Bacterial Pathogenesis III

5, spread to other sites 

• Multifaceted

1, invade into host cells and their circulatory system

2, disrupt host cells to gain deeper tissue access

3, miscellaneous mechanisms - fribinolysis and actin-mediated locamotion 

S. aureus spreading via Staphylokinase

• it complexes with plasminogen to activates plasmin proteolytic activity
• this causes the breakdown of fibrin clots - helps in bacetria spreading

ActA is a direct homologue of a host protein involved in actin polymerisation. The bacteria have adapted a host cell protein via horizontal acquisition to manipulate cellular functions. 

ActA functions:

• profilin - actin binding protein
• Arp2/3 complex - initiates of ew filaments
• VASP - actin filament elongation
• Actin monomers 

Polar localisation 

ActA located on the surface is responsible for polymerisation of actin at the bacterial surface. The polarisation of ActA gives polarity in bacetrial division. It is trapped at 'old' pole where peptidoglycan turnover is slow. 

During division, new membrane is needed therefore old migrate to poles to make way for the new. 

6, tissue damage

Advantages:

• access to nutrients 
• transmission to new sites
• target immune cells

Disadvantages:

• cell death can initiates immune response 

There are two types of toxin:

Exotoxins - soluable and actively secreted 

Endotoxins - natural products released only after bacterial lysis 

Exotoxins give rise to virulence factor. It could damage the host by destroying cell and disrupting cellular metabolism.

Type I exotoxins

• act from the extracellular cell surface 
• bind to receptor on the surface and stimulates intracellular signalling pathways 

Type II exotoxins

• designed primary to disrupt the cellular membrane - channel-forming toxins
• it may be clel type specific or non specific 

Type III exotoxins 

• intercellular toxins that gain access to cytoplasm in order to exert effects

Inject toxins from bacterial to target cell cytosol - E.g. T3SS, T4SS, T6SS

A-B or A-B5 intracellular toxins 

ADP-ribosyl group is transfered from NAD to a side chain of a host cell target protein by ADP-ribosyltransferase. 

A-B5 toxin prevents inactiviations of mammalian adenyl cyclase which results in excess cAMP. 

Clostridial neurotoxins 

Zinc-dependent metalloproteases. It cleaves neurospecific proteins.

Anthrax toxins

Dermonecrotic toxins

E.g. Bordetella pertussis. A G-protein deamiddases which can polymerise as well as depolymerise 

Nucleases

Can cleave DNA, rRNA and inhibit protein synthesis 

Type IV exotoxins 

• Damage the extracellular matrix to enhance bacterial spread to deeper tissue

Hyaluronidase and collagenase - breaks the bnd beween proteins that form connective tissue

Non-specific toxins

B.pertussis tracheal toxin

• It's a peptidoglycan monomer - can breakdown products during bacterial division
• This triggers a violent coughing episodes

Mycobacterium ulcerans mycolactone toxins

• Derived from polyketide necrotizing exotoxin with pro-apoptotic and anti-inflammatory activities
• devastates the skin lesions - abnormalities of an organisms tissue

Contain pathogen associated molecular patterns - PMAPs - recognised by pattern recognitions receptors - PRRs: Extracellular - TLRs; Intracellular - NLRs (nod-like receptors). 

They are largely responsible for dramatic clinical manifestations of abcetrial infections. 

Addaptation of pathogenic bacetria to new environments 

Phenotypic modulation 

• this is done through QS
• S. aureus process species specific QS system called Agr - it is expressed the most in stationary phase when cell density is high. 

Autoactivation of agr locus 

Production of AgrD propeptides is matured by proteolytic digestion before being secreted into excellular environment. The secretion is carried by anchored membrane protein AgrB. When cell density is high, autoinducer peptide level is also high. (QS effect). The level of ArgB is sensed by AgrC - a sesor kinase. The phosphate residue is relay back to AgrA - the P~AgrA activates transcription from P2 and P3 promoters. 

This may be done by targeting DNA promoters to create binding sites for additional regulatory proteins and to provide access of Shine-Dalgarno seqeunce of binding by Ribosomes. 

May target activity of proteins. 

Regulation by small RNAs in bacteria 

Regulates both transcription and post-transcriptional effects. 

bvgAS locus is a tranmembrane sensor kinase and a DNA-binding response regulator. It response to environment signals (Temperature and MgSO4 level) to become autophosphorylated - relayed onto bvgA to bind to DNA to activates vags (virulence activated genes) and turn off vrgs (virulence repressed genes). 

Temperature

Causes the pathogen to alternates between environment reservior, insect vector and mammalian host - used by bacetria to sense their environment and control virulence gene expressio.

Involved prfA - post transcriptionally regulated. The RNA secondary structure in the UTR of prfA senses temperature - DNA topology bends or supercoil DNA according to the temperature. 

Sensing the target cell environment

Through cell receptor or iron concentrations. 

Salmonella 

The two T3SS are never expressed at the same time or place (temporal or spatial). the bacteria can sence their surroundings and change their spatial and temporal gene expression patterns. 

Low Ca response trigger T3S by Yersinia spp.