MIIM30011 Bacterial immune evasion strategies .pdf

Bacterial immune evasion strategies. MIIM30011 A/Prof Maria Liaskos [email protected]  Overview of this lecture To understand that bacteria can evade immunity during various steps in pathogenesis To understand that b...

Bacterial immune evasion strategies. MIIM30011 A/Prof Maria Liaskos [email protected]  Overview of this lecture To understand that bacteria can evade immunity during various steps in pathogenesis To understand that bacteria use various mechanisms to evade innate immunity To understand that bacteria can modify key virulence factors to evade adaptive immunity Roadmap to Disease To cause disease most pathogens must: 1) Enter the body 2) Colonise the host 3) Evade host defences 4) Multiply and disseminate 5) Cause damage to the host Roadmap to Disease To cause disease most pathogens must: 1) Enter the body 2) Colonise the host 3) Evade host defences 4) Multiply and disseminate 5) Cause damage to the host  Steps of pathogenesis What a pathogen ultimately aims to achieve Brock Biology of Microorganisms. Figure 23.9  Steps of pathogenesis What a pathogen ultimately aims to achieve Immune evasion Brock Biology of Microorganisms. Figure 23.9  Kinetics of Innate and Adaptive Immune Responses Bacterial pathogens need to evade immunity upon entry into the host Bacterial pathogens need to overcome innate and adaptive immune defences to mediate pathogenesis in the host Bacterial pathogens aim to avoid detection and clearance by the immune system 1. Innate immune system Physical barriers and innate immune defences Immune receptors Immune proteins eg. complement Immune cells (macrophages and neutrophils) 2. Adaptive immune response Lymphocytes (B/T cells) Immunoglobulins (Antibodies) Major histocompatibility complex (MHC) Evasion of the innate immune system by bacterial pathogens Physical barriers and innate immune defences Immune receptors Immune proteins eg. complement Immune cells (macrophages and neutrophils) Evasion of the innate immune system by bacterial pathogens Physical barriers and innate immune defences Immune receptors Immune proteins eg. complement Immune cells (macrophages and neutrophils)  Protecting against bacterial infections. Physical surface barriers protect us from bacterial infections  Natural defences of specific sites that protect us against bacteria- Simple but effective SITE DEFENCE Eyes Tears- washing, lysozyme that degrades peptidoglycan Airways Mucus- traps bacteria ciliated epithelium- removes bacteria Stomach Mucus, Acid (pH 2-3) Small intestine Continuous renewal of epithelial cell surface Epithelial cells (skin, stomach) Defensins (antimicrobial peptides) Colon, Vaginal tract Resident Microbiota to prevent colonisation Microbiota can produce bactericidal compounds  Natural defences of specific sites that protect us against bacteria- Simple but effective SITE DEFENCE Eyes Tears- washing, lysozyme that degrades peptidoglycan EVASION Bacteria modify their PG to be resistant to lysozyme Airways Mucus- traps bacteria ciliated epithelium- removes bacteria Stomach Mucus, Acid (pH 2-3) EVASION Helicobacter pylori produces urease to neutralise acid Small intestine Continuous renewal of epithelial cell surface Epithelial cells (skin, stomach) Defensins (antimicrobial peptides) EVASION Bacteria can alter their LPS to be resistant to defensins Colon, Vaginal tract Resident Microbiota to prevent colonisation Microbiota can produce bactericidal compounds Evasion of the innate immune system by bacterial pathogens Physical barriers and innate immune defences Immune receptors Immune proteins eg. complement Immune cells (macrophages and neutrophils)  Activation of TLRs and other innate immune receptors results in the production of cytokines and inflammation Pathogens Binding by phagocyte PRR activates phagocyte to kill pathogen. TLR2 TLR4 Phagocyte NF-kB Cytokines (Interleukin-8, IL-8) Brock biology of Microorganisms. Fig. 24.3 The TLR family of bacterial pathogen recognition molecules (PRMs) and the ligands they recognise Wilson, et. al., Bacterial Pathogenesis, a molecular approach The TLR family of bacterial pathogen recognition molecules (PRMs) and the ligands they recognise Wilson, et. al., Bacterial Pathogenesis, a molecular approach Pathogens can alter their composition to avoid detection by innate immune pathogen recognition receptors (PRRs) Pathogens Binding by phagocyte PRR activates Some pathogens avoid detection by host PRRs phagocyte to kill pathogen. Eg. Helicobacter pylori avoids detection by TLRs TLR2 Modifications in LPS to avoid detection by TLR4 TLR4 Modification in flagella to avoid detection by TLR5 Phagocyte NF-kB Cytokines (Interleukin-8, IL-8) Brock biology of Microorganisms. Fig. 24.3 Evasion of the innate immune system by bacterial pathogens Physical barriers and innate immune defences Immune receptors Immune proteins eg. complement Immune cells (macrophages and neutrophils)  Complement A set of proteins produced by the liver Complement proteins circulate in blood and enter tissues all over the body Primary function is to allow phagocytic cells to rapidly clear pathogens Are inactive until they undergo proteolytic processing (cascade of activation) Then they are converted to their active form Complement activation occurs during an infection There are 9 proteins C1-C9  Functions of complement in bacterial pathogenesis Migration of lymphocytes to an area: C3a acts as a vasodilator C5a act as a vasodilator and a gradient to facilitate the migration of monocytes and PMNs from the bloodstream to the site of infection Facilitate phagocytosis (opsonization): C3b binds to the surface of bacteria to facilitate phagocytosis Activation of complement cascade: recruitment of complement molecules form the membrane attack complex (MAC) that kills the bacteria by forming holes in the membrane Activation of complement by bacterial pathogens Activation of complement by bacterial pathogens Activation of complement by bacterial pathogens Activation of complement by bacterial pathogens MBL= Mannose binding lectins (MBL) Part of the collectin family of proteins Produced in liver Bind to mannose groups commonly found on the surface of bacteria but not host cells Activate complement  Activation of complement by bacterial pathogens MBL= Mannose binding lectins (MBL) Part of the collectin family of proteins Produced in liver Bind to mannose groups commonly found on the surface of bacteria but not host cells Activate complement Immune cell recruitment Opsonisation Bacterial lysis (MAC) Role of complement: Clearance of bacteria assisted by complement and/or antibodies Bacteria can evade opsonisation by preventing C3b or antibody binding Prescott Fig. 33.6  Mechanisms of complement evasion by bacterial pathogens Bacterial pathogens have evolved a range of strategies to avoid complement activation mimicking host surfaces attracting host complement regulators through surface- exposed proteins targeting complement components with secreted proteins. Serruto D. et. al., Nat Rev Microbiol. 2010 Jun;8(6):393-9. doi: 10.1038/nrmicro2366. Neisseria meningitidis factor H-binding protein (fHbp), Borrelia burgdorferi outer surface protein E (OspE) and CspA, Staphylococcus aureus binder of immunoglobulins (Sbi), Streptococcus pneumoniae pneumococcal surface protein C (PspC), Streptococcus BibA, Bordetella pertussis filamentous haemagglutinin (FHA), N. meningitidis PorA, Yersinia enterocolitica adhesin A (YadA), Group A Streptococcus M protein, S. aureus clumping factor A (ClfA), staphylokinase (sAK), staphylococcal complement inhibitor (sCIN), staphylococcal protein A (spa), staphylococcal superantigen-like (ssL). Evasion of the innate immune system by bacterial pathogens Physical barriers and innate immune defences Immune receptors Immune proteins eg. complement Immune cells (macrophages and neutrophils)  Pathogens use a range of mechanisms to evade innate immune cells Bacteria can avoid phagocytosis and being cleared by innate immune cells by: Expressing a capsule Mimicking the host- Molecular mimicry Biofilm production Evasion of complement Intracellular survival- surviving phagocytosis  Capsule prevents complement binding and phagocytosis of bacterial pathogens Capsule functions to prevent the binding of complement and complement complex formation on the surface C3b cannot bind on the surface to enable opsonization Also prevents the formation of C3 convertase Less C3b formation means less C5b is produced Resulting in less membrane complex attack is formed on the bacterial surface Brock biology of Microorganisms  Mimicking the host to evade clearance Mimicking the host: capsule composition Host antibodies bind to capsule Bacteria can produce capsule that contains polysaccharides that resemble the host S. pyogenes hyaluronic acid capsule: component of host extracellular matrix polysaccharide N. meningitidis sialic acid capsule: a component of host cell glycoproteins Mimicking the host: LPS composition H. pylori alters the O antigen of its LPS H. pylori LPS expressed carbohydrate moieties mimicking the human Lewis X and Lewis Y antigens expressed by gastric epithelial cells Autoimmune gastritis  Biofilms Biofilms Dense layers of bacterial communities that attach to surfaces Are refractory to treatment with antibiotics Protect bacteria within the community against phagocytosis Medical Implications of biofilms Body surfaces- Pseudomonas aeruginosa, cystic fibrosis Surfaces- Legionella pneumophila- Legionnaires disease Medical devises- catheters, plastic implants (valves, cochlear)  Biofilms: Bacteria attach to a surface and each other via extracellular polysaccharide slime, that also contains DNA Figure 1. Stages of the biofilm lifecycle. In stage 1, planktonic bacteria initiate attachment to an abiotic surface, which becomes irreversible in stage 2. Stages 3 and 4 feature biofilm maturation and growth of the three dimensional community. Dispersion occ... Meghan S Blackledge et. al., Current Opinion in Pharmacology, Volume 13, Issue 5, 2013, 699–706 Snapshot: Immune cells being killed within a biofilm Cell Picture Show  Intracellular survival- surviving phagocytosis Phagocytosed bacteria can protect themselves from phagolysosomal degradation by Neutralising the phagosomal components Resistance to reactive oxygen species and nitric oxide Prevention of phagolysosomal fusion Escape from the phagosome  Intracellular survival- surviving phagocytosis Phagocytosed bacteria can protect themselves from phagolysosomal degradation by Neutralising the phagosomal components Resistance to reactive oxygen species and nitric oxide Prevention of phagolysosomal fusion Escape from the phagosome Intracellular survival of Legionella pneumophila: prevention of phagolysosomal fusion Wilson et. al., Bacterial pathogenesis Chapter 11 Intracellular survival of Mycobacterium tuberculosis: prevention of the acidification of phagolysosome Wilson et. al., Bacterial pathogenesis Chapter 11  Intracellular survival- surviving phagocytosis Phagocytosed bacteria can protect themselves from phagolysosomal degradation by Neutralising the phagosomal components Resistance to reactive oxygen species and nitric oxide Prevention of phagolysosomal fusion Escape from the phagosome L. monocytogenes can escape from the phagosome to invade adjacent cells Wilson et. al., Bacterial pathogenesis Chapter 11 Evasion of adaptive immune responses by bacterial pathogens Adaptive immune response Lymphocytes (B/T cells) Immunoglobulins (Antibodies) Major histocompatibility complex (MHC) Genetic exchange and diversification by pathogenic bacteria- Phase variation Phase variation Refers to changes in the expression of important virulence proteins that occur at relatively high frequency compared to spontaneous mutations Occurs via several different mechanisms By changing the composition of a highly antigenic component, bacteria are able to avoid elimination by the host’s immune system  Phase variation in Salmonella- switching between flagella genes Once example of how bacteria can avoid immune clearance via phase variation is the ability of Salmonella strains to change the expression of their flagella Flagella proteins are highly immunogenic so Salmonella modifies its flagella proteins to avoid immune clearance Switching between the expression of different types is caused by a DNA invertase which promotes inversion of sequences upstream of the H2 flagellin gene  Phase variation in Salmonella- altering flagella type hixL hixR fljB fljA fliC hin Hin invertase Hin hixR hixL fljB fljA fliC hin Hin invertase Genetic exchange and diversification by pathogenic bacteria- Antigenic variation Antigenic variation Pathogens can avoid the host immune system by changing their surface antigens through gene shuffling events- called antigenic variation Results in host antibody responses becoming obsolete by providing a new antigenic variant that is no longer recognised by the hosts current antibodies Example of virulence factors that can be changed by antigenic variation to avoid immune clearance includes Pili variation by Neisseria gonnorrhoeae Wilson et. al., Bacterial pathogenesis Fig 11-6  Antigenic variation of pili in Neisseria Neisseria gonorrhoeae uses pili to attach to epithelial cells Uses antigenic variation by recombination between different pilin genes Recombination between various pilin pilS and pilE genes results in a new pilE This results in a new pilin protein on the surface which is not recognised by host antibodies and therefore cannot be easily cleared by the host N. gonnorrhoeae antigenic variation of pilin genes pilS pilE New pilE  Lecture Outcomes To know that bacteria can use a range of mechanisms to evade the immune response To know the types of natural defences used by the host to protect itself against bacterial pathogens To know the key mechanisms used by bacteria to evade innate immunity (eg. evade innate immune defences and avoid complement, immune detection, phagocytosis, degradation etc) To know how bacteria can modify themselves using phase and antigenic variation to avoid clearance by the adaptive immune response To know how bacteria can avoid adaptive immunity  Further reading Bacterial Pathogenesis, a molecular approach. Wilson, Salyers, Whitt and Winkler Relevant sections from - Chapters 2 Innate Immune system - Chapter 7 Antigenic and phase variation - Chapter 11 Bacterial evasion