Lecture 15 - Immunity to Bacteria II Flashcards
Describe generally how pathogenic bacteria evade host immunity
List the various mechanisms
Subvert normally effective defence mechanisms of macrophages:
• Avoid effector arm of the immune response
• Secure systemic spread
Mechanisms: • Antigenic variation • Inhibition of C' activation • Resistance to phagocytosis • Scavenging of ROS • Resistance to NETs
Describe how bacteria use antigenic variation to avoid the immune response
Which bacteria do this?
- Neisseria gonorrhoeae
- Pneumococcus
- Streptococcus pneumoniae
By modifying surface molecules, neutralising Abs are no longer able to act on the bacteria
e.g. Streptococcus pneumoniae
• 90 different serotypes; i.e. 90 different carbohydrate capsules
• Once infected w/ S. pneumoniae, an Ab response is launched
• On subsequent infection, it will likely be a different serotype
• Previously formed Abs are not neutralising against this serotype
• A new response must be launched
Describe the Strep. pneumoniae vaccine
Strep vaccines aim to include as many of these serotypes as possible to ensure that the individual is protected against as many serotypes as possible
There is a limit to how many polysaccharides can be included, and this is quite expensive to produce
Those that are most common in a region are selected for the vaccine
This leads to serotype replacement:
• Gives the chance for other serotypes to infect
The immunogen is a conjugate molecule:
• Capsule polysaccharides (T cell independent)
• Protein conjugated (T-cell dep.)
List some of the ways that bacteria avoid the effector mechanisms of macrophages
Interfere with: • Receptor mediated recognition • Phagocytosis • Acidification of phagosomes • Phago-lysosome fusion • Production of reactive oxygen and nitrogen intermediates • Cytokine and/or chemokine production • Ag processing and presentation
How does Listeria avoid macrophage killing?
Escape into the cytosol to avoid degradation in the phagosome
Describe the example of how P. aeruginosa modifies PAMPs to avoid the immune system
LPS:
• Change in Lipid A:
- Penta-acylation, as opposed to hexa-acylation
• TLR4 can no longer recognise LPS
Early in infection:
• P. aeruginosa expresses penta-acylated LPS
• Decreased LPS recognition by TLR 4
• Decreased production of TNF-alpha and IL-8, allowing the bacteria to avoid macrophages
• Bacteria are able to colonise the surfaces
Later in infection: • P. aeruginosa switches to hex-acylated lipid A structure • TLR 4 recognises LPS • High levels of TNFa and IL-8 • These cytokines induce pathology
Describe the structure of LPS
Lipid A:
• Allows embedding in the plasma membrane
• When hexa-acylated, is recognised by TLR4
Core glycolipid
O-specific polysaccharide chain
Describe the Yersinia pestis infection cycle
Bacteria infect fleas, which parasitise rodents
Bacteria can jump from these natural reservoirs to humans, causing plague
How does Y. pestis avoid the immune system?
In humans, WT Y. pestis expresses tetra-acylated LPS
• Temperature dependent
• In the natural reservoirs, LPS is hex-acylated
• At human body temp, it is tetra-acylated
LPS not recognised by TLR 4, and the bacteria is not destroyed by macrophages, and has the opportunity to grow and establish infection
Later on in infection, it switches to hexa-acylated LPS, which induces a strong inflammatory response which leads to immunopathology in the host
Describe the ways in which the following compartments of the immune system provide protective immune responses against bacteria: • Extracellular; Innate • Extracellular; Adaptive • Intracellular; Innate • Intracellular; Adaptive
Extracellular:
• Innate: macrophages and PMNs
• Adaptive: Abs
Intracellular:
• Innate: NK cells
• Adaptive: CTLs
Which bacteria cause pneumococcal disease?
What are these diseases?
Strep. pneumoniae
Strep normally are part of the microflora in the oropharynx
Certain factors play a role in the bacterium spreading to other sites to cause invasive disease
The bacteria cause:
• Meningitis
• Pneumonia
• Otitis media
What is the importance of pneumococcal disease?
One of the biggest killers of children under the age of 5 worldwide
Causes more deaths in children under the age of 5 than Malaria, HIV and TB combined
Which factors determine susceptibility to invasive pneumococcal disease?
Host factors:
• Age
• Ethnicity
• Asplenia
Microbiological factors:
• Influenza A infection
• HIV-1 infection
Environmental factors:
• Air pollution
Describe the interplay of influenza A infection and IPD
IPD: Invasive pneumococcal disease
Experiments involving influenza A infection in mice
- 5 day old mice colonised w/ S. pneumoniae
- 14 day old mice infected w/ influenza A
- Can visualise the bacteria in the live animals with a special camera
Effects of influenza:
• Increases the bacterial load in the nose and ears
• This is probably why co-infection means that an individual is more infectious
Compare the outcome of WT and modified Y. pestis infection
WT:
• Tetra-acetylated LPS
• No TLR4 stimulation
• No inflammation or induction of the adaptive immune response
• Individual suffers from overwhelming infection and dies
Modified:
• Hexa-acetylated LPS
• Results in TLR4 stimulation, inflammation and induction of the adaptive immune response
• Bacteria are cleared and the individual recovers
