Abstract
Pathogenicity of many microbes relies on their capacity to resist innate immunity, and to survive and persist in an immunocompetent human host microbes have developed highly efficient and sophisticated complement evasion strategies. Here we show that different human pathogens including Gram-negative and Gram-positive bacteria, as well as the fungal pathogen Candida albicans, acquire the human terminal complement regulator vitronectin to their surface. By using truncated vitronectin fragments we found that all analyzed microbial pathogens (n = 13) bound human vitronectin via the same C-terminal heparin-binding domain (amino acids 352–374). This specific interaction leaves the terminal complement complex (TCC) regulatory region of vitronectin accessible, allowing inhibition of C5b-7 membrane insertion and C9 polymerization. Vitronectin complexed with the various microbes and corresponding proteins was thus functionally active and inhibited complement-mediated C5b-9 deposition. Taken together, diverse microbial pathogens expressing different structurally unrelated vitronectin-binding molecules interact with host vitronectin via the same conserved region to allow versatile control of the host innate immune response.
Highlights
Upon infection and colonization of the human host, infectious agents are immediately attacked by the complement system, which forms the first and central line of the host innate immune defense
The complement system is activated by three major pathways; the alternative pathway is spontaneously activated on surfaces and foreign particles, and the classical and lectin pathways are induced by specific pattern recognition molecules and by antibody-antigen complexes [2]
Transformed Escherichia coli M15 or BL21 expressing Lpd, Msf or Efb were grown in Luria Bertani (LB) broth supplemented with 100 μg/ml carbenicillin and/or 25– 50 μg/ml kanamycin
Summary
Upon infection and colonization of the human host, infectious agents are immediately attacked by the complement system, which forms the first and central line of the host innate immune defense. Activation of the complement system leads to generation of antimicrobial compounds, release of anaphylatoxins, C3b deposition on surfaces (opsonisation) and formation of the terminal complement complex (TCC) [1]. All three pathways converge and form C3 convertases and this activation step is followed by formation of C5 convertases, release of potent inflammatory C5a and in the assembly of the TCC. C6 and C7 bind to this newly formed C5b, and the C5b-7 complex attaches to and subsequently inserts into the target membrane. When C5b-9 is inserted into the target membrane the osmotic pressure changes and results in cell lysis. Complement activation can lead to extensive damage of host cells and tissues, and a series of regulators protect the host surfaces [4]
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