Bacterial defence systems Flashcards
Defences in the GI tract – low pH and bile salts
Acidic pH
Gastric acidity is a 1st line of defence against oral infection route, pH can be as low as 1.5
Bacterial survival requires an acid tolerance response that promotes survival & growth at low pH
Bile salts
Component of bile, which is discharged into small intestine to aid digestion. Antimicrobial activity linked to detergent-like properties
Bacterial resistance is based around decreasing porin expression and boosting efflux systems
Phagocytosis – protection against infection
Macrophages, neutrophils & dendritic cells
Killing of phagocytosed microbes occurs within specialized compartments, termed phagolysosomes
Bactericidal mechanisms in phagolysosome: ROS antimicrobial peptides, and acidification
Bacteria are ingested into the phagosome. The phagosome then undergoes a process of maturation where it fuses with the lysosome to become a phagolysosome. Some bacteria can evade killing in the phagolysosome - these bacteria are sometimes referred to as “professional intracellular pathogens”
Bacterial resistance to oxidative killing
The sod enzymes catalyze the dismutation of superoxide into oxygen and hydrogen peroxide. The process can be viewed as two half reactions, the first generating oxygen, the second generating hydrogen peroxide. The hydrogen peroxide can then itself be detoxified by the action of catalase or peroxidase enzymes.
Superoxide dismutase (SOD) enzymes detoxify superoxide (O2-) - converts it to H2O2
Fenton reaction makes a OH radical from H202
Also reactive nitrogen species:
Nitroxyl (NO) can be converted to nitrite or peroxynitrite
To evade this bacteria produce enzymes:
KATs (catalase deactivates h202)
AHPs alkyl hydro peroxidase (deactivates peroxynitrite), Sods (superoxide dismutase)
OxyR senses h2o2, bond forms between 2 sulfhydyl groups on the protein, causing a conformational change on the protein, this allows it to begin transcribing KatG and AHP
Ways of evading phagocytosis
- the capsule: predominantly polysaccharide
Escaping the phagosome
Listeria monocytogenes manages to escape from the phagosome/vacuole
Achieved through the action of Listeriolysin (LLO) a pore-forming toxin belonging to the family of cholesterol-dependent cytolysins (CDCs, are targeted SPECIFICALLY to host membranes). Activity is regulated by pH.
Rocketing into neighbouring cells via actin cytoskeleton results in the listeria being encased in a double membrane. It escapes via:
Phagosome destabilisation is also achieved by two phospholipases (PLC):
PC-PLC and PI-PLC
These work in addition to LLO
Actin ‘comet tails’ Listeria utilise host actin to propel itself once out of the phagosome and into a neighbouring cell. This is regulated by PH also.
PrfA (protein release factor) regulates Listeria virulence
It is a TRANSCRIPTIONAL ACTIVATOR
LLO also has roles in autophagy - can hijack the autophagy pathway.
Autophagy can degrade intracellular bacteria. Several pathogens can subvert this either by exploiting the autophagosome as a replication niche or by actively avoiding recognition by the autophagic machinery
Inhibition of the respiratory burst - stop the production of ROS and acidification
inhibiting the phagosome
e.g. M tuberculosis prevents phagosome fusion
Even if fusion occurs, TB phagosomes characterised by
1. Paucity of vacuolar H+ ATPase
2. Subsequent inefficient luminal acidification
3. Inadequate levels of mature lysosomal hydrolases
Inhibition of phagosome acidification possibly due to a secreted tyrosine phosphatase PtpA (secreted by TB): dephosphorylates a component of the tethering complexof VPS proteins that recruits the vacuolar atpase
Resistance to antimicrobial peptides
Common theme is to apply positive charges to membrane molecules to repel the +vely charged AMPs (anti microbial peptides)
e.g phoP/Q recognises an acidic environment and causes transcription of genes that cause modification of the outer membrane and adding positively charged molecules to the LPS to repel the cationic anti microbial peptides
Very important defence system
In gram positives: GRAS/GRAR two component system (glycopeptide resistance association) glycopeptides are cationic amps in G+ve
Lysosome contains glycopeptides that will damage these. GRAS/R TCS controls the transcription of the DLT operon (LTA of G+ve cell wall is negatively charged) upregulated transcription of DTA causing +ve alanine to be added on to the LTA (lipoteic acid) of the G+ve cell wall
Both result in the repulsion of the +ve AMPs
Iron aquisition
Some bacteria (e.g. TB) secrete Exochelins (they chelate iron) Salmonella acquires ferric iron by secreting the siderophores enterobactin and salmochelin
Enterobactin uses two membrane receptors IroN and FepA to pull the siderophore back but the receptors can also pull in other species exochelins
Required by salmonella to evade nutritionally immunity in macrophages and cause persistent infection in mice
In TB the siderophore is called Mycobactin.
Deletion of the genes encoding the biosynthetic apparatus leads to attenuation.
Life within the phagosome
T3 and T4SS are activated by acidification of the phagosome
e.g. salmonella have T3SS which are activated by phagosome acidification
Salmonella pathogenicity island II
