A first step has been taken toward a treatment for gonorrhea, a sexually transmitted disease (STD) notorious for its high reinfection rates. This news comes within days of a troubling update from the U.S. Centers for Disease Control that placed the STD on a list of “urgent threats” in the fight against drug-resistant bacteria. According to the CDC, Neisseria gonorrhoeae, the bacteria that causes the malady in humans—which can initially result in painful inflammation and discharge, and can cause infertility and even death if not treated—requires urgent and aggressive action from the medical research community. Researchers from the University at Buffalo, S.U.N.Y., think the answer may lie in marshaling the immune system against gonorrhea.
The study, published in The Journal of Infections Diseases, found gonococcal infections in mice could be cured by introducing into the genital tract a cytokine, or immunoregulatory protein, known as interleukin-12 (IL-12), which is also being investigated as a cancer-fighting agent. Michael Russell, a microbiologist and immunologist at S.U.N.Y. Buffalo and one of the study’s authors, says that his 20-year investigation into gonorrhea and its resilience led him to suspect that it was actively altering immune systems, preventing human hosts from developing long-term resistance to it.
The exact mechanism of the alteration remains unclear, but Russell thinks it has to do with the two distinct “arms” of vertebrate immune systems: innate and adaptive. Russell observed high levels of a cytokine called interleukin-10 (IL-10) in gonococcal infections, and observed that it induces an innate immune response. IL-10 seems to suppress adaptive responses—like the formation of antibodies that can be used again to fight later infections—in favor of more general, short-term innate responses. Meanwhile, the innate responses, such as inflammation, are easy for N. gonorrhoeae to beat. If IL-12 could counteract the effects of IL-10, Russell hypothesized, it could help the body fight gonorrhea more effectively, and could be used in a treatment for the STD. When his colleague Nejat Egilmez developed a new delivery mechanism for the otherwise toxic IL-12, in which microspheres of slow-releasing nanoparticles of the cytokine could be targeted directly onto immunosuppressant tumors, Russell’s team decided to try injecting them into the vaginal tracts of infected mice.
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“And it worked,” he says, “very nicely.”
Not only did mice treated with IL-12 respond more quickly to antibiotics, they were also significantly less likely to be reinfected than controls when exposed to the same strain a month later. “We found that the IL-12 treatment allows the development of an adaptive immune response not usually seen,” Russell says. It seems that by counteracting the IL-10 present at gonococcal infections, the treatment prevents immune systems from being tricked out of developing adaptive responses to the disease. The effect, he says, lasts for several months.
The results come just in time, as the CDC now reports that of the 800,000 estimated cases of gonorrhea that occur each year in the U.S., at least 30 percent are resistant to current antibiotic treatments. With 23 percent of cases now resistant to tetracycline, the CDC recommends that gonococcal infections be treated with a combination of two antibiotics—ceftriaxone in combination with either azithromycin or doxycycline—although a slow but steady increase in strains resistant to ceftriaxone indicate this combination may soon be useless as well.
The new treatment would increase the antibiotics’ effectiveness, but researchers hope that one day it might wean us off the drugs for good. “Since the second world war,” Russell says, “we’ve been treating infections by throwing antibiotics at them. Now that bacteria are emerging with antibiotic resistance, we have nothing else in the pipeline to deal with gonorrhea.” But the IL-12 treatment, he says, can turn the infection into a “live vaccine,” allowing the body to develop immunity. He hopes that further research will show a resistance that carries over from strain to strain, indicating his team has paved the way for a gonorrhea vaccine.
Sanjay Ram, an infectious disease specialist at the University of Massachusetts Memorial Medical Center who was not affiliated with the study, called the work “extremely important,” adding that it “provides nice clues for vaccine development. It would be useful in high-risk women who get repeat infections, with the first occurrence acting as a vaccine for subsequent infections.” Caution is necessary, however, he notes—there are differences between the immune systems of mice and humans, and we’re not sure what high levels of IL-12 might do to a human genital tract. One worry in particular is that higher levels of T cells, which IL-12 stimulate, would mean higher levels of so-called T helper, or CD4, cells. Although vital to the immune system, these cells are also a vulnerable point at which HIV can enter the body. Having high levels of them in the genital tracts of at-risk women would be troubling. But, Ram says, with the state of crisis created by the disease’s advance, any lead is a promising one. "One could go on and on about possible downsides,” he says, “but the fact is that we have a multidrug-resistant disease on our hands.”
The STD crisis notwithstanding, Russell says that human application is a long way off. First, he will see just how long and how effectively IL-12 therapy can protect mice from the rapidly mutating bacteria. He also hopes to learn more about the exact mechanism by which the IL-12 cytokines stimulate the immune responses seen in the study. The answer remains largely a mystery and would have to be documented before human trials could commence. But eventually he hopes to see this novel approach to the treatment of infectious diseases—the stimulation of an immune response at the site of infection—deployed to fight gonorrhea, along with other diseases.