A reason why some people recover from sepsis while others die was reported last week.
Writing in the latest edition of Cell, Dr Miguel Soares at the Instituto Gulbenkian de Ciência (IGC), Portugal, says a mechanism involving blood cell protein ferritin and glucose appears to be protective against sepsis - and could help in the search for new therapies to fight the infection.
Dr Soares’ team used experimental models of sepsis in mice to prove that those who recover from the infection develop a protective response that maintains the function of vital organs.
It was already known that a key element in disease tolerance is how the levels of iron are controlled in different tissues and that the pathogenesis of sepsis is associated with deregulation of glucose metabolism.
What Dr Soares’ team discovered is that those two phenomena are intimately linked because controlling iron metabolism is needed to sustain the production of glucose in the liver. This is then used as a source of energy by other organs.
The team induced sepsis in laboratory mice and compared how disease progressed in mice that express ferritin.
They found that ferritin is needed for the liver to produce glucose after an infection and hence to protect mice from succumbing to sepsis.
Co-first author Sebastian Weis, of Jena University Hospital, Germany, said: 'Typically in mice, after infection, there is an increase of blood glucose levels followed by a quick drop, which can become lethal.
'In humans with infectious disease this also occurs in a subset of patients and is known to lead to higher death rates. Our results showed that ferritin controls glucose production in the liver so that blood glucose levels are maintained within a range that allows survival. Without ferritin, the glucose levels continued to drop and mice eventually die from sepsis.'
Colleague Ana Rita Carlos, also co-first author, also discovered that when ferritin is absent, iron deregulates the expression of the glucose 6 phosphatase protein, which leads to the liver losing its capacity to secrete glucose. When this happens, glucose cannot be delivered and used by other vital organs as a source of energy.
'It is very interesting that while essential to support many vital cellular functions iron must be tightly controlled in the liver so that it cannot interfere with the production of glucose,' she said.
'The molecular mechanism via which this occurs relies on the expression of ferritin, a protein complex that binds iron and devoid iron from interfering with glucose production.'
Source: Weis S, Carlos AR, Moita MR et al. Metabolic Adaptation Establishes Disease Tolerance to Sepsis. Cell/ 169: 1-13.
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