C Diff Protects Itself Using Blood Cell Cofactor

The bacterium Clostridioides difficile (C diff), can cause significant inflammation in the gastrointestinal tract, often resulting in diarrhea and bleeding in those who contract it. C. diff is a major health threat to people, particularly older adults who have extended stays in nursing homes or hospitals, and can even lead to death. It can be very difficult to knock out, and recurrent infections are not unusual.

A new report may shed some light on why C diff is so hardy and tough to defeat. Scientists recently discovered that C. diff is able to zero in on heme, a cofactor of the red blood cell protein hemoglobin, and repurpose it as a barrier against antibiotics and the body’s natural immune responses.

In a study published in Cell Host & Microbe, a team at Vanderbilt University Medical Center in Nashville described this process. When a person contracts C diff and experiences inflammation and tissue damage, blood cells lyse, or burst open. This lysis releases heme, the part of blood that attaches iron to oxygen and gives blood its red color. But like a shark smelling blood in the water, C diff deploys a unique protein system to capture the heme as soon as it is released from the cells. The heme is bound and turned into a protective mechanism, enabling the bacteria to blunt the impact of therapies employed against it.

Scientists named the protein system HsmRA, for heme sensing membrane proteins R and A, which work in tandem. “All of this heme is dumped at the site of infection, and the HsmR can sense this key molecule of blood,” Eric Skaar, PhD, MPH, director of the Institute for Infection, Immunology & Inflammation at Vanderbilt University Medical Center and an author of the study, told Contagion. HsmR then activates HsmA, which binds to the heme sensed by HsmR by coating it with a protein heme complex. This protects the pathogen from the oxidative stress generated by immune-system molecules.

It doesn’t take much heme to activate the expression of HsmRA, which is quite sensitive and revs into action immediately upon sensing heme. “When 1 red blood cell pops, there’s clearly enough heme,” Skaar said.

HsmRA, however, doesn’t do its work entirely on its own. Because heme is highly reactive and consequently toxic to C diff, a second system called HatRT works to pump out excess heme and protect the bacteria from heme’s damaging effects. The two systems operate in concert to allow C diff to flourish.

As HsmA enables the reduction of oxidative stress against C diff, the scientists discovered that the protein system might protect the pathogen from the actions of antibiotics, which are commonly prescribed to treat C diff. “The most exciting thing, from a clinical or therapeutic standpoint, is that HsmRA makes the bacteria inherently resistant to oxidizing compounds,” Skaar said, mentioning vancomycin and metronidazole, 2 standard antibiotics prescribed for the infection.

Although scientists don’t understand the exact mechanisms behind how C. diff survives and thrives in the gut, the revelation of HsmRA’s actions brings experts a step closer to finding ways to blunt the bacteria’s ability to protect itself. Skaar mentioned that therapeutics reducing inflammation in the gut might possibly prevent some of the damage from C. diff, as might heme chelators that would bond to heme and prevent it from stimulating HsmRA’s protective actions. There currently are no commercially available heme chelators, although “conceptually, at least, it’s a really interesting idea,” he said.