5: Virulence factors - Immune system interplay & Red Queen hypothesis Flashcards
What are the effectors of the innate immune system?
Phagocytosis, antimicrobial peptides/lysozyme, reactive oxygen/nitrogen species, complement activation, iron/nutrient withholding, neutrophil granules, and neutrophil extracellular traps.
What are S. aureus’ mechanisms against the innate immune system?
- S. aureus blocks the migration of neutrophils by the production of CHIPS that bind to formulated peptide receptors on neutrophils (makes neutrophils blind) so they can’t migrate to the pathogen.
- S. aureus produces toxins that kill immune cells receptor-dependent.
- PVL is also a toxin that kills PMNs and Monocytes by binding the C5a and CCR5 receptors of humans and it is an important virulence factor of S. aureus. So virulence factors are also host-specific!
How does S. aureus blocks the complement system?
Staphylococcus produces Protein A which binds to antibodies to block classic activation of complement. (molecular mimicry)
Also, the CHIPS bind parts of the complement system.
S. aureus produces highly redundant blocking proteins against complement.
Most of these complement-interaction proteins are derived from each other.
How does the Herpesvirus block an immune reaction?
Herpesvirus inhibits the proteasome or TAP in the MHC-I loading pathway and so prevents cytotoxic T-cell activation. Also, other parts of the MHC-1 presentation pathway are targeted.
What is the unique mechanism of the Trypanosoma brucei against the immune system?
It has a VSG coat with 10^7 proteins on the surface which protects against the complement. VSG coat can be targeted by specific antibodies, but there can be mutated pathogens that escape the antibodies. There can be more than 1.000 different proteins expressed by the pathogen. The VSG gene is located in telomeric expression sites, but only one expression site is active at the time. There are special polymerase involved (Pol I), a special location in the nucleus, and is regulated by epigenetic regulation (probably chromatin remodeling) which leads to allelic exclusion. It works because there is only one antigen created every time, if the proteins would all be expressed all antibodies will be made and it will not escape the Immune system. 1000 extra VSG genes can be found outside expression sites. These can be expressed by telomere exchange or gene conversion.
What is the Red Queen Hypothesis?
Evolutionary change in the immune system gives a temporary advantage, but after adaptation of the pathogen, the end result is similar.
What is special in the immune system of long-lived invertebrates?
Long-lived invertebrates have extended innate immune response. They don’t have an adaptive immune system but have hundreds of specific TLRs so they can recognize many different pathogens.
What is an example of the Red Queen hypothesis?
The fight for Iron. Iron is an important micronutrient for both pathogen and host. The host is trying to prevent pathogens from getting access to this iron. Pathogens have evolved to counteract host defenses.
What is the bacterial response to iron withdrawal?
-The direct uptake of host molecules (Transferrin, Lactoferrin, Haem).
-The production of siderophores, which bind iron with a higher binding strength than host molecules. E. coli produces one of the strongest siderophores, enterobactin. They also have a second siderophore, aerobactin which binds iron less well than enterobactin.
Lipocalin is produced by activated neutrophils and protects against E. coli infections by binding enterobactin. So the E. coli had to produce something new that is not bound by lipocalin.
How does the host ensure that the amount of available iron in the body is extremely low?
Transferrins and lactoferrins bind iron with a high affinity, hemoglobin binds iron in the blood, ferritin binds iron in the liver, haemopexin binds free heme, and haptoglobin binds free hemoglobin.
What is the function of lipocalin?
Lipocalin is produced by activated neutrophils and protects against E. coli infections by binding enterobactin (but not aerobactin). Tear lipocalin already binds a broader range of siderophores.
What is the function of the HIV-1 gene vif?
HIV-1 gene vif mutation replication is cell-dependent. The difference in cell line susceptibility to HIV-1 is the expression of APOBEC3G, which is encapsulated in the virion (explains the effect in the receiving cell, instead of the producing cell). It specifically deaminates Cytosine residues in single-stranded DNA.
Non-permissive cells express APOBEC3G so they can not get infected by HIV-1.
VIF on virus binds APOBEC3G and stops it from going into the virus and so into the newly infected cells. It actively tags the APOBEC3G to be degraded by the proteasome.
