Abstract
An important effector function of the human complement system is to directly kill Gram-negative bacteria via Membrane Attack Complex (MAC) pores. MAC pores are assembled when surface-bound convertase enzymes convert C5 into C5b, which together with C6, C7, C8 and multiple copies of C9 forms a transmembrane pore that damages the bacterial cell envelope. Recently, we found that bacterial killing by MAC pores requires local conversion of C5 by surface-bound convertases. In this study we aimed to understand why local assembly of MAC pores is essential for bacterial killing. Here, we show that rapid interaction of C7 with C5b6 is required to form bactericidal MAC pores on Escherichia coli. Binding experiments with fluorescently labelled C6 show that C7 prevents release of C5b6 from the bacterial surface. Moreover, trypsin shaving experiments and atomic force microscopy revealed that this rapid interaction between C7 and C5b6 is crucial to efficiently anchor C5b-7 to the bacterial cell envelope and form complete MAC pores. Using complement-resistant clinical E. coli strains, we show that bacterial pathogens can prevent complement-dependent killing by interfering with the anchoring of C5b-7. While C5 convertase assembly was unaffected, these resistant strains blocked efficient anchoring of C5b-7 and thus prevented stable insertion of MAC pores into the bacterial cell envelope. Altogether, these findings provide basic molecular insights into how bactericidal MAC pores are assembled and how bacteria evade MAC-dependent killing.
Highlights
When bacteria invade the human body, they are attacked by the immune system that tries to clear the infection
In this paper we focus on how the complement system, an essential part of the immune system, kills bacteria via so-called membrane attack complex (MAC) pores
The Membrane Attack Complex (MAC) is a large, ring-shaped pore that consists of five different proteins, which is assembled when the complement system is activated on the bacterial surface
Summary
When bacteria invade the human body, they are attacked by the immune system that tries to clear the infection. Gram-negative bacteria can be directly killed by the complement system, a family of proteins in blood and bodily fluids, that forms toroid-shaped Membrane Attack Complex (MAC) pores into bacterial membranes [1,2,3,4]. MAC assembly is initiated when recognition molecules, such as antibodies and lectins, bind to bacterial surface structures and recruit early complement components to the target cell surface. This triggers activation of the complement system, a proteolytic cascade that labels the surface with convertase enzymes that cleave the central components C3 and C5 [5]. Membrane-bound C5b-7 subsequently recruits one copy of C8 and up to 18 copies of C9, which oligomerize and form of a 1.2 MDa transmembrane MAC pore (C5b-9) [9,10,11]
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