Tag Archives: University of Virginia School of Medicine

University of Virginia School of Medicine Researchers Find Why Certain Patients Are Highly Susceptible to C.diff. Infections

The new finding from the University of Virginia School of Medicine (UVA) explains why certain patients are highly susceptible

to C. diff infections, provides doctors with a way to predict disease severity and points to a new way to treat the often-deadly condition.

The UVA researchers found that the immune response to C. diff causes tissue damage and even death through a type of immune cell called Th17. This solves a longstanding mystery about why disease severity does not correlate with the amount of bacteria in the body but, instead, to the magnitude of the immune response. It also explains why patients with inflammatory bowel disease are more likely to suffer severe C. diff infections and more likely to die from them.

Lingering Effects

The bowel condition colitis, the researchers determined, has a lingering effect on the immune system, priming the patient for a worse C. diff infection.

While scientists have known that C. diff and other bacteria produce toxins that are harmful to the body, they assumed this was a simple matter: more toxin, more sickness.

But UVA’s research reveals that the truth is far more complex. Oftentimes, the type of immune response generated by the body can dictate the outcome of disease independent of bacterial toxin.

“When we, as a lab, started working on this, we were actively discouraged from working

on C. difficile because [some] people in the field thought, ‘Oh, this is a toxin-mediated disease. You don’t need to understand anything more than the fact that the bacteria make toxins,’” UVA’s Dr. William A. Petri Jr. said. “So, it’s been a wonderful opportunity for us because we went in and we sort of countered the prevailing wisdom. Yes, the toxins are important, but the toxins are important because they affect the immune system in dramatic ways.”

Inflammatory Bowel Disease

Seeking to understand why patients with inflammatory bowel disease are so susceptible to C. diff, researcher Mahmoud Saleh created a mouse model of colitis, one of the common forms of inflammatory bowel disease. He was able to determine that mice that recovered from colitis actually had changes in their immune system – an adaptive immune response. Immune cells known as Th17 cells had become hyper-charged, primed to cause a severe reaction to subsequent C. difficile infection. Even the same amount of the bacteria would now cause a dangerous, outsized response. “If we infect a month later, we see that these [T helper cells] alone can cause severe infection,” Saleh said. “So, these cells are sufficient for that increased severity of C. difficile infection.”

The researchers then looked at human samples to determine if their finding would hold true. It did, and they were able to use substances in the blood, including a protein known as interleukin 6 (IL-6), to predict disease severity. Patients with high amounts of IL-6 were almost eight times more likely to die from C. difficile than those with low levels.

Petri, of UVA’s Division of Infectious Diseases and International Health, explained: “Now we know from Mahmoud’s work that if I, as a physician, measure IL-6 in one of my patients with inflammatory bowel disease, I’ll be able to know how severe disease will be in that person and I can make the decision about whether the person needs to be admitted to the hospital … or even go to the intensive care unit.”

Preventing C. diff

The research also suggests a potential new way to treat or prevent severe C. difficile relapses. “We know that in mice by targeting T cells we protect from disease, and that leads to the question, could we do something similar and people to provide better therapy?” Petri said. “It is an interesting and terrible situation right now that C. diff is not resistant to antibiotics, but is resistant to treatment. And so even though we have very, very good antibiotics for this, the [body’s] response is so severe that even though we’re killing the bacteria with the antibiotics, patients are suffering from their own immune response.”

While more research will need to be done to create such a treatment, Petri and Saleh are proud to have solved a big mystery about C. difficile. “When you look at how much bacteria are growing or how much toxin is being produced, a lot of time there is no direct correlation,” Saleh said. “Now we know that what’s making that difference is this immune response.”

Findings Published

The researchers have published their findings in the scientific journal Cell Host & Microbe. The research team consisted of Saleh, Alyse L. Frisbee, Jhansi L. Leslie, Erica L. Buonomo, Carrie A Cowardin, Jennie Z. Ma, Morgan E. Simpson, Kenneth W. Scully, Mayuresh M. Abhyankar and Petri.

The research was supported by the National Institutes of Health, grants T32GM008715, T32AI007496, T32AI007496, T32AI07496, 5F31AI114203, 1R21AI114734 and 1R01AI124214; and the UVA Wagner Fellowship.

 

To review this article in its entirety – please click on the link below to be redirected:

https://news.virginia.edu/content/revealed-secret-superpower-makes-c-difficile-so-deadly?utm_source=dlvr.it&utm_medium=twitter

 

University of Virginia School of Medicine; Promising New Antibiotic to combat C. difficile

* In the news *

A new antibiotic being developed at the University of Virginia School of Medicine to combat the dangerous C. difficile superbug also appears effective against a wide array of other pathogens, including the Helicobacter pylori bacterium, a new study suggests.

With antibiotic resistance a growing concern – and an alarming shortage of new antibiotics in development – the drug is notable because it works in a way that prevents microbes from becoming resistant to it.

U.Va.’s new findings challenge conventional wisdom that the best way to develop new treatments for Clostridium difficile, a growing problem in health care settings nationwide, is to target that infection specifically and to use an antibiotic that concentrates in the gut. U.Va.’s drug, Amixicile, does neither – yet early testing suggests it could be significantly more effective than existing options.

Sparing Good Gut Bacteria

Amixicile may prove particularly effective against C. difficile because, unlike other antibiotics, it spares beneficial probiotic and other beneficial bacteria. There is growing evidence to suggest that probiotic bacteria help prevent C. difficile re-infection and relapse, so antibiotics that concentrate in the gut and kill off the intestinal flora indiscriminately make it easier for

C. difficile to regain a toehold. Mice infected with C. difficile that were treated with other antibiotics commonly relapsed and died, but there were no relapses in mice treated with Amixicile, the researchers report.

Unlike other C. difficile therapeutics,  Amixicile concentrates in the bloodstream, rather than in the gut, and emerges only at infected sites. Thus, Amixicile may be useful in treatment of systemic anaerobic and parasitic infections as well as gastric infections caused by H. pylori. More broadly, because of its low toxicity and immunity to mutation-based drug resistance, it potentially could be used as a lifelong prophylactic to prevent flare-ups of chronic diseases such as Crohn’s disease and ulcerative colitis. It may even prove effective against anaerobes associated with periodontal disease.

“If the drug works even half as well as what we’ve found to date, there would be nothing like it in the existing antimicrobials,” said Paul S. Hoffman of the U.Va.  Division of Infectious Diseases and International Health and the Department of Microbiology, Immunology and Cancer Biology.

Overcoming Drug Resistance

Amixicile avoids the problem of mutation-based drug resistance by its unusual mechanism of action. Amixicile targets the function of the vitamin B1 cofactor of pyruvate, ferredoxin oxidoreductase, an enzyme uniquely found in anaerobic pathogens and not present in humans or in the probiotic beneficial gut bacteria.

The vitamin cofactor, a small molecule, is not susceptible to mutation, offering a remarkably reliable – and therefore very attractive – target. Because the target won’t change, the risk of bacteria becoming resistant to the antibiotic is lessened dramatically.

Next Steps

More preclinical work needs to be done before the researchers can gain FDA approval to begin testing Amixicile in people. They next intend to evaluate maximum tolerable doses in animals and examine whether the drug has any genetic or mutagenic effects. If all goes well, they will eventually proceed to human testing.

The researchers’ latest findings have been published online by Antimicrobial Agents and Chemotherapy, a journal of the American Society for Microbiology, and will appear in the August issue. The article’s credited authors are Hoffman; Alexandra M. Bruce of U.Va.’s    Department of Chemistry; Igor Olekhnovich, Cirle A. Warren and Stacey L. Burgess of U.Va.’s Division of Infectious Diseases and International Health; Raquel Hontecillas, Monica Viladomiu and Josep Bassaganya-Riera of the Virginia Bioinformatics Institute at Virginia Tech; Richard L. Guerrant of U.Va.’s Division of Infectious Diseases; and Timothy L. Macdonald of U.Va.’s Department of Chemistry.

Media Contact: