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I am Professor Tomas Ganz from the
Department of Medicine at the University
of California, Los Angeles.
I will speak to you today about "Iron
Metabolism and Innate Immunity".
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Iron is an essential trace metal.
It is a component of oxygen carriers as
well as redox enzymes involved in energy
metabolism, nucleotide synthesis,
and other intermediary metabolism.
Iron is also essential for microbes and
it can be limiting for microbial growth.
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During infection, microbes depend
on host derived iron to supply
themselves with this
essential trace element.
They use at least three different
mechanisms to obtain the iron
that they need.
They secrete small organic
molecules called siderophores,
which are potent iron chelators.
Once loaded with iron, the siderophores
are taken back up by the microbes and
the iron is utilized.
Microbes also have pumps that are capable
of transporting inorganic iron.
And finally, some microbes are also
capable of transporting host derived
ferroproteins and reutilizing their
iron for their own metabolic needs.
Taking advantage of the extreme
dependence of the invading
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microorganisms on iron,
the host responds by sequestering iron,
making it more difficult for
the microbes to obtain it.
Intracellular microbes reside
within the phagocytic vacuole.
And this environment is subject to the
activity of Nramp1, an iron transporter,
which pumps iron from the phagocytic
vacuole to the cytoplasm.
This action is thought to decrease the
concentration of iron in the phagocytic
vacuole and makes it more difficult for
the microbes to get this
essential trace element.
Humans and animals with mutated
versions of Nramp1 are more susceptible
to intracellular microbes.
Extracellular microbes are subject
to the activity of host defense cell
derived lactoferrin and siderocalin,
two proteins which bind iron.
Lactoferrin binds ferric iron, and
siderocalin binds iron
within certain siderophores.
Regardless of which of these
two proteins acts, it deprives
the extracellular microbes of an essential
portion of their supply of iron.
The iron regulatory hormone hepcidin,
which is the main subject
of today's lecture,
acts on the transport mechanisms which
supply iron to the extracellular fluid.
Under the influence of hepcidin,
iron becomes depleted in the extracellular
fluid, making it again more difficult for
the microbes to obtain it.
This figure illustrates the effect
of hepcidin in a mouse.
