The discovery opens the door to a new arsenal of tools for dealing with antibiotic-resistant bacterial infections, such as those caused by methicillin-resistant S. aureus or MRSA, that have killed thousands of people around the world. They are increasing in hospitals and nursing homes, and also rising in prisons, among athletes, people in the military, and other places where many people are in close and frequent contact.
The team members behind the work are from Cedars-Sinai Medical Center, the Linus Pauling Institute at Oregon State University (OSU), the University of California Los Angeles (UCLA), and other research centers. They write about it in a paper published online this week in the Journal of Clinical Investigation.
Potential for Use with AntibioticsCo-author Adrian Gombart is an associate professor in the Linus Pauling Institute at OSU. He told the press the study could be very significant, but the results have to be replicated in humans first:
"This could give us a new way to treat staph infections that can be deadly, and might be used in combination with current antibiotics," said Gombart.
"It's a way to tap into the power of the innate immune system and stimulate it to provide a more powerful and natural immune response," he added.
Although antibiotics are very effective against bacterial infections, an increasing number of bacteria types, especially Staphylococcus aureus, are becoming resistant to them, leaving fewer and fewer options for treatment.
Some believe the widespread use of antibiotics, coupled with mismanagement of their doses, creates an evolutionary pressure that helps increase the emergence and spread of resistant strains.
One of the most common of these is MRSA, which the investigators included in this study.
Gene Mutation Causes Vulnerability to Bacterial InfectionA decade ago, Gombart discovered that a mutation of the C/EBPε gene in humans makes some people more vulnerable to bacterial infection. Working on this problem led to finding that nicotinamide can "switch on" some of the disabled anti-microbial genes, giving immune cells greater capacity to kill infectious bacteria.
The authors summarize this in their abstract:
"The myeloid-specific transcription factor, CCAAT/enhancer-binding protein ε (C/EBPε) is a critical mediator of myelopoiesis. Mutation of this gene is responsible for neutrophil-specific granule deficiency in humans, a condition that confers susceptibility to Staphylococcus aureus infection."
The StudyIn this latest study, the team showed mice bred to be deficient in C/EBPε were severely affected by infection with S. aureus, and it was deficiency of the C/EBPε protein in their neutrophils (a type of white blood cell that kills and devours harmful bacteria), that was responsible.
They then showed that high doses of vitamin B3 (the molecule acts as an "epigenetic modulator", that is it can switch genes on an off) increasing expression of C/EBPε in cultures of the appropriate (myeloid) immune cells.
In another experiment, they also found that vitamin B3 increased the activity of the gene, and selected bacterial targets, particularly in neutrophils.
And finally, in a mouse model, as well as in mouse and human blood cultures, they showed vitamin B3 "enhanced killing of S. aureus by up to 1,000 fold", but it had no effect when given to mice that were either deficient in C/EBPε or in mice depleted of neutrophils.
The researchers found that in human blood, vitamin B3 was able to wipe out the staph infection in a few hours.
Implications"Our findings suggest that C/EBPε is an important target to boost killing of bacteria by the innate immune system," conclude the authors.
Co-senior author George Liu, an infectious disease expert at Cedars-Sinai, said:
"This vitamin is surprisingly effective in fighting off and protecting against one of today's most concerning public health threats."
Approaches like this could help reduce dependence on antibiotics, he added.
The doses used in the study were megadoses, at therapeutic levels, which are much much bigger than the amount of vitamin B3 in a normal diet. However, such levels have been used safely in humans for other medical reasons.
But this fact, together with the findings of this study, are not sufficient reason for people to start medicating themselves with high doses of vitamin B3.
Several grants from the National Institutes of Health helped pay for the study.