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A new twist from an old foe

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It was quickly appreciated by infectious disease investigators that the MRSA that killed these children – "community-associated" MRSA – was not the same "strain" as the hospital-associated bug.

But it was something potentially more worrisome.

While the hospital-associated MRSA is somewhat clunky and slow-growing, the community-associated bug is a "trimmed down, more svelte version of MRSA," Creech says. This would theoretically allow it to spread rapidly and out-compete the antibiotic-sensitive, "regular" staph that have long lived with and infected us.

Probing Staph's battle plans
Under the microscope, staph bacteria look like tiny clusters of grapes. But innocuous fruit staph is not.

It is the leading cause of pus-forming skin and soft tissue infections, the leading cause of infectious heart disease, one of four leading causes of foodborne illness, and the number one hospital-acquired infection. Antibiotic-resistant forms like MRSA make it all the more difficult to treat.

"Staph's just out there, and every decade or so, it seems to raise its head in an interesting way," Creech says. In the 1960s, a highly virulent form of staph

circulated in newborn nurseries; in the mid-to-late 1970s, toxic shock syndrome associated with tampon use claimed lives; in the 1980s and 90s, hospital-associated MRSA became firmly entrenched; and since the late 1990s, community-associated MRSA infections have been climbing.

Staph is "arguably the most important bacterial pathogen in the United States," says Eric Skaar, Ph.D., M.P.H., assistant professor of Microbiology and Immunology.

Skaar and his team are studying the basics of how staph infects its human hosts and causes disease.

The primary immune system cells that respond to staph infections are neutrophils, which "basically gobble up bacteria," Skaar says.

"In its simplest form, a staph infection is a fight between the staph and the neutrophil."

Skaar is taking advantage of cutting-edge proteomics technologies available at Vanderbilt to identify proteins that are part of that battle. Those proteins might make good targets for new antibiotic therapeutics, he says.

In pilot studies, Skaar and his colleagues compared staph infections in normal mice and in mice lacking neutrophils. Using mass spectrometry to study kidney abscesses in these mice, the investigators identified up to 70 proteins in the staph-containing abscesses that are present in a neutrophil-dependent manner, suggesting that they are part of the staph vs. neutrophil battle.

One of these proteins, when purified and added to staph, kills the bacteria.

"We're following up on the preliminary data with that one protein, and it's pretty exciting to think about what the other 69 proteins might be," Skaar says.

Blocking iron-stealing to thwart infection
Skaar's team is also after the mechanisms staph uses to acquire iron, a key nutrient that it and all other bacteria require to successfully cause infection.

Iron is the only nutrient which is difficult for bacteria to come by inside the human body, an environment that may be "the most iron-starved place on Earth from the standpoint of iron availability," Skaar says.

Iron is "hidden" inside human cells by iron-binding proteins – mostly heme-containing proteins like hemoglobin. This iron-hiding strategy is one of the most important first lines of defense against bacterial pathogens – a process known as "nutritional immunity."

Skaar and his colleagues are studying how staph "steals" iron away from its binding proteins.

"We found that staph gets iron by popping open your red blood cells – during a blood-borne infection – pulling out the hemoglobin, removing the heme, sucking that up and eating it," Skaar says.

The team has identified a heme transport system, present in a number of Gram-positive pathogens including staph and Bacillus anthracis (anthrax), that recognizes human hemoglobin, removes heme from hemoglobin, transports heme through the bacterial cell wall, and degrades the heme to release free iron.

But heme-eating is a little tricky for staph: The right amount is required, but too much is toxic.

"We figured that staph must have some mechanism to monitor heme levels so that it doesn't eat too much but eats enough to satisfy its iron requirement," Skaar says.

In recently published studies, Skaar and colleagues again turned to proteomics technologies to examine the proteins produced by staph exposed to iron-rich and iron-poor conditions. The investigators found that staph coordinates a change in its central metabolism to alter the end products it pumps out.

When iron is scarce, it produces chemicals that make the environment more acidic, which causes iron to pop off the proteins that are hiding it.

Understanding the mechanisms staph uses to get iron could point to novel anti-microbial targets. And because all bacteria need iron, the targets may be common to many types of bugs, Skaar says.

"It's a simple idea: this is the food they need; this is how they get it. If you could inhibit iron acquisition, they don't get food, and you don't get sick."

Moving toward a staph vaccine
New antibiotics are desperately needed against a bug that "can be resistant to just about every antibiotic that we have," Skaar says. Some investigators have suggested that we are returning to a pre-penicillin-like era, when systemic staph infections had an approximately 80 percent fatality rate, he adds.

"Staph adapts quickly to whatever we do to it," Creech says. When methicillin – a penicillin-type antibiotic with a component that was supposed to block bacterial resistance to penicillins – was introduced, it took less than a year for physicians to see staph infections resistant to the new drug, he notes.

"This pattern that staph shows of rapid adaptation and drug-resistance is inevitable with most antibiotics, it seems," Creech says.

"What we need are new strategies for treatment and new strategies for prevention of staph infections."

A vaccine against staph may be the best bet for preventing infections. Several companies are in various stages of developing staph vaccines.

Farthest along is a product called StaphVAX, which showed early promise in preventing staph infections in dialysis patients. A larger phase 3 trial of the vaccine, also in dialysis patients, failed to reduce the number of staph infections in the vaccinated group. The company that produces StaphVAX is continuing to study how best to make the vaccine and test it in patient populations at risk for staph infections, Creech says.

The perfect vaccine for staph will need to have several components that hit staph at multiple pathways, Creech believes.

"Staph's been with us for a long time, and it knows how to be redundant to evade our defenses," he says.

As part of its battle plan, staph coats itself in sugars and proteins that keep our immune system from "seeing" it, pumps out toxins that poke holes in our cells, and produces proteins that help it avoid being killed if it gets taken prisoner by an enemy neutrophil.

"If we can figure out how to hit all those things, we can potentially outsmart it," Creech says.

Staph is "one of the more challenging pathogens we face," he adds, "and it's going to take the continued collaboration of basic scientists, epidemiologists, immunologists, vaccine developers and clinicians to make an impact in preventing and treating infections from this bug." VM

 

A rising tide of drug-resistant staph infections

A nosy bacteria

 
   

Staph infecting a hair follicle

   
   
 
 
   
 
 
 
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