Passing through the physical barrier

Breach Physical Barrier

Pass through

Avoid the innate immune defenses at the host interface

Types of Physical Barriers

Skin

Mucosal Surface

Mucosal Surfaces Defenses

Enzymes (Lysozymes)

Antimicrobial peptides (Defensins)

Immunoglobulines (IgA)

Enzymes

Lysozymes are a family of enzymes that damage bacterial cell walls by catalyzing the hydrolysis of the peptidoglycan.

tLysozyme is the most abundant

Antimicrobial peptides

Defensins have been considered as ‘natural peptide antibiotics’ to combat infections.

Defensins are toxic for microorganisms and combat viral infections.

Immunoglobulines (IgA)

Neutralize toxins, viruses, limit attachment of pathogens to the host surfaces. Effector functions such as initiation of phagocytosis.

Inhibitors that Prevent Lysozyme Activity

SIC (Streptococcal Inhibitor of Complement) : 31 kDa protein secreted by a few highly virulent strains of Streptococci. Binds to, and inhibit lysozymes.

MliC (Membrane-bound Lyzozyme Inhibitor) a periplasmic protein produced by the Gram-negative organism Pseudomonas aeruginosa.

Definsin mechanisms

Bacteria = - charge

Phospholipids and peptidoglycan = - charge

Defensins = + charge w/ hydrophobic residues ->

Destabalize microbial membranes creating pores and cell lysis

Defensins in secretions, host tissue, phagocytic cells

Interference with the activity of Defensins

Interference with the activity of IgA

-Proteases that specifically cleave IgA (Streptococcus pneumoniae)

- Production of IgA-binding proteins that compete with Fc receptors (Group A and B Streptococcus)

Host innate immune defenses

-Antimicrobial peptides (defensins)
-Complement
-Phagocytosis

activated complement system response

Membrane Attack Complex (MAC): Cell lysis

Opsonization of the pathogen to trigger phagocytosis

Initiates inflammatory response:
Chemotaxis, increase of microvasculature permeability…

Interference with the complement

1-Inactivation of the complement by proteases

2-Attachment of soluble host complement regulators and production of complement inhibitors

Inactivation of the complement by proteases

P. aeruginosa cleaves C3b, inhibiting the deposition of C3b onto the bacterial surface.

LPS variants that diminish C3b deposition.

Host complement regulator

CRASP (Complement Regulator Acquiring Surface Proteins): Factor H is a regulator of complement activation that protects self cells from complement activation. Factor H normally binds to host cell surfaces and inhibits the activation of the complement system.  P. Aeruginosa binds to factor H.

complement inhibitor

staphylococcal complement inhibitor (SCIN). SCIN is a protein secreted by S. aureus that specifically binds to and inhibits the activity of the C3 convertases on the bacterial surface.

What is a capsule?

The capsule is a layer of polysaccharides outside the cell wall of bacteria. The capsule protects the bacteria from phagocytosis, activation of the complement system, desiccation. Prevents access of MAC to the outer membrane.

Capsule of Staphylococcus aureus and group B Streptococci inhibit the activation of the complement- SERUM RESISTANT-

interference with complement - modification of lps

prevents access of MAC to outer membrane

• SALMONELLA AND E. COLI SMOOTH STRAINS HAVE LONG O-ANTIGEN CHAINS
• ROUGH MUTANTS ARE KILLED EASILY BY COMPLEMENT AND ARE "SERUM SENSITIVE"

Avoid Phagocystosis by...

How to kill the phagocyte to avoid phagocytosis

examples

2-Avoid phagocytosis

How to avoid recognition for phagocytosis

masking structures recognized by receptors

disguisins as host

2-Avoid phagocytosis

avoiding recognition by disguising as host examples

        -Streptococcal M-protein binds fibrinogen
        -Neisseria mimics host cell surface carbohydrates     (look like blood group antigens).

2-Avoid phagocytosis

avoiding recognition by masking structures recognized by phagocytic receptors

    – Avoid complement deposition
    – Avoid antibody deposition
    – Mask determinant recognized by phagocytic receptors

2-Avoid phagocytosis

What happens when staphylococcal protein A and G coat the bacteria?

Fc portion of antibodies bind to protein A and G:
    – No complement deposition
    – No binding to receptors on phagocytes

2-Avoid phagocytosis

Examples of capsules

    – Streptococcus pneumoniae: The polysaccharide capsule of Streptococcus pneumoniae is the main virulence factor, which makes the bacterium resistant to phagocytosis.
    – Klebsiella pneumoniae
    – Hemophilus influenzae type B
    – E. coli - K-antigens
    – Yersinia pestis

2-Avoid phagocytosis

Avoid recruitment of phagocytic cells

-Blocking the activation of the complement system that normally releases chemotactic peptides (C5a and C3a).

    -Production of virulence factors that inhibit chemotaxis.

3-Survive Phagocytosis

Examples of pathogens that are ingested and resist microbicidal activites

    -Mycobacterium leprae Cell wall resistant to enzyme attack.
    - Staphylococcus aureus catalase positive destroy hydrogen peroxide (H2O2).
    -E. coli produce a superoxide dismutase that destroys superoxide (O2-).

what is Cf

Evasion from the Specific Immune Responses

Evasion from the Specific Immune Responses

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-Antibody deposition with the wrong orientation

Fc receptor binds instead of variable portion (upside down)

Evasion from the Specific Immune Responses-Inhibition of antibody production-

Protein A: Binds to IgM on B cells

Proliferation and apoptosis of B cells

Depletion of a significant proportion of the B cell repertoire

Evasion from the Specific Immune Responses-Antigenic variation-

Evasion from the Specific Immune Responses-Antigenic variation-

spontaneous mutations vs phase variation

Spontaneous mutations, which occur at a frequency of approximately 10-8 to 10-6 mutations

phase variation occurs at frequencies higher than 10-5 switches and always affects the same phenotype(s)

Strain to strain variation in antigenic molecules

molecules is common,
antigenic variation refers to a single strain specifically changing a subset of its antigens, either to sustain an ongoing
infection or re-infect hosts even though the first infection was successfully cleared.

Evasion from the Specific Immune Responses-Antigenic variation-

1-Gene conversion

Involves a recombination event between a silent copy of a gene and another copy that is expressed, and leads to the formation of a new chimeric gene. When several copies of the silent gene are present, numerous chimeric sequences can be theoretically generated, allowing to express various forms of an antigen.

What is the causal agent of Lyme disease and what does it do?

Borrelia burgdorferi

can generate variants expressing different antigenic forms of a surface lipoprotein

What is the virulence componenet in gonorrhea

Development of symptoms associated with gonorrhea
is correlated with the ability of N. gonorrhoeae
cells to attach and colonize mucous membranes via
their pili, despite urinary flux.

Pil S can exchange portions of variable regions with PilE locus

What is an On/Off switch?

Variable gene expression based on differential DNA methylation. DNA methylation-dependent phase variation of the pap operon in E. coli . 

Evasion from the Specific Immune Responses
-Antigenic variation-

involving on/off switch

2-Multiple but different copy of a molecule, each of which is under an independent on/off switch  

How do you turn pap expression on and off

LRP bound GATCdist region = activator/on

LRP bound GATCprox region = repressor of pB transcription/off

methylation at GATCdist decreased binding affinity = making it stay in off phase

Evasion from the Specific Immune Responses
-Interfering with T cells-

1. Block T cell activation and proliferation

2. Expression of superantigens in host

3. Induction of T cell apoptosis

Example of T cell blocking

How do superantigens interfere with T cells

Expression of superantigens in the infected host also prevents development of a normal immune response. Antigen-specific T cells fail to proliferate in response to antigens that are presented normally by MHC class II due to a phenomenon called anergy.

what does listeriolysin O do

induces apoptotic response in T cells and macrophages