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Iron and Infections: Back to the Future (EHA2024) · EHA Unplugged

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  In this episode of EHA Unplugged, we will revisit a
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  spotlight talk from EHA 2024. Professor Domenico Jarelli from
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  the University of Verona will discuss the complex relationship
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  between iron metabolism and infection.
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  My name is Domenico Girelli, I am Professor of Internal
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  Medicine at the University of Verona, and I have a long
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  standing interest in iron metabolism.
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  The title of this talk is Iron and Infection Back to the
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  Future, because this story is very, very long.
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  And the first of all, I would like to recall you about the one
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  of the most important problem that we have in healthcare
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  nowadays that is multi drug resistance to antibiotics.
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  According to several agencies, including The Who, but also
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  including our European Community, MDR resistance is one
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  of the major healthcare problem in the coming year and it is
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  predicted to become the leading cause of that, especially for
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  patients in in the in the hospital.
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  This is the reason why The Who has endorsed the so-called One
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  Health approach. That means that we have to take
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  care not only of our health but also of the health of the planet
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  and the altar of the animals. Because as you know, most of the
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  multi drug resistance is due to livestocks.
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  So we have to take care on the planet, on our cells and also of
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  animals, and the awareness of the iron infection interaction
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  could help us in fighting these rising problem.
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  So according to Otto Varberg, the Nobel Prize winner in 1925,
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  life without iron would be impossible.
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  And as a as a matter of fact, iron was essential for the
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  development of the 1st forms of life in the Archean ocean.
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  But also iron is essential for all living organisms, including
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  the microbes, and it is relatively scarce.
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  So as you will see, there is during an infection there is a
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  sort of battle for iron between the hosta and between the
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  pathogen. So we as hematologists are in
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  the habit of consider iron important only for the synthesis
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  of hemoglobin and the iron storage in myoglobin in muscles.
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  But iron due to its oxy reductive properties is actually
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  essential for many other vital function and including the
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  production of energy in the mitochondria and the synthesis
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  and the repair of DNA that is crucial for cell proliferation.
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  So you can imagine that during an infection we have from one
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  side iron is needed to the microbes in order to growth and
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  from the other sides iron is needed to our immune system in
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  order to to mount an immune response against the invading
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  pathogen. So there is a battle in this
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  sense. Key role in this context is
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  played by epciding. All of you are aware that
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  epsiting is the most important regulator of iron metabolism by
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  inhibiting for reporting. But you have to consider also
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  that epsiting is very close from a chemical point of view to the
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  defenses. Defenses are small peptides that
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  are produced by leukocytes, by neutrophils and other cells and
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  are the first line of defence against infection because they
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  have an antimicrobial effect which is direct.
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  But epsidine also have an antimicrobial effect that is
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  indirect by subtracting iron from the invading pathogens
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  during an infection. For example from a gram negative
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  bacteria we have the production of LP's and then the stimulation
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  of the immune cells to produce interleukin 6 that stimulates
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  the production of websiting in the liver and epsiting block for
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  reporting in the macrophages. And in this in this way iron is
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  not available to the to the the the pathogen.
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  And this of course is the one of the main mechanism that is
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  involved in the so-called anemia of inflammation that in this
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  sense can be considered as like a byproduct of the response of
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  an acute infection. There are other way in which our
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  body responded to an infection. Not only the synthesis of
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  epciting that is stimulated by interleukin 6 and many other
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  interleukin, but also our immune cells secrete the some molecules
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  that are named ciderophores that are characterized by the high
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  affinity for iron. On the other side, the bacteria
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  also produce a number of ciderophores in order to catch
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  up the the the the iron. Among the human ciderophore we
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  have lactoferrin, we have lipochalin and and many other
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  molecules and each different strain of bacteria produces its
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  own ciderophore and in order to to acquire iron.
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  So this is the basis for the synthesis of a new class of
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  antibiotics that could help in responding to the problem of the
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  multi drug resistance. This is a kind of a Troyan horse
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  strategy because for example there is a new anti be
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  antibiotics that here that is similar to the classical
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  Cephalosporin that is named cephidericol.
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  Cephidericol is beca beta lactamine that is conjugated
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  with the aciderophore and these allow the the entry of the
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  antibiotic within the bacterial wall because in the bacterial
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  wall there there are some specific receptors for the
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  siderophore and then when the the antibiotics is inside the
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  cell it the antibiotic is released and can act against the
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  the the the pathogen. So these is a new class of anti
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  antibiotics, Chefidericol is the first one class but there are
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  many other products that are under developing from the other
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  side. We have to consider also that
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  whenever we have an infection our immune systems have to
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  respond and B lymphocytes and T lymphocytes have to proliferate
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  and the need a lot of energy in order to produce for example
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  antibodies. So in during an infection the
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  our immune system needs iron and in condition of iron deficiency
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  that could be pre-existing the infection, we could have
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  diminished the immune response because of the iron deficiency
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  and this may represent A cause of an altered response to
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  vaccination. Indeed, there are some examples
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  of these problems. In the last two years, some
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  papers have been published by the group of Aldrake Schmidt and
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  Nicole Stoffel at the Oxford University.
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  They have done a lot of work regarding the role of iron
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  deficiency as possible problem in mounting an efficient immune
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  response to several vaccines. And indeed it has been
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  demonstrated in children from the Ghana in Africa that
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  pre-existing anemia or iron deficiency can lead to a
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  decreased response to some vaccines, especially against
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  pertussis, against diphtheria and against pneumococcal
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  infection. Similarly, also in elderly
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  individuals, it has been reported that the response to
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  the influenza vaccines may be diminished in conditions of iron
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  deficiency. Another point and my last point
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  regarding the complex relationship between iron
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  metabolism and infection is regarding the the role of common
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  iron disorders that can influence the immune function.
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  This is an active field of the researcher as as you know, iron
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  deficiency is one of the most frequent disease on a global
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  perspective. It has been estimated that about
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  1/3 of the world population is affected by anemia and the
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  majority of anemic subjects actually suffers from iron
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  deficiency. And in this condition, as I said
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  before, that could be an ultra response to some vaccines.
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  But there is also an rare disorder that is characterized
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  by mutation in the transferring receptor that is expressed in
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  all cells but also of course in lymphocytes.
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  And patients with these defect are only mildly anaemic, but
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  actually they are immunodeficiency.
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  And this is a sort of a proof of concept that iron is really
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  important for mounting a an appropriate immune response.
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  On the other side, iron overload is also a condition that is
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  characterized by some alteration in the the immune response.
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  And recently it has been published a very good paper on
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  blood that was presented the last year here in EHA, in which
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  it has been demonstrated that people with hemochromatosis are
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  more susceptible to infection. And another point is that they
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  are especially subjected to infection by Vibrio vulnificas,
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  that is microorganism that is present in the water.
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  And so from a practical point of view, our patients with
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  hemochromatosis should be advised to avoid contact with
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  contaminated water, especially if they are if they have found.
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  So in conclusion, I hope to convince you that the
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  hostopathogen battle for iron is key for the outcome of most
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  infectious disease. I have shown you the novel
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  metallo antibiotics that represents an attractive option
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  for MDR pathogen. Both iron deficiency and iron
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  overload are risk factors for an impaired immune response to
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  pathogens and vaccines. And of course further results is
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  needed in this field. But if you consider the global
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  prevalence of anemia and iron deficiency and the burden of the
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  vaccine preventable diseases, even if iron deficiency only
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  moderately diminishes the effectiveness of a subset of
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  vaccines, counteracting iron deficiency could yield
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  significant benefits. Thank you very much for your
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  attention. I want to know about your idea
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  about iron prescription for the patient inpatient setting for
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  anemia correction and also with concomitant infection.
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  Do you suggest? This is a very, very important
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  question. Thank you very much.
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  In principle, I think that we should avoid giving iron even if
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  the patient is iron deficiency iron deficient whenever there is
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  an active infection. OK, so we have to cure the
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  infection and then give iron.