Scientists at the NYU Langone Medical Center report the discovery of a novel mechanism by which Staphylococcus aureus bacteria attack and kill off immune cells. They say their findings (“Staphylococcus aureus Leukotoxin ED Targets the Chemokine Receptors CXCR1 and CXCR2 to Kill Leukocytes and Promote Infection”), published today in the journal Cell Host & Microbe, explain a critical survival tactic of a pathogen that causes more skin and heart infections than any other microbe, and kills more than 100,000 Americans every year.

“The Staphylococcus aureus leukotoxin ED (LukED) is a pore-forming toxin required for the lethality associated with bacteremia in murine models,” wrote the researchers. “LukED targets the chemokine receptor CCR5 to kill T lymphocytes, macrophages, and dendritic cells. LukED also kills CCR5-deficient cells like neutrophils, suggesting the existence of additional cellular receptors. Here we identify the chemokine receptors CXCR1 and CXCR2 as the targets of LukED on neutrophils.”

“Staph has evolved the clever ability to target the immune system at different stages,” explained Victor J. Torres, Ph.D., assistant professor of microbiology, and senior author of the study.

Scientists have long known that Staph releases an arsenal of toxins to puncture immune cells and clear the way for infection. But only recently have they begun to understand exactly how these toxins work. Earlier this year, Dr. Torres and his team published a paper in Nature explaining how LukED fatally lyses T-cells, macrophages, and dendritic cells, all types of white blood cells that help fight off infection. The LukED toxin, they showed, binds to CCR5 (the same one exploited by HIV). “It attaches to the surface receptor and then triggers pore formation,” continued Dr. Torres.

But their discovery failed to explain how the bacterial toxin kills other types of white blood cells, such as neutrophils, that lack the CCR5 receptor.

Their most recent work solves this puzzle, showing for the first time how receptors on neutrophils also enable binding of the LukED toxin. The researchers found that LukED latches onto CXCR1 and CXCR2, creating the same deadly pores that it does when it latches onto CCR5 receptors. “The mechanism is the same,” pointed out Dr. Torres. “The strategy makes Staph deadlier in mice.”

One therapeutic strategy is to block CCR5 receptors and spare the secondary immune response.

“We know we can block CCR5 receptors without crippling the rest of the immune system. Some people lack CCR5 and they are perfectly healthy and immune to HIV as well,” according to Dr. Torres. “But just blocking CCR5 isn’t enough.”

Drugs are available to block CXCR1 and CXCR2 receptors, but those will impair neutrophil recruitment and function. “The lesson is to target the toxin itself and prevent it from attaching to any receptors,” added Dr. Torres. “We have to think globally.”

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