Week 6.1 Molecular mechanisms of bacterial adhesion and invasion Flashcards
Lecture 1 is on
Molecular mechanisms of bacterial adhesion and invasion
Interactions between bacteria and human hosts range from a benign, symbiotic collaboration ……to a competition that my prove fatal
Give an example of each
What are the two attach stratergies used by bacteria
mitochondrion encoded proteins are most similar to those
from free-living alpha-proteobacteria (ca 2 billion years ago)
____
More people worldwide still die every year from infectious disease than from any other cause.
Attack strategies:
Frontal attack (eg. Vibrio chlorae)
Stealth attack - involves alot of protein in overcoming host system (eg. Shigella flexneri, Listeria monocytogenes, …)
Vibrio chlorae
What does it secrete?
What is origin of chloera toxin gene transfer, from?
- secretes a potent toxin (AB5) via a T2SS
- origin of cholera toxin is horizontal gene transfer from a bacteriophage
- ensures bacteria is disseminated into environment
Bacterial toxins
What do bacterial toxins cause to cells?
What is there classification based on?
Are exotoxins from both Gram +ve and Grame -ive bacteria?
What are endotoxins?
- Soluble substances released from bacteria which cause damage to cells, tissues, organism.
- Classified on their resultant action e.g. cytotoxins, enterotoxins, neurotoxins, haemolysins, leukocidins, ciliastatic toxins
- Exotoxins – proteins from Gram +ve and Gram –ve bacteria; Endotoxins – Lipid A portion of LPS found in Gram –ve bacteria (non-toxic unless released from the cell)
Classification of bacterial exotoxins
Where do they act?
A-B toxin, which is the enzyme, which is involved in binding?
What is the role of injected toxins - type 3?
What is the role of injected toxins - type 4?
Surface acting
Bind to membrane and cause damage or signal an effect
A-B toxins
A is the enzyme; B is involved in binding
Injected toxins, type III
Kinases, activation/inactivation of Rho GTPases
Injected toxins, type IV
e. g. CagA from H. pylori
Gram negaive need to get through two membranes, and use secretion systmes such as type 3 and 5
Summary of Cholera toxin
What is the binding part? where does it bind?
What enzyme is delivered into the cytoplasm where it is ribosylates the alpha subunit of the G protein?
ADP-ribosylated-Ga cannot hydrolyse…?
What does PKA do the CF regulator?
- B5 binds to receptor GM1 gangliosides on host cell.
- Enzyme A is delivered into the cytoplasm where it ribosylates the a-subunit of the G protein.
- ADP-ribosylated-Ga cannot hydrolyse GTP to GDP trapping Ga in the GTP-bound state.
- Adenylate cyclase usually controlled by association with G protein becomes activated, over activates cytosolic protein kinase A (PKA).
- PKA phosphorylates the cystic fibrosis transmembrane conductance regulator (CFTR) chloride channel proteins.
- ATP-mediated efflux of chloride ions into the intestinal lumen leading to severe dehydration via watery diarrhoea.
Lifestyle of cholera
Where may it have lived pre-historically?
What did it aquire?
If it had aquired a type 3 secretion system what would have happened?
It is possible Vibrio lived in the intestine of man until eventually engaged by the immune system
Man would have been a dead end
Then a strain acquired the toxin by horizontal gene transfer and could be disseminated back to engage the next host
Acquisition of T3SS and effectors would have lead to a different lifestyle
Bacterial protein secretion systems
How many membranes does gram negative have?
Gram negative bacteria have two cell membranes.
Both nutrient sequestration and interaction with host cells require the export of proteins.
What are the characteristics of frontal attack?
Short incubation period
Acute clinical symptoms
Engages the innate immune system
Requires transmission to new susceptible hosts
Rapid microbial replication
Carrier state is uncommon
Transmission often requires close contact
Reservoir is often a specific host or opportunistic
Often induces sterilizing immunity
How does the stealth attack work?
Stealth assaults, on the other hand, typically involve a slower infection process in which the microbes subvert the host’s innate and adaptive immune systems to set up a chronic or persistent infection (eg Mycobacterium tuberculosis – slow growing with waxy protection)
Example of Helicobacter pylori
How many of the worlds population infected?
What percentage of those infected will suffer from disease? what range of disease?
- Infects over 50% of the world’s population
- Persists for the lifetime of the host, even when faced with a robust host immune system
- The bacterium exclusively infects human and non-human primates, and persists in the harsh environment of the stomach
- About 20% of those infected with H. pylori will ultimately suffer diseases ranging from gastritis and ulcer disease to gastric cancer.
Mechanisms used by Helicobacter pylori to persist
- Overcomes acid stress in stomach, urease hydrolyses urea to carbon dioxide & ammonia
- Ammonia buffers the cytoplasm & secreted into microenvironment
- Helps maintain proton motive force across inner membrane
- Bypasses the TLR of the innate immune system
- LPS not recognised TLR
- VacA (vacuolating cytotoxin)
- blocks T-cell receptor signalling events & cytokine production
- CagA – represses B-cell apotosis may contribute to mucosa-associated lymphoid tissue lymphoma
- May become intracellular & hide from classic host defences
What do stealth like bacteria produce?
They produce a wide range of proteins to minipulate a whole host of cellular functions: table bellow illustrates this
References
Scott, M.D. & Falkow, S. (2004) Nature 430, 259-256 - READ for Shock Vs Stealth
Remaut, H. & Waksman, G. (2004) Curr. Opin. Str. Biol. 14, 161-170.
Campellone, K.G. & Leong, J.M. (2003) Curr. Opin. Microbiol. 6, 82-90.
