Iron metabolism Flashcards
Overview of role of iron in bacterial infections
Environment High Iron Entry
host low iron immune clearance/ enhance iron acquisition
how is Iron used in biological systems
• essential nutrient for almost all living cells
• functioning of biological processes
- Fe3+ Fe2+ inter-conversion generates redox potential
- necessary for activity of key metabolic enzymes
• Free iron is limited in the environment
- free ferric iron virtually insoluble
- bound to proteins in body
• Acquisition of iron is major microbial virulence determinant
whats the The trouble with iron?
- Ferric iron is a catalyst in Haber-Weiss-Fenton reactions producing free radicals
- Free radicals cause breakage of DNA and disruption of membranes by peroxidation of lipids
- In mammals/birds iron is complexed with proteins: haemoglobin (in red blood cells), haemoglobin-haptoglobin (in serum), haem-haemopexin (in serum), transferrin (in serum, lymph),
what are the Consequences of iron-binding capacity
- free ferric iron levels are too low to support bacterial growth
- Injection of animals with iron compounds increases susceptibility to infection
- Upon infection, iron levels are reduced even further - hypoferraemia. IL-1 is the key cytokine in this process increased transferrin levels, release of lactoferrin from PMNs, transfer of iron from transferrin to lactoferrin,
and transport to liver for storage in ferritin
explain Bacterial iron acquisition at low iron
- environmental signal to switch on virulence determinants
what are the specialised bacterial mechanisms for scavenging iron form the host at low iron?
- surface ferric reductases (Listeria monocytogenes)
- haemolysins, cytotoxins
- transferrin-specific proteases (Bacteriodes)
- receptor-mediated systems
- haem (Yersinia pestis)
- haemoglobin, haptoglobin (H. influenzae, S. aureus)
- transferrin (Neisseria, H. influenzae, B. pertussis)
describe Receptor mediated iron uptake
- Dependent on direct contact between bacterial receptor and host iron binding protein
- Involves specific receptor-protein interaction
- Ferric ion transferred from binding protein to receptor (energy-dependent mechanism)
- Then via a periplasmic binding lipoprotein to an inner membrane permase
what is Transferrin species specificity?
– Neisseria - human only
– Haemophilus influenzae - human, bovine, rabbit
– Bordetella pertussis - can use any source
Specialised mechanisms for scavenging iron from host
- surface ferric reductases
- haemolysins, cytotoxins
- transferrin-specific proteases
- receptor-mediated systems
- siderophore systems
what are Siderophores
name the two types of siderophores
catechols and hydroxamates
give an example of each type of Siderophore
c- vibriobactin - Vibrio cholera
h- mycobactin - Mycobacterium spp
explain Siderophore-mediated iron uptake
• Bacteria that synthesise a particular siderophore will express the cognate transporter
• Many bacteria also express transporters for siderophores produced by other microorganisms
siderophore piracy!
how is the Ability to use a wide range of siderophores is highly advantageous
- obtain iron with minimum expenditure of energy
* prevent other bacteria from using the iron
name a iron acquisition mechanisms required for virulence
aerobactin in invasive E. coli – UTI
name a pathogenicity island that contains iron uptake systems
yersinia enterocolitica
name 4 virulence determinants that are iron regulated
- Shiga toxin of Shigella dysenteriae
- Vero-cytotoxin of enterohaemorrhagic E. coli
- Haemolytic toxin of Vibrio cholerae
- Diphtheria toxin
how does Iron regulation of genes work?
- Bacterial iron uptake systems are tightly regulated, primarily at transcriptional level
- Global iron regulator – Fur (ferric uptake regulation)
- 17-kDa polypeptide with high histidine content
- Acts as repressor when complexed to ferrous iron
- Binds ‘Fur box’ in promoters of iron-regulated genes
explain how Fur homologues work in 3 organisms
- Yersinia enterocolitica haem receptor expression regulated by a Fur protein 84% homologous with E. coli Fur
- Neisseria meningitidis has a Fur protein, regulates the iron-responsiveness of iron-receptor proteins plus some secreted proteins and energy metabolism genes
- Vibrio cholerae has a Fur protein highly homologous with E. coli Fur, controls siderophore production, etc
when is Fur repressed
High Iron conditions
explain Regulation of Diphtheria Toxin
- Diphtheria Toxin (DT) is major virulence factor of
Corynebacterium diphtheria - Lethal dose is 0.1 mg/kg of body weight
- DT production is greatest when bacteria grown under
iron-limiting conditions - DT is encoded by tox gene on corynephage
- The regulator DtxR is encoded on bacterial chromosome and represses DT expression when bound to a divalent metal ion
explain the Corynebacterium diphtheriae DtxR Regulon at High Iron
DtxR
226 aa
Binds Fe2+, Ni2+, Co2+, and others Functions as a dimer Dimers stabilized by metal ion interaction
DT – no expression
what are DtxR Homologs
DtxR homologs are called IdeR
Foundin Mycobacterium,Staphylococci,Treponema
palladium, Brevibacterium and Streptomyces
High conservation – 50-60% identity in amino acid sequence Regulons include iron uptake and storage systems
Some species have both DtxR and Fur homologs
summarise Iron Metabolism
- Multiple pathways exist in humans to restrictiron levels and hence growth of bacteria
- Bacteria encode multiple pathways to acquire iron from their hosts; including receptor proteins for iron-containing host proteins and siderophores
- Iron acquisition and other virulence factors are regulated by iron levels (usually through the iron- response regulator, Fur, but also by IdeR homologs)
