Article

Spatial localization of bacteria controls coagulation of human blood by 'quorum acting'

Department of Chemistry and Institute for Biophysical Dynamics, The University of Chicago, 929 East 57th Street, Chicago, Illinois 60637, USA.
Nature Chemical Biology (Impact Factor: 13.22). 01/2009; 4(12):742-50. DOI: 10.1038/nchembio.124
Source: PubMed

ABSTRACT Blood coagulation often accompanies bacterial infections and sepsis and is generally accepted as a consequence of immune responses. Though many bacterial species can directly activate individual coagulation factors, they have not been shown to directly initiate the coagulation cascade that precedes clot formation. Here we demonstrated, using microfluidics and surface patterning, that the spatial localization of bacteria substantially affects coagulation of human and mouse blood and plasma. Bacillus cereus and Bacillus anthracis, the anthrax-causing pathogen, directly initiated coagulation of blood in minutes when bacterial cells were clustered. Coagulation of human blood by B. anthracis required secreted zinc metalloprotease InhA1, which activated prothrombin and factor X directly (not via factor XII or tissue factor pathways). We refer to this mechanism as 'quorum acting' to distinguish it from quorum sensing--it does not require a change in gene expression, it can be rapid and it can be independent of bacterium-to-bacterium communication.

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Available from: Andrei P Pomerantsev, Aug 25, 2015
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    • "In addition, this bacterium has increasingly been recognized as an opportunistic pathogen that triggers local and systemic infections such as endophthalmitis, meningitis or septicaemia, which are particularly harmful for immunocompromised patients. Extraintestinal infections arise from the non-specific activities of an array of extracellular, tissue-destructive and cytolytic proteins (for reviews see Stenfors Arnesen et al., 2008; Bottone, 2010), and it has been suggested that the combined activities of haemolysins, neutral proteases and immune inhibitor metalloproteases might counteract host immune responses (Kastrup et al., 2008; Cadot et al., 2010; Guillemet et al., 2010). In contrast, food-borne illnesses , resulting in the diarrheal syndrome or in emetic intoxications, are attributed to specific agents: the poreforming enterotoxins Nhe, CytK and Hbl that act on epithelial cells in the intestine (Beecher and Macmillan, 1991; Lund and Granum, 1996; Lund et al., 2000), and cereulide, a cyclic peptide toxin (Agata et al., 1994). "
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    ABSTRACT: Bacillus cereus causes gastrointestinal diseases and local and systemic infections elicited by the depsipeptide cereulide, enterotoxins, phospholipases, cytolysins and proteases. The PlcR-PapR quorum sensing system activates the expression of several virulence factors, whereas the Spo0A-AbrB regulatory circuit partially controls the plasmid-borne cereulide synthetase (ces) operon. Here, we show that CodY, a nutrient-responsive regulator of Gram-positive bacteria, has a profound effect on both regulatory systems, which have been assumed to operate independently of each other. Deletion of codY resulted in downregulation of virulence genes belonging to the PlcR regulon and a concomitant upregulation of the ces genes. CodY was found to be a repressor of the ces operon, but did not interact with the promoter regions of PlcR-dependent virulence genes in vitro, suggesting an indirect regulation of the latter. Furthermore, CodY binds to the promoter of the immune inhibitor metalloprotease InhA1, demonstrating that CodY directly links B. cereus metabolism to virulence. In vivo studies using a Galleria mellonella infection model, showed that the codY mutant was substantially attenuated, highlighting the importance of CodY as a key regulator of pathogenicity. Our results demonstrate that CodY profoundly modulates the virulence of B. cereus, possibly controlling the development of pathogenic traits in suitable host environments.
    Molecular Microbiology 05/2012; 85(1):67-88. DOI:10.1111/j.1365-2958.2012.08090.x · 5.03 Impact Factor
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    • "B. anthracis InhA, however, has also been suggested to play a role in anthrax virulence through cleavage of numerous host substrates (Chung et al., 2006). More specifically, InhA cleaves host proteins involved in the coagulation cascade potentially facilitating circulatory dissemination of bacteria (Chung et al., 2006; Kastrup et al., 2008). In an anthrax mouse model DinhA (background Ames 35) bacterial infection was less lethal than wild-type Ames 35 bacterial infection (Mukherjee et al., 2011). "
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    • "However, this filtered anthrax blood, when placed in contact with fresh blood, rapidly generated agglutinated globules in as great or larger number than observed in (animals with) anthrax disease, possibly due to the presence of an enzyme formed by the bacteria. " The basis for this agglutination phenotype and whether ET or LT or neutral proteases such as InhA [184] contribute to it remains unknown. In his great summary of Pasteur's work, C.H. Chamberland also included a detailed description of the stages of anthrax disease provided by Delafond and Pasteur, which is remarkably similar to modern descriptions of the disease course in humans. "
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