Key events in bacterial pathogenesis and host colonisation Flashcards
What are the key events in bacterial pathogenesis?
Colonisation: of epithelial/mucous membranes. Can involve stable adhesion on an epithelial surface and/or entry into cells
Multiplication: requires ability to evade or survive host defences. Can lead to spread, locally or to distant sites
Transmission: to a new host
Damage: results from host cell malfunction or death caised directly by toxins or invasion and/or indirectly from host response to bacterial infection
Bacterial pathogen uses specialised virulence factors, encoded by virulence genes, to thrive in the host. Pathogenesis is often multifactorial, involving many virulence factors
Virulence genes
a) overview of function
b) How are they distributed through the genome (+ example)
a) specialised and not usually constitutively expressed, but switched on in response to host environment. Often co-regulated in response to the same signals. Often carried on extrachromosomal plasmids and bacteriophage, and/or grouped on pathogenicity islands (PAI) in the chromosome. Often encode proteins or other molecules that are exported to bacterial surface and secreted into environment, or delivered into host cells
b) most genes required for infection and survival in host aren’t randomly didtributed in genome, rather grouped on PAIs. These evolved by integration of transposons, plasmids and bacteriophage and incorporation of transformed DNA (typically have G&C content that differs from surrounding chromosomal DNA).
Can include dozens of genes. Salmonella has SPI-1 and SPI-2 which determine entry into non-phagocytic cells and survival in macrophages, respectively. These decrease dissemination of virulence traits and facillitate virulence gene co-regulation
Cell motility (+ example of bacteria that use)
Important in colonisation. Many bacteria move through liquids by means of rotary flagella. Some use flagella to ‘swarm’, moving rapidly across surfaces (like the urinary tract epithelium) as a coordinated population.
Vibrio cholerae, Helicobacter pylori require motility to enable them to move through mucous
Cell surface adhesins (+ example of bacteria that use them)
enable bacteria to attach stably to host cells or extracellular matrix, via carbohydrate or glycolipid recepotrs. Adhesin proteins assembled on tips of long rigid pili (fimbriae) projecting from bacterial cell.
Example: P-pilus adhesin of uropathogenic E. coli (UPEC), which binds to kidney receptor.
Bacterial urinary tract infections
Most commonly caused by uropathogenic E. coli (UPEC) from host’s own bioflora by ascending infection. Mostly occur in women as urethra shorter, also associated with catheter use (often caused by Proteus). Infections can ascend to kidney and cause pyelonephritis.
Pap / type 1 pili subunits transported across inner membrane by Sec transporter. Chaperones transport subunits across periplasm to an usher protein on outer membrane, which has an associated adhesin molecule. The pili subunit is added to adhesin. Further subunits are added to the chain, leading to pili formation. Pap (P-pili) adhesin bind to receptors on the kidney. Damage by pore-forming toxin haemolysin and inflammation as a result of LPS detection. In Proteus, urease cleaves urea to ammonia and causes kidney stones. Type 1 pili bind to bladder cells (cell motility aiding ascention of urinary tract)
UPEC and consequence of long term colinisation
UTIs caused by UPEC frequently recur, which is linked to cell invasion and growth of intracellular bacterial communities in bladder epithelial cells. In acute infection, superficial epithelial cells undergo ‘exfoliation’, allowing UPEC to invade underlying epithelial cells where they persit as quiescent reservoirs, protected from antibiotic treatment. Quiescent UPEC can then resurge and enter bladder lumen, causing further acute infection.
Tight adhesion via pedestal formation (what bacteria uses it)
enteropathogenic E. coli (EPEC) and enterohaemorrhagic E.coli (EHEC) achieve and even tighter form of adhesion to epithelial cells. Interaction with host cell cytoskeleton induces pedestal formation by host. Bacterium uses specialised needles to deliver proteins into the host cell, including a specific translocated intimin receptor (Tir). Binding of bacterial surface protein intimin to Tir subverts host cell signal transduction and promotes actin polymerisation.
Host colonisation by formation of biofilms (+ examples of bacteria that use)
Some adherent bacteria establish complex biofilms that are difficult to eradicate by immune system and antibiotics.
Plaque-forming Streptococcus mutans and other bacteria on teeth (glucan formed from food sugar, acid leads to demineralisation - caries)
Staphylococci which colonise catheters (eg in urinary tract)
Pseudomonas aeruginosa which can colonise contact lenses, causing conjunctivitis
Pseudomonas aeruginosa and establishment of biofilms
Gram-negative P. aeruginosa is an opportunistic pathogen possessing combinations of virulence factors and causing many infections (burns, wounds, eye infections, nonsocomial UTI). Damage is both direct by toxins and indirect from inflammation. Genes encoding virulence factors and biofilm formation are co-regulated by quorum sensing.
P. aeruginosa biofilms form in the lungs of individuals with cystic fibrosis. A critical component in chronic biofilm lung infections by P. aeruginosa is the production of copious alginate polysaccharide slime. This protects the biofilm from the host immune response and antimicrobials. These opportunistic pathogens are often multidrug resistant, largely due to multiple drug efflux pumps in their cell envelope.
Host colonisation by invasion of host cells
Rather than remaining on epithelial/mucosal surfaces, some bacteria force entry into non-phagocytic cells (eg intestinal epithelial cells). Can use two mechanisms, both which induce remodelling of the host cell cytoskeleton by binding actin directly and/or subverting host signal transduction.
ZIPPER mechanism uses receptor mediated endocytosis, used by Listeria. Bacterial invasins mimic eukaryotic ligands (eg fibronectin, a component of the host ECM that bind integrins)
TRIGGER mechanism uses subversion of host cells by bacterial effector proteins, some binding to actin, that are delivered directly into the target host cell through bacterial needles, used by Salmonella. The invasins mimic host cell proteins such as SipA and SipC involved in actin binding polymerisation, hence subvert signal transduction to lead to cytoskeletal rearrangement whereby bacteria is taken up. Salmonella has the genes encoding invasins and the needle on pathogenicity island SPI-1.
