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Flashcards in Iron metabolism Deck (24):
1

Overview of role of iron in bacterial infections

Environment High Iron Entry
host low iron immune clearance/ enhance iron acquisition

2

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

3

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),

4

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

5

explain Bacterial iron acquisition at low iron

- environmental signal to switch on virulence determinants

6

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)

7

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

8

what is Transferrin species specificity?


– Neisseria - human only
– Haemophilus influenzae - human, bovine, rabbit
– Bordetella pertussis - can use any source

9

Specialised mechanisms for scavenging iron from host

- surface ferric reductases
- haemolysins, cytotoxins
- transferrin-specific proteases
- receptor-mediated systems
- siderophore systems

10

what are Siderophores

11

name the two types of siderophores

catechols and hydroxamates

12

give an example of each type of Siderophore

c- vibriobactin - Vibrio cholera
h- mycobactin - Mycobacterium spp

13

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!

14

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

15

name a iron acquisition mechanisms required for virulence

aerobactin in invasive E. coli – UTI

16

name a pathogenicity island that contains iron uptake systems

yersinia enterocolitica

17

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

18

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

19

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

20

when is Fur repressed

High Iron conditions

21

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

22

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

23

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

24

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)