Professional Pathogens

Define colonisation

when an organism lies on us but is not causing infection

Define infection

when an organism enters the body, increases in number and damages the host in the process

(invasion, replication, damage)

Define A pathogen

someone who eats with you’ – an organism which lives on us / in our gut but doesn’t cause

infection

Define A commensal

someone who eats with you’ – an organism which lives on us / in our gut but doesn’t cause infection

Define Symbiosis

mutual benefit

Define parasite

unequal benefit, used colloquially for eukaryotic infections (malaria, tape worms) but

technically applies to infection causing bacteria too

Define Virulence

fundamental properties of the organism which determine how it causes the diseases it does.

Define True or “professional” pathogens

True or “professional” pathogens – cause disease in any susceptible host

Define “Opportunistic” pathogens

“Opportunistic” pathogens – only cause disease in immunocompromised patients

Staphylococcus aureus

A normal commensal of anterior nares found in 20-60% of healthy adults at any one time

Highly adapted

To a host species - to Homo sapiens

To a site on our bodies - nose

Golden colonies when cultured on agar

Gram positive cocci in clusters which look like bunches of grapes down a microscope

S. aureus virulence

surface proteins which mainly function as adhesion molecules

A group of secreted proteins

A capsule around the organism and

A cell wall associated enzyme called Coagulase

A quorum sensing regulatory system that controls gene expression

S. aureus: cell wall-associated adhesins

Adhesins: bind host proteins:

Tissue adherence -> colonisation or deep infections

Immune evasion ->‘cloaking’e.g Protein A

Protein A

Binds the Fc portion of IgG

Amongst surface factors two of the most important are the adhesins.

Some bind host proteins like elastin and allow attachment; but they also can coat the bacterium in host proteins so that the immune system doesn’t notice them

A very specific version of this is protein A which binds immunoglobulin -

S. aureus: secreted protein exotoxins

Cytotoxins

Pore-forming toxins, lyse host cells

Eg Panton-valentine leukocidin (PVL) – lyses polymorphs

Exfoliative toxins

Proteases which target epidermal structural proteins

Enterotoxins

Superantigens

Stimulate massive T cell activation ?immune evasion

and more... complement inhibitors

Many of these are encoded on mobile genetic elements – only present on a proportion of strains

S. aureus coagulase

Cell wall-bound enzyme

Stimulates clotting

Plays a role in immune evasion

Also used as a test to distinguish S. aureus from other less virulent staphylococci in the laboratory

S. aureus capsule

Like many virulent bacterial species S. aureus has a polysaccharide capsule

Masks cell surface features from recognition by the immune system

Compared with other bacterial species the S. aureus capsule is typically thin - ”microcapsule” but helps avoid phagocytosis by neutrophils

Gene regulation

Some genes are constitutively expressed as essential for cell survival.

Some allow for cell replication and growth when conditions are favourable.

Others, the virulence factors, are expressed to establish infection.

S aureus can survive and adapt to different conditions by sensing environmental cues and altering the production of virulence factors needed to survive.

Bacterial quorum sensing

Gram positive bacteria produce auto-inducing peptides (AIPs).

The concentration of intra- and extra-cellular AIP reflects the local concentration of bacteria.

Bacterial quorum-sensing

Detection of AIP occurs via a 2-component signal transduction circuit, activating a response regulator protein.

This then binds to promoter DNA and regulates transcription of QS-regulated genes

The gene cluster that encodes the peptide quorum-sensing system in S. aureus is called the accessory gene regulator (agr)

Is S. aureus or S. epidermidis more severe?

S. aureus is a common cause of infections in patients who need vascular access devices for e.g. cancer treatment

S. aureus line infections commonly ‘seed’ in the blood to distant body sites

Heart valves

Bones and joint

This is because of S. aureus adhesins

S. epidermidis is actually a more common cause of line infections. However, these are much less severe and rarely seed in the blood

S. aureus can cause food poisoning - true or false

True

Ingestion of Staphylococcal enterotoxins in contaminated food:

”entero”= gut

Rapid brief illness

Vomiting +++

Minimal diarrhoea

Secondary ‘metastatic’ foci of infection

Endocarditis

Osteomyelitis

Septic arthritis

Almost anywhere else

Features of gram positive

Thick peptidoglycan layer

Lipoteichoic and teichoic acid

Gram negative bacteria features

Gram negative

Outer membrane

Lipopolysaccharide

Proteins and pores

Thin peptidoglycans

Inner membrane

LPS review

Lipopolysaccharide (a.k.a. endotoxin): only in Gram negatives

Lipid A = long-chain fatty acid anchor (active component)

Core polysaccharide chain

Variable CHO chain (= O antigen)

Major structural component

Effective permeability barrier (including to antimicrobials)

Modulates host immune response

Innate immune system is very sensitive to Lipopolysaccharide

Human evolution has (probably) selected for sensitive detection of Gram negative bacteria which predominate in bites, contaminated wounds etc.

This allows very early recognition of infection

LPS interacts with “Toll-Like Receptors” (esp. TLR4) on

Monocyte / macrophage lineage cells

Vascular endothelium

Results in activation of:

Inflammatory pathways

Coagulation and clotting pathways

Changes in endothelial integrity - make blood vessels leaky

“cross the bloodbrain barrier by disrupting tight junctions between endothelial cells, enter the subarachnoid space and establish meningitis”

1. Primary adhesion is mediated by meningococcal type IV pilus to laminin receptors on brain endothelial cells.

2. Cortical plaques protect bacteria from complement mediated opsonisation and lysis.

3.  They also disrupt tight junctions between endothelial cells and so allows paracellular spread into CSF

However, has ability to invade the bloodstream and cause septicaemia; or cross the bloodbrain barrier by disrupting tight junctions between endothelial cells, enter the subarachnoid space and establish meningitis.

Secretory IgA protease function

Breaks down secreted immunoglobulin A, preventing mucosal clearance

Pneumococcal surface protein A (PspA) function

Inhibits complement deposition and hence activation of cascade and clearance of bacteria; also neutralises lactoferrin’s bactericidal activity

Capsule function

Polysaccharide coat prevents complement-mediated phagocytosis.

Specific antibodies to capsule required (implications for immunisation)

>100 different capsular types