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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    • "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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    • "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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