17 - Bacterial Adhesins and Colonisation Flashcards
Colonisation
- Establishment of stable bacterial population in host
- First critical step in establishment of disease
- Mucosal epithelium primary sites of colonisation (e.g. respiratory tract)
Two possible outcomes after colonisation
- Pathogen is confined to epithelial surfaces (e.g. V. cholerae in intestinal tract)
- Pathogen crosses epithelial surfaces, invades deeper tissues, some may cause systemic infection (e.g. S. enterica –> systemic typhoid fever)
Mucous
- Secreted by goblet cells & subepithelial glands
- Major component is mucins
- Glycosyl chains of mucins
- Mucins bind to and trap bacterial pathogens
Mucins
Family of filamentous proteins
Glycosyl chains of mucins
- Protect peptide from bacterial degradation
- Receptors for bacterial surface ligands
Mechanical removal of bacterium by host innate defences
- Eye: Flushing action of blinking, tears
- Oral cavity: Flushing action of salivary flow
- RT: Sneezing, coughing
- GIT: Peristalsis and excretion
- UT: Flushing action of urination
Requirements of successful colonisation
- Avoid being trapped in mucous layer
- Penetrate mucous layer to reach epithelial cell surface
- Adhesion to epithelial cell receptors via adhesions
How can bacteria penetrate mucous layer to reach epithelial cell surface
- Via motility (flagella)
- Via mucinases (dissolve mucous layer)
Bacterial adhesins
- Specialised surface structures that bind to specific host receptors
- “lock and key” interactions occur between adhesins and receptors
Epithelial cell receptors
- Glycoproteins
- Glycolipids
- Microbial adhesin binds to sugar moiety of receptor
Lock and key adhesion by pili
Bacterial cell at a distance from epithelial cell overcomes electrostatic repulsion (Bacterial & epithelial cells are negatively charged)
Lock and key adhesion by afimbrial adhesins
Tight binding of bacteria to cell may follow pilus adhesion, as depolymerisation of pili brings bacterium closer to cell
Pilus morphology
- 5-7nm diameter
- 0.5 to >10nm long
- Peritrichous or at one pole
- varied morphology
- a few to several hundred per cell
Pilus shaft/rod
- Repeating protein subunits (pilins) assembled into helical array
- PapA
Specialised tip structure
- PapG adhesin at tip of Pap pili
- PapF, E, K proteins form a thin fibril at the end of the pilus
Fibrillae morphology
- Finer fibrous organelles 2-3nm in diameter
- Long multidomain proteins attached at cell surface
- Found widely in G+ve and G-ve but less well studied than pili
Receptor specificity of pili
Determines tissue colonised by pathogens
Receptor of UPEC PapG protein at pilus tip
- Globotriasylceramide
- Tissue specific as uroepithelial cells have this receptor
Advantages of anti-virulence antimicrobials
- Inhibit bacterial virulence instead of bacterial growth
- Hope to avoid resistance development (resistance would not provide survival advantage, therefore wouldn’t be selected for)
- No effect on microbiota
Strategies of anti virulence antimicrobials
- Anti adhesion agents
- Anti quorum sensing
- Anti biofilm
- Antitoxin
- Anti T3SS
Adhesins as vaccine candidates
Ab blocks adhesin binding pocket - inhibits binding of pathogen to epithelial receptor
Stable, high affinity analogues of receptor
- Competitively inhibit binding of adhesin
- Prevent colonisation of epithelium
- Prevent infection
Inhibitors of pilus assembly (pilicides)
- Pap & type 1 pilus subunits form helical rod
- Assembly is via action of conserved periplasmic proteins (pilin chaperones)
- Chaperones interact with C-terminal residues of pilin subunits (essential for pilus assembly)
- 2-pyridones resemble PapG C terminus and inhibit chaperone binding
- Thus pilus is not assembled
Problems and challenges with anti adhesin vaccines and drugs
- “cocktail” vaccines or multi epitope fusions may be necessary (multiple adhesins are expressed in a time- and tissue- specific manner during the course of an infection)
- Rapid and precise diagnosis is needed
- A drug may be non specific and interfere with microbiome
- May have weak activity in vivo
Does adherence always guarantee colonization
- NOOOO
- Pathogens may have adhesins that recognise host receptors but may still fail to colonise host tissue
Two major mechanisms through which beneficial bacteria provide colonization resistance to pathogens
- Indirect mechanisms: microbiota-stimulated host immunity
- Direct mechanisms
Direct mechanisms of beneficial bacteria providing colonisation resistance
- Antagonise/compete with pathogen
- Directly compete for same niche( compete for nutrients)
- Secrete antimicrobial peptides and toxins e.g. bacteriocin
Bacteriocins
- Small, antimicrobial proteins secreted by normal flora
- E.g. Streptococcus mutans (normal flora) secrete bacteriocins that inhibit other streptococci
