10. How bacteria evade the human immune system to cause disease Flashcards
What is the red queen hypothesis?
- A term coined in evolutionary biology to explain the evolution of interacting species for survival in a common environment.
- Species must adapt and evolve not solely for reproductive advantage but also for survival against competing organisms who are also evolving.
- This continued development is needed to maintain relative fitness to the system it is co-evolving with.
- This was compared to the bit in Alice in Wonderland where the queen and Alice are running but not moving.
How does the Red Queen Hypothesis apply to host pathogen interactions?
- Pathogens are constantly encountered by the host and are detrimental to their hosts, thus pathogens exert high selection pressure on their host.
- Hosts can also exert similar levels of selection on the pathogen to prevent infection. This results in ongoing cycles of reciprocal adaptation between the 2 organisms.
- Involves host developing immunity to a pathogen and the pathogen then evolving mechanisms to evade host immunity and then the host to counter evolved and so on…
What are the main aspects of the human innate immune response?
- Physical barriers.
- Chemical and enzymes barriers
- Innate response like inflammasome, complement, antimicrobial peptides, cytokines and innate cells.
What are the main aspects of the human adaptive immune response?
- Cellular and humoral immunity
- APC activate a naive CD4 T cell
- These drive B cell and T cell responses.
- cytokines are important for determining function of immune cells and communication.
What are the 3 main classes of bacterial immune evasion?
- Manipulation of innate immune responses
- Disruption of adaptive immune responses.
- Bacterial life cycle adaption
How can bacteria manipulate the innate immune response?
- Complement evasion
- Disruption of phagocyte recruitment
- Disruption of phagocytosis and NETosis.
- Evasion of bactericidal innate immune molecules.
- Targeted destruction of immune cells.
How can bacteria disrupt adaptive immune responses?
- Targeting B cells for destruction and/or manipulation of antibody production.
- Manipulation of T cell responses like superantigens.
How can bacterial change their lifecycle to evade immune responses?
- Invasion/internalisation of host cells.
- Biofilm development
- Formation of persisters like spores
What are the main examples of immune evasion included in this lecture?
- Evasion of the complement system.
- Protection against phagocytes
- Manipulation of T cell responses.
- Adopting an intracellular lifecycle
What are the 3 complement pathways?
- The classical pathway
- The lectin pathway
- The alternative pathway
How is the classical complement pathway activated?
- IgG bound to bacteria interacts with the C1q complex.
- This causes C1q to undergo a conformational change.
- This activates serine proteases.
- This causes C4 and C2 to cleaved and C4b and C2a forms a C3 convertase.
How is the lectin complement pathway activated?
- Mannose binding lectin (MBL) recognises mannose and other sugars on the bacterial surface.
- This causes MBL to undergo a conformational change.
- This activates and releases serine proteases.
- The causes C4 and C2 to be cleaved and C4b and C2a to form a C3 convertase.
How is the alternative pathway different to the other complement pathways?
- It is always on
- Controlled by spontaneous hydrolysis of C3
How is cleaved C3 generated in the alternative complement pathway?
- C3 undergoes spontaneous hydrolysis into C3-water.
- This binds to Factor B.
- The C3-water factor B complex is a substrate for factor D.
- This leads to the cleavage of C3 to make C3b.
What is Properdin?
- A positive regulator of the alternative complement pathway.
- It increases C3 cleavage under the right conditions.
What is the central complement component?
C3
How do the classical and lectin complement pathways generate C3b?
By generating C3 convertases made up of C4b and C2a
How does C3 orchestrate the complement response?
- C3 is cleaved to C3b which is deposited on the cell surface.
- C3a is also generated and it is an anaphylatoxin.
- Other C3 convertases lead to a massive build up of C3b.
- C3b opsonised bacteria are recognised by phagocytes that bind C3b.
- Then more build up of C3b causes C5 convertase formation and activation.
- C5a is another anaphylatoxin that recruits neutrophils.
7.C5b binds to the bacterial surface. - This recruits C6, C7 and C8 and multiple C9 fragments.
- This leads to the formation of the membrane attack complex that punctures holes in the gram negative membrane to lyse cells.
- gram positives are not susceptible to MAC but can be opsonised.
How does the body control the complement?
- It dampens the complement to reduce by stander tissue damage.
- Plasma proteins like factor H
- Cell bound regulators like CD59
What are C3 convertases important for?
- C3b deposition on the bacterial surface.
- Flagging to the immune system
How does S. aureus evade the compliment?
- It secretes a number of different complement evasins.
- Extracellular fibrinogen binding protein (Efb) that targets C3d.
- Extracellular complement binding protein (Ecb) that targets C3d.
- Staphylococcal complement inhibitor (SCIN) that targets C3b
Where does SCIN bind to C3 convertases?
- Its N-terminal tail interacts with MG6 and MG7 and Bb.
- This prevents C3 convertase interactions with C3.
- This results in no C3 cleavage.
Where are S. aureus C3 convertase inhibitors encoded?
- On Immune evasion clusters.
- These are mobile and can undergo horizontal gene transfer.
- IEC genes are specific for the human complement suggesting they have a role in colonisation and infection
What mechanism do lots of pathogens use to evade the complement?
- Proteases
- Molecules that bind and block complement proteins.
- Conversion of plasminogen to plasmin via streptokinase.
- Inhibition of membrane attack complex formation.
What is streptokinase?
- A bacterial proteins that converts host plasminogen to plasmin.
- Plasmin can cleave C3b on the surface of bacteria.
What is factor H?
- A 155kDa plasma glycoprotein.
- It helps down regulate the complement by inhibiting the alternative pathway.
- made up of 20 homologous complement control protein domains (CCP)
- It is produced in the liver and locally in certain cells.
- Reverse recognition as it binds to initial deposits of C3b on cells.
What is the function of factor H?
- It accelerates the decay of alternative pathway C3 convertases.
- Acts as a co-factors for Factor I to cleave and inactivate C3b.
- Compete with factor B for interaction with C3b.
- Promotes C3bBb disruption.
How do microbes take advantage of factor H?
- They can actively recruit factor H
- This prevents complement activation in response to the microbe.
What is C4b binding protein?
- A 500 kDa plasma glycoprotein
- Major soluble inhibitor of the classical and lectin pathway.
- Contain seven identical chains and one ß chain that interacts with the anticoagulant protein S.
What is the function of C4-binding protein?
- It binds and limits the function of activated C4b.
- It acts as a cofactor for Factor I and inactivates soluble and cell bound C4b and prevents C4b2a convertase.
- Can accelerate the natural decay of the classical convertase.
- Acts as a cofactor to factor I to cleave C3b in the fluid phase which effects the alternative pathway.
How do microbes take advantage of C4b-binding protein?
- They can actively recruit C4b-binding protein.
- This prevents complement activation in response to the microbe.
Why do most soluble complement inhibitors bind to specific CCP domains?
- They can interact with C3b and leads to factor H activity.
- This prevents C3b deposition on the bacterial surface.
What is the process of complement mediated phagocytosis?
- C3b is deposited on the surface of the bacteria.
- This is detected by CR1 on the phagocytes.
- This enhances phagocytosis.
What is the process of antibody-mediated phagocytosis?
- The Fab antibody region binds to the pathogen.
- The Fc region binds to the FcR on the macrophage to trigger phagocytosis
What bacterial mechanisms can block phagocytosis?
- Complement inhibition
- Capsule formation
- IgG binding proteins
How does inhibiting complement inhibit phagocytosis?
- Complement mediated phagocytosis is blocked
- This is because C3b is not deposited on the bacterial surface.
What is a bacterial capsule?
An extracellular physical barrier that is made from polysaccharides.
How does a capsule block phagocytosis?
- It blocks the access of complement activation fragments to the bacterial surface.
- Prevents the membrane attack complex reaching the bacterial surface.
- It can block binding between ligand and complement receptors to prevent opsonisation.
- It can block antibodies from binding to their antigens.
- Capsule production can be induced by human stimuli.
What bacterial can make polysaccharides capsules?
- S. aureus
- E. coli
- Pneumococcus
What does making a capsule require?
Lots of energy
What are IgG binding proteins?
- Proteins that bind to IgG and IgM to prevent proper antibody-antigen recognition.
- They can be soluble or membrane-bound.
How do IgG binding proteins prevent phagocytosis?
- They prevent antibody antigen recognition
- They bind the antibody in the wrong orientation to prevent recruitment of phagocytes.
- They bind to the Fc region of antibodies.
- They can be soluble and bind to serum antibodies to sequester them.
What else can IgG binding proteins do?
- They can act as super antigens and cross-link IgM on the B cell.
- This causes B cell apoptosis.
- The reduces antibody production and dampens immunity.
What are CHIPS?
Chemotaxis inhibitory proteins
What does CHIPS do?
- It binds to chemokine receptors like C5aR and formyl peptide receptor.
- This prevents cells like neutrophils from detecting the chemotaxis gradient.
- This prevents the migration of immune cells.
4.CHIPS prevents C5a binding to the C5aR. - It also prevents F-MP to the formyl peptide receptor.
What are NETs?
- Neutrophil extracellular traps
- They are stimulated by a variety of triggers like pathogens.
- NETs are composed of DNA and coated with histones.
- They trap microbes as they are a concentration of antimicrobial peptides
What are the 2 pathways that form NETs?
- NETosis
- Non-lytic NETosis
What is NETosis?
- Intracellular rearrangement and disassembly of the nuclear envelope.
- Cellular depolarisation and chromatin decondensation.
- Plasma membrane rupture and release of NETs.
What is non-lytic NETosis
- Degranulation and explusion of chromatin.
- Extracellular assembly of NET
- Bacterial cell death
What are the 3 ways bacteria can evade NETs?
- They have molecules that mimic sialic acids to dampen down ROS generation and reduce NETosis.
- The production of capsules that defend against antimicrobial peptides produces during degranulation.
- Secretion of endonucleases that degrade NETs.
- Some bacteria can secrete specialised molecules that convert NET products into toxic components that kill immune cells
How does S. aureus evade NETs?
- Uses nuclease and adenosine synthase A.
- These convert NETs to 2’-deoxyadenosine which triggers macrophage apoptosis.
- This is an amazing evolutionary feat
What are the phagocytic killing mechanisms?
- Oxygen dependent methods involve the assembly of membrane-bound NADPH-dependent oxidase, which generates ROS.
- Both include degrative enzymes and cationic peptides within granules that are trafficked to and fuses with phagosomes.
- Combine oxygen dependent and independent methods contribute to the elimination of bacterial pathogens.
How do bacteria survive in the phagosome?
- They can neutralise ROS via superoxide dismutases, catalases and alkyl hyperperoxide.
- They can mitigate antimicrobial peptides. eg staphyloxanthin
- Incorporation of D-ala into teichoic acids and L-lysine into phosphatidylglycerol to reduce the negative charge on the bacterial membrane to limit the action of antimicrobial peptides.
- O-acetylation of peptidoglycan by OatA to change the structure of peptidoglycan to resist lysozymes.
What can trigger different mechanisms of evading phagocytosis?
- Cell stress.
- Presence of human factors like blood
How can bacteria manipulate T cell responses?
Through superantigens.
How do bacterial T cell superantigens work?
- They alter the immune response by binding directly to MHC class 2 and the TCR as the same time.
- This activates T cells without antigen recognition basically bypassing the TCR.
- This causes the uncontrolled activation of large numbers of conventional CD4+ and CD8+ T cells.
- This plays are major role in proinflammatory diseases like scarlet fever and toxic shock syndrome.
What mechanism do superantigens use to activate T cells?
- Superantigens link the TCR and MHC2.
- This activates the Lck tyrosine kinase pathway.
- After several rounds of phosphorylation, phospholipase C is activated.
- This hydrolyses PIP2 into IP3 and DAG.
- This downstream signalling causes the 3 T cell nuclear transcription factors: NFAT, AP-1 and NF-kB.
- This triggers gene expression that causes T cell activation, proliferation and cytokine production.
How do superantigens reduce immune responses?
- They reduce TCR recognition of the antigenic peptide.
- They prevent the mounting of an antigen-specific immune response to the bacteria.
What T cell responses can superantigens activate?
- CD4 and CD8 T cells
- iNKT cells and MAIT cells.
- Skew T cell responses to Th1, Th2, Th17, or Treg depending which can play a role in specific clinical manifestations.
What can low concentrations of superantigen induce?
- Immunosuppression
- Promotes a Treg response with IL-10
Why is manipulating the T cell response so effective for bacterial evasion?
- It is an important and central part of the immune system.
- Preventing this prevents a proper antigen-specific response to bacteria
How can superantigens promote abscess formation?
- In invasive infection, superantigens can promote abscess formation due to excessive IFNy production.
- Excessive and rapid IFNy production can inhibit immune response due to broad-spectrum recruitment of immune and inflammatory cells
- These cells, along with high IFNy, impede the clearance of intracellular pathogens like S. aureus.
- This can spread to the liver and cause abscess formation as the bacteria replicate inside the macrophages.
What is listeria monocytogenes?
- A gram positive pathogen.
- Causes the food borne disease listeriosis.
- Opportunistic infections mainly occur in young, old, pregnant and immunocompromised patients.
- Listeria creates an intracellular niche in susceptible cells to evade immune detection.
How does listeria monocytogenes adopt an intracellular lifestyle?
- It invades host cells via interaction of surface internalins which target host cell receptors E-cadherin and C-Met.
- Listeria becomes endocytosed but escapes from phagosome before fusion with the lysosome.
- This escape is mediated by the secretion of the pore-forming toxin LLO and PLC.
- It can replicate in the cytosol.
How does Listeria spread between cells?
- Via actin polymerisation
- ActA drives bacterial propulsion by inducing actin polymerisation on the bacterial surface, permitting intracellular motility and cell to cell spreading.
- Rupture of the plasma membrane is also mediated by LLO and PLC
How does listeria evade intracellular immunity?
- Normally Listeria is detected by TLR2 or NOD like receptors.
- It can remodel its cell wall
- It can also dampen host inflammatory responses.
How does listeria remodel its cell wall to evade immunity?
- It uses peptidoglycan N-deacetylation to avoid PRR.
- It uses O-acetyltransferase to change peptidoglycan to increase resistance to lysozymes.
How does listeria dampen host pro-inflammatory responses to evade immunity?
- It secretes InLC to inhibit NF-kB.
- InLC directly interacts with IKKa kinase to prevent phosphorylation of the inhibitor of NF-kB (IkB).
- IkB is no longer degraded in response to pro-inflammatory signals.
- This sequesters NF-kB in the cytosol and reduces pro-inflammatory signalling.
How can Listeria block cell death?
- InLB blocks Fas mediated cell death.
- This protects the host cells from CD8+ T cell mediated killing via Fas.
- This allows cells to survive longer in the blood and results in listeria transfer to the brain and intestinal tissue.
- This releases listeria in the faeces and the environment.
- This means bacterial survival and spread.
How does listeria’s InLB inhibit fas mediated cell death?
- InLB upregulates FLIP.
- FLIP is a competitive inhibitor of procaspase 8.
- This competitively inhibits cleavage of caspase 8 which blocks FasL-Fas mediated cell death.
