Microbial Hijacking of Complement-Toll-Like Receptor Crosstalk

Department of Microbiology and Immunology, University of Louisville School of Medicine, Louisville, KY 40292, USA.
Science Signaling (Impact Factor: 6.28). 02/2010; 3(109):ra11. DOI: 10.1126/scisignal.2000697
Source: PubMed


Crosstalk between complement and Toll-like receptors (TLRs) coordinates innate immunity. We report a previously unknown immune subversion mechanism involving microbial exploitation of communication between complement and TLRs. Porphyromonas gingivalis, a major oral and systemic pathogen with complement C5 convertase-like activity, synergizes with C5a (fragment of complement protein C5) to increase cyclic adenosine monophosphate (cAMP) concentrations, resulting in suppression of macrophage immune function and enhanced pathogen survival in vitro and in vivo. This synergy required TLR2 signaling, a pertussis toxin- and thapsigargin-sensitive C5a receptor pathway, with protein kinase A and glycogen synthase kinase-3beta as downstream effectors. Antagonistic blockade of the C5a receptor abrogated this evasive strategy and may thus have important therapeutic implications for periodontitis and atherosclerosis, diseases in which P. gingivalis is implicated. This first demonstration of complement-TLR crosstalk for immunosuppressive cAMP signaling indicates that pathogens may not simply undermine complement or TLRs (or both) as separate entities, but may also exploit their crosstalk pathways.

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Available from: Hisanori Domon, Oct 03, 2015
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    • "The disease is a polymicrobial infection caused by a diverse group of periodontal pathogens (Pihlstrom et al., 2005; Hajishengallis et al., 2012a). Accumulating evidence suggests that the interactions between the complement system and those periodontal pathogens play a pivotal role in periodontal inflammation and the progression of the disease (Hajishengallis, 2010; Wang et al., 2010; Hajishengallis et al., 2012b). Among those periodontal pathogens, Porphyromonas gingivalis, Tannerella forsythia and Treponema denticola (often referred to as 'red-complex' bacteria) have been considered as primary aetiological agents of periodontitis (Holt and Ebersole, 2005; Socransky and Haffajee, 2005). "
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    ABSTRACT: Neuraminidases (sialidases) catalyze the removal of terminal sialic acid from glycoconjugates. Bacterial pathogens often utilize neuraminidases to scavenge host sialic acid, which can be utilized either as a nutrient or as a decorating molecule to disguise themselves from host immune attacks. Herein, a putative neuraminidase (TDE0471) was identified in Treponema denticola, an oral spirochete associated with human periodontitis. TDE0471 is a cell surface-exposed exo-neuraminidase that removes sialic acid from human serum proteins; it is required for T. denticola to grow in a medium that mimics gingival crevice fluid, suggesting that the spirochete may use sialic acid as a nutrient in vivo. TDE0471 protects T. denticola from serum killing by preventing the deposition of membrane attack complexes on the bacterial cell surface. Animal studies revealed that a TDE0471-deficient mutant is less virulent than its parental wild-type strain in BALB/C mice. However, it causes a level of tissue damage similar to the wild type in complement-deficient B6.129S4-C3(tm1Crr) /J mice albeit the damage caused by both bacterial strains is more severe in these transgenic mice. Based on these results, we propose that T. denticola has evolved a strategy to scavenge host sialic acid using its neuraminidase, which allows the spirochete to acquire nutrients and evade complement killing.
    Molecular Microbiology 06/2013; 89(5). DOI:10.1111/mmi.12311 · 4.42 Impact Factor
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    • "Gram-negative bacteria, co-evolving alongside human hosts, have adapted to occupying available ecological niches as extracellular symbiotes, facultative or true intracellular pathogens. Bacterial interactions with the host reflect their role in the niche, allowing establishment of stable populations or host colonisation relying on evasion of the host immune system by immunomimicry [1], [2], epithelial disruption and invasion of host immune cells. The host response to environmental stimuli, associated with bacterial presence, is governed by cell surface receptor-activated cascades [3], [4]. "
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    ABSTRACT: Lipopolysaccharide (LPS) is a major constituent of bacterial outer membranes where it makes up the bulk of the outer leaflet and plays a key role as determinant of bacterial interactions with the host. Membrane-free LPS is known to activate T-lymphocytes through interactions with Toll-like receptor 4 via multiprotein complexes. In the present study, we investigate the role of cholesterol and membrane heterogeneities as facilitators of receptor-independent LPS binding and insertion, which underpin bacterial interactions with the host in symbiosis, pathogenesis and cell invasion. We use fluorescence spectroscopy to investigate the interactions of membrane-free LPS from intestinal gram-negative organisms with cholesterol-containing model membranes and with T-lymphocytes. LPS preparations from Klebsiella pneumoniae and Salmonella enterica were found to bind preferentially to mixed lipid membranes by comparison to pure PC bilayers. The same was observed for LPS from the symbiote Escherichia coli but with an order of magnitude higher dissociation constant. Insertion of LPS into model membranes confirmed the preference for sphimgomyelin/cholesterol-containing systems. LPS insertion into Jurkat T-lymphocyte membranes reveals that they have a significantly greater LPS-binding capacity by comparison to methyl-β-cyclodextrin cholesterol-depleted lymphocyte membranes, albeit at slightly lower binding rates.
    PLoS ONE 06/2012; 7(6):e38677. DOI:10.1371/journal.pone.0038677 · 3.23 Impact Factor
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    • "C5aR appeared to associate with P. gingivalis in a TLR2-dependent way since the P. gingivalis-C5aR FRET association was abrogated in Tlr2 −/− macrophages. (The data are from the reference Wang et al. 2010) (Used by permission). "
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    ABSTRACT: The periodontal pathogen Porphyromonas gingivalis undermines major components of innate immunity, such as complement, Toll-like receptors (TLR), and their crosstalk pathways. At least in principle, these subversive activities could promote the adaptive fitness of the entire periodontal biofilm community. In this regard, the virulence factors responsible for complement and TLR exploitation (gingipain enzymes, atypical lipopolysaccharide molecules, and fimbriae) are released as components of readily diffusible membrane vesicles, which can thus become available to other biofilm organisms. This review summarizes important immune subversive tactics of P. gingivalis which might enable it to exert a supportive impact on the oral microbial community.
    Advances in Experimental Medicine and Biology 01/2012; 946:69-85. DOI:10.1007/978-1-4614-0106-3_5 · 1.96 Impact Factor
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