Pathogens capable of surviving exposure to antibacterial peptides and the complement system appear to employ several fundamentally distinct strategies. To cause disease, micro-organisms survival depends to a large extent on the ability to evade, avoid or resist host defences (Greenwood et al., 2007), which can ultimately result in acute disease and chronic infection. The host immune defence system consists of two components: innate and adaptive immunity. According to Nicklin et al. (2002), the innate immunity is mediated by a variety of nonspecific mechanisms. These operate automatically to protect the host against infection without the need for previous contact with the infectious agent. The innate immunity is the first line of defence. On the other hand, the adaptive immunity comprises of a number of effector mechanisms initiated and stimulated by specific recognition of an infectious agent by the host immune system as stated by Irving et al (2005). Successful microbial pathogens have evolved complex and efficient methods to overcome innate and adaptive immune mechanisms. Although the various virulence strategies used by bacterial pathogens are numerous, there are several general mechanisms that are used to subvert and exploit immune systems (Finlay and McFadden, 2006).
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The most effective way to protect against the antimicrobial action of the complement system is to prevent its activation. The complement is composed of a group of sequentially interacting proteins that play an important effector role in both innate and adaptive immunity. The complement activity is initiated by interactions with antigen-antibody complexes but can also be initiated by innate immune mechanisms as stated by Madigan et al (2009). There are three pathways of activation: the classical pathway initiated by antibody antigen complexes, the lectin pathway, highly analogous to the classical pathway (Matsushita and Fujita, 2001), and the alternate pathway which is triggered by microbial surface molecules. Activation causes a cascade of proteolytic reactions which leads to the production of a number of products that activate the immune system as shown in figure 1 (Nicklin et al., 2002). The end result is the generation of several active molecules which mediate distinct biological properties such as opsonization, anaphylaxis, chemotaxis and cell lysis.
Figure 1: Pathways for complement activation. a: The classical pathway is initiated by the binding of the C1 complex to antibodies that are bound to antigens on the surface of bacteria. b: The lectin pathway is initiated by the binding of either mannose-binding lectin (MBL) or ficolin associated with MBL-associated serine protease 1 (MASP1), MASP2, MASP3 and small MBL-associated protein (sMAP) to an array of carbohydrate groups on the surface of a bacterial cell. c: The alternative pathway is initiated by the low-grade activation of C3 by hydrolysed C3 (C3(H2O)) and activated factor B (Bb). These pathways use similar activation mechanisms to generate C3 convertases, the enzymes that cleave C3. The attachment of C3b to acceptor cells is necessary to initiate phagocytosis, formation of the membrane attack complex (MAC) and enhancement of humoral responses to antigens (Gasque, 2004). Image reproduced from Nature Reviews Immunology RE (2002) Macmillan Magazines Ltd.
Bacterial pathogens prevent activation of the complement system in several ways; by masking activating substances that activate the alternative pathway by coating with immunoglobulin A (IgA) antibodies and secreting a carbohydrate capsule that covers the activators (Medoff et al., 1999).This evasion strategy is used by most extracellular bacterial pathogens. For example, the pneumococcus relies on its capsule to prevent antibody and complement deposition on its surface, hence avoiding opsonization and phagocytic clearance. Likewise, bacterial pathogens that cause meningitis such as Haemophilus influenzae, Neisseria meningitides and Escherchia coli K1, rely on capsules within the host (Finlay and McFadden, 2006). These are seen by the immune system as self-antigens, hence do not succeed in generating an antibody response. Some organisms take advantage of the host's mechanism for evading activation of the complement by forming capsules containing hyaluronic acid that resemble host polysaccharide and incorporate sialic acid, the sugar that inhibits the complement fixation. Sialic acid is a host polysaccharide and is therefore not recognized as foreign matter. An example is gonococcus which adds sialic acid to the terminal sugar of their lipopolysaccharide (LPS), making them resistant to complement lysis (Goering et al., 2008). Meningococci have a different strategy of evading the complement by coating with circulating IgA antibodies, which hinders the other antibodies capable of activating the complement by the classical pathway from reaching the surface of the organisms (Medoff et al., 1999).
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Another strategy devised by bacterial pathogens is the evasion of the membrane attack complex.
Bacterial pathogens such as Salmonella do not hinder the formation of the complement MAC but hinder its access to the bacterial outer membrane. Bacterial mutants with the 'smooth' long O antigen LPS limits the membrane attack complex to their outer membrane. 'Rough' mutants have a short or even lack in the O antigen thus less virulent (Greenwood et al., 2007). Gram positive bacteria can also evade the MAC due to the thick cell wall which acts like a shield to the cell membrane. Evasion of MAC is also achieved by the Streptococcal inhibitor of complement (SIC), a 31 kDa excreted protein that fulfils many different roles in immune evasion by Group A Streptococci (GAS). The SIC is found in the highly virulent M1 type and is a terminal complement pathway inhibitor since it binds the soluble C5b-7 complex preventing its insertion into the pathogens cell membranes (Akesson et al., 1996 and Fernie-King et al., 2001). The SIC works against the antibacterial actions of secretory leukocyte proteinase inhibitor (sLPI) and lysozyme (Fernie-King et al., 2002), inactivates human neutrophil α-defensin (HNP-1) and LL-37 (Frick et al., 2003) and alters cellular processes by binding to intracellular proteins in epithelial cells and neutrophils (Hoe et al., 2002).
Staphylococcus aureus has evolved the means to resist and evade antimicrobial host components such as the lysozyme, the α-defensins, human neutrophil peptide (HNP) and the β-defensin hBD2 (Peschel et al., 2001). It has a membrane protein, Staphylococcal protein A (SpA), bound to the cell wall via the C terminal and the N terminal has IgG binding domains which Fc portions of IgG can bind to (Verhoef et al., 2004). The SpA alters the complement activation by blocking Fc-receptor mediated phagocytosis and interfers with the binding of C1 (Silverman et al., 2005). S.aureus also has a vital protein, clumping factor A (ClfA) on its surface which binds to fibrinogen which in turn binds to C3 and inhibits the classical pathway,hence the process of opsonisation. It also inactivates complement factor C3b and IgG molecules bound to the surface of opsonized bacterial cells using staphylokinase (SAK), a plasminogen activator. S. aureus secretes the protein Staphylococcus complement inhibitor (SCIN) which binds to C4b2a and C3bBb inhibiting C3b formation. Stabilization by SCIN blocks the amplification loop and it also impairs the enzymatic activity of the convertases hence proving the virulence of S. aureus as a bacterial pathogen (Rooijakkers and van Strijp, 2007). Borrelia burgdorferi is a bacterial pathogen that evades the complement system. It shares both antigenic and functional similarities with human CD59, a natural membrane-bound inhibitor of MAC which hinders cell lysis by preventing the polymerisation of C9 and the formation of MAC. (Pausa et al., 2003). On the other hand, Pseudomonas aeruginosa inactivates the complement chemotaxin C5a by producing elastases. Streptococcus group A and B are also known to contain C5a peptidases which cleave the complement components into inactive fragments (Cleary et al., 1992).
The complement system is controlled by a number of specific glycoproteins present in the fluid phase such as factor H, factor H-like protein (FHL-1), C4b binding protein and C1 inhibitor and also on cell membranes by CD21, CD35, CD46, CD55 and CD59. These prevent inappropriate complement activation and cell destruction (Morgan and Harris, 1999). Several strains of groups A and B streptococci and pneumococcus interfere with the complement regulatory proteins by expressing M-proteins and PspC, that acquire host fluid-phase complement regulators FH, FHL-1 or C4b protein to their surfaces inhibiting and controlling complement activation directly on the surface of the pathogen (Jarva H et al., 2003). The M protein of the Streptococcus pyogenes prevents complement deposition at the bacterial surface by binding to both fibrin and fibrinogen which hinders the access of complement activated by the alternative pathway. The N-terminus of the M-protein binds to C4bp and FHL-1 which results in the RCAs retaining their biological function but inhibit the complement system (Greenwood et al., 2007). Other bacterial pathogens evade the host defence systems by binding to the membrane bound RCA proteins CD46 and CD55. For instance, CD46 is extensively expressed on our cells and is also a receptor for N.gonorrohoeae and N.meningitidis whereas CD55, also known as decay-accelerating factor (DAF) stimulates the decay of C3 convertases by binding to a schistosome, is similarly expressed on human cells (Kraiczy and Wurzner (2005). This evasion strategy is vital in these bacterial pathogens for their survival in the host.
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Antibacterial peptides are small cationic peptides, composing cysteine-rich residues and allow interactions with the bacterial cytoplasmic membrane, which usually comprises negatively charged phospholipids. These peptides are also known as cationic antimicrobial peptides (CAMPs) (Peschel, 2002). They are part of the first line of host defense against invading pathogens. Antibacterial peptides are present constitutively in certain phagocytic cells. Their synthesis by epithelial cells can be induced by infection, inflammation, or trauma (Shaffer et al., 1998). The CAMPs produced by human beings are; defensins, which have a β-sheet structure and are located in human tissues and neutrophils (Lehrer and Ganz, 2002); thrombocidins, which are released from platelets and arise from carboxy-terminal deletions of the CXC chemokines neutrophil-activating peptide 2 and connective tissue-activating peptide 3 (Krijgsveld et al., 2000); and cathelicidins, which are released from precursor proteins bearing an amino-terminal cathepsin L inhibitor. The α-helical LL-37 is found on various epithelia and in neutrophils (Lehrer and Ganz, 2002).
Bacterial pathogens evade antibacterial peptides by altering the LPS structure. Lipid A is the essential core component of LPS, and is highly conserved among most Gram negative organisms and thus plays a vital role in activation of toll-like receptors (TLRs) such as TLR4. Bacterial pathogens have evolved ways of altering these molecules such that they are not recognized by the immune systems. Gram negative pathogens modify lipid A to alter TLR4 responses (Portnoy, 2005). The bacterial pathogens bind to TLRs to dampen inflammation and also inject effectors to inhibit downstream inflammation signaling. Salmonella typhimurium incorporates palmitate to lipid A and phosphate and phosphoethanolamine to the core polysaccharide. This modifies lipid A phosphate group with ethanolamine and aminoarabinose with the addition of the fatty acid. The two component regulatory system, PhoP and PhoQ in Salmonella typhimurium, control the gene pagP, which alters the structure of lipid A on the outer membrane of the bacterium. This modification reduces the permeability of the outer membrane in response to CAMPs and it increases the stability of the membrane structure (Guo et al., 1998). On the other hand, Staphylococcus aureus modifies its membrane lipid phosphatidylglycerol with D-lysine and adds D-alanine to teichoic acid (Peschel et al., 2000). Bacterial pathogens have devised evasion strategies that involved degrading the antibacterial peptide. For example, S.aureus secretes staphylokinase which has a defensin peptide binding activity and an extracellular metalloprotease aureolysin that cleaves and inactivates human defensins (McAleese et al., 2001). Other bacterial pathogens such as Neisseria meningitids and Salmonella typhimurium evade the antibacterial peptides by hiding within the epithelial cells of the host living intracellularly (Irvin et al., 2005). Gram negative bacteria produce endotoxins to degrade the extracellular matrix and the resulting fragments bind to antibacterial peptides. This could result in septic shock leading to organ failure and eventually death (Nicklin et al., 2002). In conclusion, an understanding of the basic evasion strategies is important for the design of new techniques of identifying new bacterial pathogens or improved evasion strategies that are discovered time to time to tackle bacterial evasion of the complement and antibacterial peptides, and reduce the virulence of these bacterial pathogens.