How the central nervous system helps control infections in peripheral tissues

Finding potent ways to limit the extent and duration of inflammation – whether in response to a bacterial infection or another form of tissue injury – is one of the holy grails of modern medicine. Several years ago, it was discovered that the central nervous system, via the vagus nerve, plays a role in limiting the inflammatory response. Now, in a paper published in the journal Immunity, a BWH research team led by Charles N. Serhan, PhD, DSc, has conducted a series of studies in mice and human leukocytes, revealing key cellular and molecular components of this process.

The researchers discovered that PCTR1, a new member of the protectin family of pro-resolving mediators whose structure was recently elucidated by the Serhan Lab, helps limit the immune response to E. coli infection in mice. Moreover, they also found that PCTR1 is produced by a subset of immune cells – known as the group 3 innate lymphoid cells (ILC3) – when these cells are stimulated by the neurotransmitter, acetylcholine.

The findings, when taken together with earlier studies by Serhan’s team, suggest that PCTR1 might also help resolve infections in humans. Research is now underway to explore this idea. If proved, PCTR1 and other members of the protectin family could become important adjuncts to antibiotics, helping to speed the clearance of harmful bacteria and reduce patients’ exposure to antibiotics – thereby minimizing the likelihood that antibiotic resistant strains will emerge.

“It is really remarkable that the vagus has a way to connect the central nervous system to the clearance of bacteria in the periphery,” said Serhan, director of the Center for Experimental Therapeutics and Reperfusion Injury in the Department of Anesthesiology, Perioperative and Pain Medicine. “What’s particularly exciting about our results is that they could have great potential for translation into human therapeutics, not just for infections but also for dealing with the debris and cellular injury that stem from inflammation.”

Paper cited: Dalli J et al. “Vagal regulation of Group 3 innate lymphoid cells and the immunoresolvent PCTR1 controls infection resolution.” Immunity. Published online Jan. 5, 2017. DOI: http://dx.doi.org/10.1016/j.immuni.2016.12.009

Nanoparticle-based method shows promise in DNA vaccine delivery

Scientists at BWH have developed a novel method for delivering therapeutic molecules into cells. The method harnesses gold nanoparticles that are electrically activated, causing them to oscillate and bore holes in cells’ outer membranes and allowing key molecules – such as DNA, RNA and proteins – to gain entry. Unlike other approaches, the nanoparticles are not tethered to their biological cargo, a refinement that can boost therapeutic potency and effectiveness.

The research team, led by Hadi Shafiee, PhD, of the Division of Engineering in Medicine and the Renal Division, together with first author Mohamed Shehata Draz, PhD, of the Renal Division, evaluated the technique’s ability to deliver a DNA vaccine – specifically, one against the hepatitis C virus (HCV) – into mice. They found that it induced a strong immune response, reflected by high levels of anti-HCV antibodies and immune cells that secrete specific inflammatory hormones. Importantly, Shafiee and his colleagues detected no signs of toxicity in the mice throughout the study period, which lasted nearly three months.

There is growing interest in DNA vaccines. First, they offer a potential alternative to conventional vaccines, which are sometimes constructed using weakened microbes – either whole or specific parts. These foreign substances can pose risks to patients, which could potentially be minimized if DNA – now readily synthesized in the laboratory – is used instead. DNA vaccines also show promise as a tool for taming cancer growth.

Although Draz, Shafiee and their colleagues began by applying their novel nanoparticle method to DNA vaccines, they underscore its wide-ranging applications.

“One of the really exciting aspects of this new method is that it enables drug delivery into tissues or cells in a universal way,” says Shafiee. “We are eager to explore its use for other important biological molecules, including RNA.”

Paper cited: M. S. Draz et al. “Electrically oscillating plasmonic nanoparticles for enhanced DNA vaccination against hepatitis C virus.” Advanced Functional Materials Published online December 14, 2016. DOI: 10.1002/adfm.201604139