Science Editor

A study published this week described how systemic inflammatory response syndrome can progress to shock, and suggested that a cell type that has long been recognized as a biomarker of systemic trouble could, in fact, be the driving force behind that progress. The work could find practical applications in shock, as well as dengue vaccine research.

To corresponding author Robert Pierce, the work's greatest significance is that "it generates a very interesting hypothesis:" namely, that immature neutrophils, rather than being just a biomarker, could be a critical first step that ultimately allows excess inflammation to progress to shock.

"Immature neutrophils, under the right circumstances, can get called out of the bone marrow," Pierce told BioWorld Today, and clinically, high levels of such immature neutrophils are "the hallmark of a patient in trouble." This paper – published in the Oct. 17, 2011, edition of The Journal of Clinical Investigation – brings up the possibility that "these cells are uniquely pathogenic."

Shock, Pierce said, is at its heart "cardiovascular collapse" that can be caused in different ways, including an allergic reaction, a cytokine storm and sepsis.

One circumstance under which shock can occur is after repeat exposure to dengue virus. The first time a person is exposed to dengue virus, the infection is nasty but usually not life-threatening. But during a second infection, prior exposure can paradoxically make the response to dengue much worse than it otherwise would be, leading to so-called hemorrhagic shock syndrome.

The syndrome, Pierce said, is why early dengue vaccines turned out to be something of a disaster.

"They actually made the disease much worse," he said. "It was almost like we were giving them that first infection and setting up the shock syndrome."

What's clear is that in order to cause hemorrhagic shock, dengue particles need to bind to the MDL-1 receptor (which also goes by the name of CLEC5A). Dengue virus particles are, in fact, the one known thing that reliably sets off the receptor.

However, when MDL-1 is activated without prior injuries, nothing much happens to the stimulated cells – certainly nothing as dramatic as hemorrhagic shock.

To work out how MDL-1 activation spells disaster, the authors used what Pierce termed "an artificial but very tractable system" in mice. They first mobilized MDL-1-receptor-bearing cells with a liver injury, and then exposed the animals to dengue virus particles.

The first surprise came from the cell type that the authors identified as the owners of the MDL-1 receptor.

"We identified these MDL-1 positive cells as immature myeloid cells," co-corresponding author Ricky Cheung told BioWorld Today. "Previously, [MDL-1] was thought to be on macrophages."

Tissue inflammation, Cheung said, "seems to be the trigger causing the mobilization."

Once the cells are activated, they produced the inflammatory cytokine TNF-alpha, as well as the signaling molecule nitric oxide – though surprisingly, that production came not through the inducible form of the enzyme, but the kind that is expressed in endothelial cells.

"There's a circuit that drives eNOS activation," Pierce said, though why that circuit should be activated after MDL-1 receptor stimulation "is anyone's guess."

Pierce said the reasons for the circuit will probably become clearer when the body's own binding partner for MDL-1 is identified. "We're going to find it – or someone else is going to find it. And then we'll know a lot more of this story. . . . I don't think that anyone thinks we evolved this receptor just so we could go into shock when we see dengue," he said.

Pierce cautioned that "we have no idea whether this [mechanism] is germane to people. But we think it's a fascinating question."

Both Pierce and Cheung are scientists at Merck Inc. and were reluctant to specify what if any plans the company has to pursue possible practical applications of the findings. But, Pierce pointed out, the molecules that are activated during shock will be familiar to many in the drug discovery world.

They include several kinases, such as Akt, Syk and PI3 kinase, that are targets of drug discovery efforts in both inflammation and cancer.

"Even if Merck wasn't to pursue this in shock, which is a difficult indication to go after from a drug company perspective . . . companies across the board are generating inhibitors against many of these molecules," he said. "The potential is there."