, our findings show that AMPK and mTOR area key players linking specific extracellular milieu and intracellular metabolism. Phenotypically, the early response (4 to 48 h) to Salmonella infection is pro-inflammatory, fueled by glycolysis and mTOR-mediated protein synthesis, whereas by the later phase (4 to 5 d), the local environment has undergone an immune-metabolic reprogramming to an anti-inflammatory state driven by AMPK-directed oxidative phosphorylation. Therefore, metabolism appears to provide a potential critical control point that can impact infection. Further understanding of metabolic control of immunity during infection should provide crucial information of the development of novel therapeutics based on metabolic modulators that enhance protection or inhibit infection.
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