Cynthia Nau Cornelissen, PhD, Professor of Microbiology and Immunology, and Director of the Center for Translational Immunology talks about new research into gonorrhea and how it may lead to a future vaccine.
How did the idea of this research come about and what is the need you’re trying to address?
CORNELISSEN: My laboratory has been studying the pathogen that causes the sexually transmitted infection (STI), gonorrhea, for the last 20 plus years. But it’s really a difficult pathogen to get a handle on in terms of both prevention as well as treatment. Gonorrhea is the second most common reportable infectious disease in the U.S., second behind chlamydia. The infection can lead to significant consequences in women including pelvic inflammatory disease, which very frequently leads to infertility. It’s one of the leading causes of infertility among young women in this country. It’s also become what’s known as an urgent threat pathogen by both the CDC and WHO because it’s a worldwide problem, not just a U.S. problem, in terms of its increasing incidence of strains that are resistant to virtually all types of antimicrobial therapy. The CDC estimates there are about 800,000 cases in the U.S. alone. Even the antibiotics that we have stopped using to treat gonorrhea, like penicillin, many of the isolates still retain resistance to penicillin. Recently, there have been several isolates that failed the primary therapy that’s recommended right now, which is a therapy with two antibiotics at the same time, intramuscular drugs plus an oral drug. We’d like to develop a vaccine to prevent the infection altogether. This is not a novel idea and it was tested decades ago. The problem is this organism is very well-adapted to our bodies. It’s an obligate human pathogen and doesn’t live in any other animals naturally, nor the environment. So, it’s adapted to our systems over many millennia. It does that because it figures out our immune system. An infection doesn’t result in protective immunity. Unlike many viral infections, if you get a virus once, you’ll never get it again because you adapt, or develop adaptive immunity, against that pathogen. With the gonococcus, people are infected repeatedly with very similar strains. There’s no adaptive immunity to protect them. That also means when we look at how to develop a protective vaccine, we don’t have the history of an infected patient to look back and say, what is it about this person that makes them immune because a natural infection doesn’t make them immune. This is complicated by the fact that the organism has been referred to as a chameleon because it can change almost everything on its surface at very high frequencies. Our immune system can’t keep up with all the different antigenic changes in the system. So, those issues have really contributed to the lack of a vaccine.
Can you talk about your current discovery with cutting off the zinc supply to inhibit it from growing?
CORNELISSEN: I mentioned that one of the problems with developing a vaccine against this organism is that almost everything they put on their surface changes at high frequency. Some of the exceptions to that are nutrient transporters. These organisms must live inside of a human host, which means they must get all their nutrients from that human host. And, they’re very exquisitely adapted to us in terms of those host proteins that they can utilize as nutrients. Virtually all bacterial pathogens require metals, including zinc and iron and other metals. The host has figured this out and deploys a process known as nutritional immunity, which is an effect or an effort on the host’s part, to hide these metals away from invading pathogens. The gonococcus is quite crafty in the sense that it has adapted its outer membrane transport systems to be able to recognize those host proteins, including the human proteins transferrin and calprotectin. These receptors bind to those human proteins and pull the metals off. We think since these transporters are stable in their expression, they’re not subject to high frequency phase or antigenic variation and might be good targets against which we can deploy a vaccine. The idea is that an antibody response, or an immune response, against these very well-conserved transporters might enable us to generate an antibody response that will block the metal uptake just by virtue of blocking the transporter from binding to its ligand. That is where we got the concept of starve and kill. The idea is if an immune response can starve the organism of these necessary metals, then they would die and not be able to cause infection and spread.
Would that affect the human host in any way if you have this vaccine that’s targeting these transporters?
CORNELISSEN: No, because the pathogen is binding to a human protein but with a bacterial receptor. Those bacterial receptors don’t look at all like the human receptors. So, there’s no possibility of a cross reaction that might cause some sort of negative impact on the host because the bacterial transporters are completely different from the human transferrin and calprotectin receptors. There’s no sequence conservation that would cause negative consequences.
Are you seeing this future vaccine as something more like the HPV vaccine or something that’s more reactive for someone that had the infection, got cured, and then this helps prevent them from getting it again?
CORNELISSEN: Both. In fact, one important, innovative aspect of the most recent NIH grant that we were awarded has a component of community outreach to ask questions about potential patient uptake and stakeholder opinions. We’re going to ask people who were involved in the HPV vaccine rollout what worked for them, what didn’t work, and what would they recommend going forward. We envision this vaccine being useful in terms of young people being vaccinated. The highest incidence is between 15 and 25 years old. And, unfortunately that’s when young women, if they get infected, become infertile and have no chance of having children. So, that would be a perfect time for us to intervene with a protective vaccine and prevent that devastating consequence. On the other hand, because people are often infected repeatedly and understand the consequences of the first infection, they might be more willing to get a preventative vaccine.
You mentioned earlier how a lot of the strains are becoming very resistant to treatment. So, what treatments do work?
CORNELISSEN: The current recommended therapy, which works most of the time, is a combination of ceftriaxone, which is delivered intramuscularly, plus azithromycin which is delivered orally. The problem is that resistance to both of those drugs individually has already happened in the gonococcal population. And, there have even been treatment failures in some populations. One published case in England last year was where a young man failed treatment with both of those drugs. Then what must happen is the organism has to be cultured from that infected person and then antibiotic resistance or antibiotic sensitivities must be determined. Hopefully there’s a drug in our group of drugs that we can utilize to which the organism, or that strain, is not resistant. The concern is that because the organisms are not losing resistance, even though we’ve stopped using penicillin and tetracycline to treat this infection decades ago, there are still many strains that are out there that are resistant to both of those drugs. They keep sort of accumulating drug resistance. The concern is there will be a time where we’ll have untreatable infections. Well, that hasn’t happened yet. The biggest help would be developing new antibiotics. And there is a big push to do that, not just against this bacterial pathogen, but others for which our repertoire of drugs is running out.
So, currently there is a push for drugs that would not be resistant? And, you’re pushing further than that and looking to prevent it altogether?
CORNELISSEN: Absolutely. This approach is using these transporters that are crucial to the organism survival in the host. Now that we know the structures of many of those transporters in combination with their ligands, another approach and another way to deploy this research is potentially to find drugs that would interfere with that protein-protein interaction. Then, those could be used as therapies as opposed to just prevention.
What implications would this have for the medical world?
CORNELISSEN: The NIH right now has a very strong emphasis on preventing and developing vaccines against all the STIs, including chlamydia and syphilis. The incidence of all three of these sexually transmitted diseases has gone up dramatically over the last five years, somewhere in the range of, depending on the pathogen, 60 to 70%. This isn’t unique to the United States either. It’s happening in Canada, Australia, and in almost every other country. It’s not completely clear why it’s happening, but if we could develop vaccines against these STI pathogens, we could nip this sort of epidemic in the bud.
What did you find most surprising during your research?
CORNELISSEN: Well, this organism is very clever in the fact that it’s sort of used a receptor system that other bacteria already use to bring in metals, including iron. Those other bacteria build a molecule called a siderophore, which they secrete. Those molecular cages go out and sequester iron from the environment and bring it back into the bacterium. What’s surprising is the gonococcus doesn’t bother with that. They don’t build their own. They just hijack all their metals from whoever they are in the environment with. They can hijack those siderophore iron complexes that other bacteria make, and the metals from their host directly from these metal-binding proteins. So, they’re sort of the ultimate kleptomaniac. They snatch their nutrients away from whatever is in the environment. And, that’s pretty clever.
Can you explain how they pull up these metals and how that allows for the growth of the pathogen?
CORNELISSEN: The metals are important for a lot of different chemical reactions. Iron is a very important catalytic center in many enzymes. And, those enzymes are mostly responsible for redox reactions and energy generation. If you can deprive the organism of those necessary metals, they won’t be able to make energy and won’t be able to catalyze these enzymatic reactions. Zinc is structurally important in many enzymes. They can’t survive in the absence of those metals because they serve such important roles in bacterial metabolism. What’s interesting about the import of these metals is that the gonococcus is in a group of bacteria known as Gram-negative, and that means they’ve got two membranes that import must come through. So, there’s an outer membrane and an inner membrane that sort of represents two physical barriers. These transporters that we’re studying sit in the outer membrane and there’s no way to generate energy out there at the outer membrane. So, the way the organism has gotten over that problem is they use a series of proteins which harnesses energy across the cytoplasm membrane and hands it off to these barrels that sit in the outer membrane. And what happens is the transporter binds to this metal binding protein and uses that energy to pry off the metal. It then transports it through the barrel in the outer membrane and releases the protein after the metal has been extracted. So, they don’t do anything to the host protein. They don’t change it or modify it at all.
Is there anything you would like to add?
CORNELISSEN: I have been asked recently if I had any thoughts or ideas of why this epidemic is happening with respect to sexually transmitted infections. And, I think one factor is clear that there’s been across the board a decrease in the effective use of condoms. Condoms are very effective at preventing the transmission of these bacterial pathogens. These barrier methods of birth control are also very effective at preventing bacterial transmission. So, in populations who don’t feel like birth control is an issue and they don’t need to use a condom, what’s happening is they’re at risk for both transmission as well as acquisition of the pathogen. There’s good evidence in both men and women that the bacterial infection, whether we’re talking chlamydia or gonorrhea, that the environment sets the stage for more effective HIV replication. So, people who are infected with both the bacterial pathogen as well as HIV have higher virus numbers in their mucosal secretions, which means it’s easier for them to transmit the HIV infection. The hope is if we can treat, or ideally prevent, the bacterial infections will decrease HIV spread as well because of that. So, effective condom use and this link to HIV is important to put out there as well.
Interview conducted by Ivanhoe Broadcast News.
END OF INTERVIEW
This information is intended for additional research purposes only. It is not to be used as a prescription or advice from Ivanhoe Broadcast News, Inc. or any medical professional interviewed. Ivanhoe Broadcast News, Inc. assumes no responsibility for the depth or accuracy of physician statements. Procedures or medicines apply to different people and medical factors; always consult your physician on medical matters.
If you would like more information, please contact:
LaTina Emerson, Associate Director of Communications
Institute for Biomedical Sciences at Georgia State University
404-413-1353
Sign up for a free weekly e-mail on Medical Breakthroughs called First to Know by clicking here
