metal sequestration Flashcards
Host mechanisms of nutritional immunity
- limit extracellular abundance
- secrete metal binding molecules
- direct inactivation of bacterial metal acquisition molecules
Limiting extracellular abundance
Haem: has a high affinity of Fe III > urethra sites, all iron is bounded to haem, none is free flowing
Ferritin: storage of iron ions, removes a large amount of iron away from pathogens
Host start: Secrete metal binding molecules
Released by neutrophils: Calprotectin (zinc and manganese) 50% of their proteins are calprotectin, lactoferrin (Fe III)
- Transferrin (iron)
direct inactivation of bacterial metal acquisition molecules
Lipocalin 2: binds proteins that bind metals and who originate from bacteria
Mechanisms of bacterial metal ion scavenging
lysis of host cells, direct acquisition of host proteins, secreted molecules, direction acquisition of metal ions
Iron-regulated surface determinant system
strat: lysis of host cells
staphylococcus aureus
Isd A, B, C, and H (anchored to cell wall) pass haem back and forth between each other
Isd D, E, F brings haem across the cell membrane into the cytoplasm
haem oxygenases (lsdG & I) breakdown haem and release iron into the cytoplasm
Transferrin binding protein A
TbpA: directly acquires Fe III that is bound to host transferrin
transferrin arms race
Transferrin is comprised of two lobes
○ C and N
○ Used to be identical
○ C lobe developed mutations to decrease interactions with TbpA
Pathogens mutate TbpA to increase binding affinity to transferrin
Siderophores
- Iron carriers
- Low molecular weight compounds
- Primarily synthesised by non-ribosomal peptide synthetases (NRPSs)
non-ribosomal peptide synthetases (NRPSs)
○ Enzymatically driven, doesn’t require ribosomes, efficient but…
○ Energetically expensive
§ Need to be able to shut off quickly
○ Rapidly change the structure Production tightly regulated by intracellular
siderophore arms race
Enterobactin synthesised by Enterobacteriaceae family
- Captured by host siderocalins (lipocalin-2)
- Glycosylated derivatives (salmochelin) can no longer be bound by lipocalin-2
○ Two carbohydrate moieties added to enterobactin > mutation
- Continued virulence in the presence of lipocalin-2
Metallophores
Bind pretty much everything except for iron Broad specificity for divalent cations (copper ii)
Enzymatically synthesised by nicotianamine synthase (NAS)
Staphylopine system
- Biosynthetic genes: make metallophore
- MFS transporter that flows metal free compound from the cell into the environment
- ABC transporter, brings the metallophore once it gets the metal that it needs
- Sometimes it can come back with a metal that it doesn’t want ~ promiscuous metal binding
○ e.g. bringing back copper instead of zinc
Needs to modulate copper abundance and still doesn’t have any zinc
ATP binding cassette (ABC) transporters
direct acquisition of metal ions
- Selectively acquire metals ions from host environment
○ Must achieve absolute specificity
○ Exclude chemically similar ligands
Must bind and release ligand in the absence of energy
Zinc-uptake ABC system (znuABC)
Regulated by the zinc uptake regulator Zur
znuA and B are functionally redundant
ABC transporter
