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plate showing a positive
streptococcus infection
Photo by Bill Branson
Patients who suffer from hemolysis have an increased risk of developing bacterial infections, and new research provides an explanation for this phenomenon.
The study refutes the idea that excess circulating iron is to blame.
Instead, it suggests that heme prevents macrophages from engulfing bacteria. And targeting this activity might reduce the risk of bacterial infection in patients with hemolytic disorders.
Sylvia Knapp, MD, PhD, of the Medical University of Vienna in Austria, and her colleagues reported these findings in Nature Immunology.
For decades, iron has been considered the prime suspect responsible for the high rate of bacterial infections in patients with hemolysis. Iron has long been established as an essential nutrient for bacteria.
Since hemolysis 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).
However, Dr Knapp and her colleagues found that heme does not act as a willing nutrient to bacteria.
“Using in vitro and preclinical models, we could clearly demonstrate that heme-derived iron is not at all vital for bacterial growth,” said Rui Martins, a PhD student at the Medical University of Vienna.
“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.”
Heme interfered with the cytoskeleton of macrophages, thereby immobilizing them.
“Heme causes cells to form numerous spikes—like hair standing on end—and then ‘stuns’ the cells within minutes,” Martins explained. “It is reminiscent of a cartoon character sticking his finger in an electrical outlet.”
The cytoskeleton is crucial for the basic functions of macrophages. It consists of long, branching filaments that act as the cell’s internal, highly flexible, and mobile framework.
Through targeted build-up and breakdown of these filaments, phagocytes can move in any direction and engulf invading bacteria. However, this requires a finely tuned signaling program in which the protein DOCK8 plays a central role.
“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,” Dr Knapp said.
In the presence of heme, the cytoskeletal resilience was lost, as filaments grew rampant in all directions, resulting in macrophage paralysis. The cells lost their ability to shape-shift and could no longer chase down and engulf the invading bacteria, allowing the bacteria to multiply virtually unrestricted.
However, Dr Knapp and her colleagues found that an antimalarial drug can restore the functionality of these paralyzed 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,” Dr Knapp said.
“This is very promising. We conclusively demonstrate that it is indeed feasible to therapeutically ‘protect’ immune cells and to restore the body’s immune defense against bacteria in hemolytic conditions.” 
plate showing a positive
streptococcus infection
Photo by Bill Branson
Patients who suffer from hemolysis have an increased risk of developing bacterial infections, and new research provides an explanation for this phenomenon.
The study refutes the idea that excess circulating iron is to blame.
Instead, it suggests that heme prevents macrophages from engulfing bacteria. And targeting this activity might reduce the risk of bacterial infection in patients with hemolytic disorders.
Sylvia Knapp, MD, PhD, of the Medical University of Vienna in Austria, and her colleagues reported these findings in Nature Immunology.
For decades, iron has been considered the prime suspect responsible for the high rate of bacterial infections in patients with hemolysis. Iron has long been established as an essential nutrient for bacteria.
Since hemolysis 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).
However, Dr Knapp and her colleagues found that heme does not act as a willing nutrient to bacteria.
“Using in vitro and preclinical models, we could clearly demonstrate that heme-derived iron is not at all vital for bacterial growth,” said Rui Martins, a PhD student at the Medical University of Vienna.
“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.”
Heme interfered with the cytoskeleton of macrophages, thereby immobilizing them.
“Heme causes cells to form numerous spikes—like hair standing on end—and then ‘stuns’ the cells within minutes,” Martins explained. “It is reminiscent of a cartoon character sticking his finger in an electrical outlet.”
The cytoskeleton is crucial for the basic functions of macrophages. It consists of long, branching filaments that act as the cell’s internal, highly flexible, and mobile framework.
Through targeted build-up and breakdown of these filaments, phagocytes can move in any direction and engulf invading bacteria. However, this requires a finely tuned signaling program in which the protein DOCK8 plays a central role.
“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,” Dr Knapp said.
In the presence of heme, the cytoskeletal resilience was lost, as filaments grew rampant in all directions, resulting in macrophage paralysis. The cells lost their ability to shape-shift and could no longer chase down and engulf the invading bacteria, allowing the bacteria to multiply virtually unrestricted.
However, Dr Knapp and her colleagues found that an antimalarial drug can restore the functionality of these paralyzed 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,” Dr Knapp said.
“This is very promising. We conclusively demonstrate that it is indeed feasible to therapeutically ‘protect’ immune cells and to restore the body’s immune defense against bacteria in hemolytic conditions.”
plate showing a positive
streptococcus infection
Photo by Bill Branson
Patients who suffer from hemolysis have an increased risk of developing bacterial infections, and new research provides an explanation for this phenomenon.
The study refutes the idea that excess circulating iron is to blame.
Instead, it suggests that heme prevents macrophages from engulfing bacteria. And targeting this activity might reduce the risk of bacterial infection in patients with hemolytic disorders.
Sylvia Knapp, MD, PhD, of the Medical University of Vienna in Austria, and her colleagues reported these findings in Nature Immunology.
For decades, iron has been considered the prime suspect responsible for the high rate of bacterial infections in patients with hemolysis. Iron has long been established as an essential nutrient for bacteria.
Since hemolysis 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).
However, Dr Knapp and her colleagues found that heme does not act as a willing nutrient to bacteria.
“Using in vitro and preclinical models, we could clearly demonstrate that heme-derived iron is not at all vital for bacterial growth,” said Rui Martins, a PhD student at the Medical University of Vienna.
“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.”
Heme interfered with the cytoskeleton of macrophages, thereby immobilizing them.
“Heme causes cells to form numerous spikes—like hair standing on end—and then ‘stuns’ the cells within minutes,” Martins explained. “It is reminiscent of a cartoon character sticking his finger in an electrical outlet.”
The cytoskeleton is crucial for the basic functions of macrophages. It consists of long, branching filaments that act as the cell’s internal, highly flexible, and mobile framework.
Through targeted build-up and breakdown of these filaments, phagocytes can move in any direction and engulf invading bacteria. However, this requires a finely tuned signaling program in which the protein DOCK8 plays a central role.
“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,” Dr Knapp said.
In the presence of heme, the cytoskeletal resilience was lost, as filaments grew rampant in all directions, resulting in macrophage paralysis. The cells lost their ability to shape-shift and could no longer chase down and engulf the invading bacteria, allowing the bacteria to multiply virtually unrestricted.
However, Dr Knapp and her colleagues found that an antimalarial drug can restore the functionality of these paralyzed 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,” Dr Knapp said.
“This is very promising. We conclusively demonstrate that it is indeed feasible to therapeutically ‘protect’ immune cells and to restore the body’s immune defense against bacteria in hemolytic conditions.”