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07 November 2016

Researchers have reported significant new discoveries about haemolysis, suggesting ways to treat the condition, it was announced last night.

The team at the CeMM Research Centre for Molecular Medicine of the Austrian Academy of Sciences and the Medical University of Vienna, Austria, says it has uncovered the molecular mechanisms that explain how haemolysis increases the risk for infections. 

It has long been believed that because haemolysis leads to the release of iron-containing heme, the threat of serious bacterial infections in these patients was attributed to the excess availability of circulating iron (heme), the researchers say. 

However, Professor Sylvia Knapp, director of medical affairs, and her team found that heme was not only failing to act as a willing nutrient to bacteria, it also paralysed the immune cells that were sent to protect the host from the bacteria.

First author Rui Martins said: “Using in vitro and pre-clinical models, we could clearly demonstrate that heme-derived iron is not at all vital for bacterial growth.

“In contrast, we found that heme acts on macrophages, the most significant immune cells that are required for mounting an antibacterial response, and it furthermore prevented these cells from eliminating bacteria.” 

They discovered that the heme molecule interfered with the cytoskeleton of macrophages, immobilising them.

“Heme causes cells to form numerous spikes, like hair standing on end and then ‘stuns’ the cells within minutes,” explained Martins. “It is reminiscent of a cartoon character sticking his finger in an electrical outlet.” 

The cytoskeleton – with its long, branching filaments that act as the cell's internal, highly flexible and mobile framework – is crucial for basic macrophage functions.

Through targeted build-up and breakdown of these filaments, phagocytes can move in any direction and 'eat' invading bacteria. 

However, this requires a finely tuned signalling programme involving the protein DOCK8. 

“Through chemical proteomics and biochemical experiments, we discovered that heme interacted with DOCK8, which led to the permanent activation of its downstream target Cdc42, with deleterious effects,” said Prof Knapp, the senior author of the study. 

Cytoskeletal resilience is lost when heme is present because filaments grow in all directions, resulting in macrophage paralysis. This means that bacteria can multiply virtually unrestricted, which could lead to life-threatening conditions.

A recent study clarified the molecular effect of heme on macrophages and ascertained that an already available medication can restore the functionality of affected macrophages. 

“Quinine, which is clinically used to treat malaria and is suspected to bind heme, blocks the interaction of heme with DOCK8 and thereby improves the outcome from sepsis,” says Professor Knapp. 

“This is very promising. We conclusively demonstrate that it is indeed feasible to therapeutically protect immune cells and to restore the body's immune defence against bacteria in haemolytic conditions.”

Martins R, Maier J, Gorki A-D et al. Heme drives hemolysis-induced susceptibility to infection via disruption of phagocyte functions. Nature Immunology 31 October 2016; doi: 10.1038/ni.3590




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