Gonorrhea researchers identify novel route to vaccine, new antibiotic

Researchers have identified a protein that powers the virulence of the bacteria that causes gonorrhea, opening the possibility of a new target for antibiotics and, even better, a vaccine.

The findings, published today in PLOS Pathogens, are especially important since the microbe, Neisseria gonorrhoeae, is considered a "superbug" because of its resistance to all classes of antibiotics available for treating infections.

Gonorrhea, a sexually transmitted disease that results in 78 million new cases worldwide each year, is highly damaging if untreated or improperly treated.

It can lead to endometritis, pelvic inflammatory disease, ectopic pregnancy, epididymitis and infertility. Babies born to infected mothers are at increased risk of blindness.

"The infections very often are silent," said Oregon State University researcher Aleksandra Sikora. "Up to 50 percent of infected women don't have symptoms, but those asymptomatic cases can still lead to some very severe consequences for the patient's reproductive health, miscarriage or premature delivery."

The need for better antibiotic therapy, and a vaccine, is pressing. N. gonorrhoeae strains resistant to the last effective treatment options have emerged, and failures in treatment are occurring.

Sikora and her research team at the OSU/OHSU College of Pharmacy and Ann Jerse's lab at the Uniformed Services University of the Health Sciences in Bethesda, Maryland, collaborated to discover a novel lipoprotein that N. gonorrhoeae uses to defeat the body's first line of innate immune defense.

The body relies on enzymes known as lysozymes that, as their name suggests, thwart bacteria by causing their cell wall to lyse, or break apart. Lysozymes are abundant both in epithelial cells, which make up the tissue on the outside of organs and the inside of body cavities, and in the phagocytic cells that protect the body by ingesting foreign particles and bacteria.

In turn, many gram-negative bacteria -- characterized by their cell envelope that includes a protective outer membrane -- have developed ways of defeating lysozymes. Prior to the work by Sikora's team, however, only one lysozyme-fighting protein had been discovered in the Neisseria genus.

Now that new targets have been identified, they can be explored as bullseye candidates for new antibiotics or a vaccine -- if the lysozyme inhibitor can itself be inhibited, then the bacteria's infection-causing ability is greatly reduced.

Sikora and her collaborators named the new protein SliC, short for surface-exposed lysozyme inhibitor of c-type lysozyme.

Studying SliC's function in culture as well as in a gonorrhea mouse model -- mice were infected with N. gonorrhoeae, then checked for SliC expression at one, three and five days -- researchers determined the protein was essential to bacterial colonization because of its anti-lysozyme role.

"This is the first time an animal model has been used to demonstrate a lysozyme inhibitor's role in gonorrhea infection," Sikora said. "Together, all of our experiments show how important the lysozyme inhibitor is. This is very exciting."

Source: https://www.sciencedaily.com/releases/2018/07/180705143834.htm

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Study characterizes mechanisms of pathogenesis, transmission of bacteria that cause gonorrhea

Researchers have come a step closer to understanding how gonorrhea infections are transmitted. When Neisseria gonorrhoeae, the bacteria responsible for gonorrhea, are exposed to seminal plasma, the liquid part of semen containing secretions from the male genital tract, they can more easily move and start to colonize. The research, led by investigators at Northwestern University in Chicago, appears in mBio-, the online open-access journal of the American Society for Microbiology."Our study illustrates an aspect of biology that was previously unknown," says lead study author Mark Anderson. "If seminal fluid facilitates motility, it could help transmit gonorrhea from person to person."

 Gonorrhea, a sexually transmitted infection, is exclusive to humans and thrives in warm, moist areas of the reproductive tract, including the cervix, uterus, and fallopian tubes in women, and in the urethra in women and men. It is estimated there are more than 100 million new cases of gonorrhea annually worldwide.

"Research characterizing the mechanisms of pathogenesis and transmission of N. gonorrhoeae is important for developing new prevention strategies, since antibiotic resistance of the organism is becoming increasingly prevalent," says H. Steven Seifert, another author on the study.

In a series of laboratory experiments, the investigators studied the ability of N. gonorrhoeae to move through a synthetic barrier, finding that 24 times as many bacteria could pass through after being exposed to seminal plasma. Exposure to seminal plasma caused hair-like appendages on the bacteria surface, called pili, to move the cells by a process known as twitching motility. This stimulatory effect could be seen even at low concentrations of seminal plasma and beyond the initial influx of seminal fluid.

Additional tests found that exposure to seminal plasma also enhanced the formation of bacterial microcolonies on human epithelial cells (cells that line body cavities), which can also promote the establishment of infection.

Researchers at the University of Cologne in Germany also contributed to the study, which was funded by the National Institutes of Health and DFG, the German Research Foundation.

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Source: https://www.news-medical.net/news/20140304/Study-characterizes-mechanisms-of-pathogenesis-transmission-of-bacteria-that-cause-gonorrhea.aspx

Chlamydia Infection May Pave Way For Cancer via DNA Damage

The bacterium Chlamydia trachomatis is a leading cause of sexually transmitted disease that infects over 90 million people worldwide every year. Chlamydia infection often goes unnoticed, can persist for years with little or no symptoms, and can damage women's reproductive organs.

As well as this, the bacterium is proving increasingly stubborn to shift: antibacterial drugs are often no longer strong enough to eradicate it completely, so it goes into persistent mode, leading to chronic infection with no symptoms.

Chlamydia Uses Various Tactics to Ensure Survival

Chlamydia uses "Trojan horse" tactics to enter host cells unnoticed. A protein called Pgp3 enhances Chlamydia's ability to enter host cells unnoticed and then evade host defences.

To ensure survival, Chlamydia needs to make the most of the resources inside the host cell, which is where the bacterium spends most of its life. Once inside the host cell, the pathogen goes about changing the cell to make itself at home. It re-arranges host cell processes to favour its own growth and proliferation. But it's not clear how this affects the cell's normal functions and whether it leads to disease.

However, there is evidence that it might: there is a growing mountain of epidemiological data linking Chlamydia infections to the development of cervical and ovarian cancer development. But exactly how this might come about has been somewhat of a mystery - until now.

Chlamydia Causes Lasting Genetic Damage to Host Cells

In this new study, the researchers show that Chlamydia makes a long-lasting impression on the genome and epi-genome of host cells. Such changes are increasingly implicated in the development of a range of cancers.

They found host cells acutely and persistently infected with Chlamydia had increased levels of different kinds of DNA breaks.

In normal cells, when these types of breaks occur, they either go into cell suicide mode (apoptosis, where the cell is removed, broken down and its material parts recycled) or DNA repair mode.

In DNA repair mode, special proteins trigger a process called DNA Damage Response which attempts to reseal the broken strands of DNA to make sure the correct sequence of genetic code is restored (so when the cell replicates it produces healthy daughter cells).

But not only did the researchers find that Chlamydia-infected cells had altered DNA, but also that their DNA Damage Response didn't work properly: so the broken DNA didn't get repaired in those cells that didn't go down the cell suicide route.

Chlamydia disrupted the host cell DNA Damage Response by stopping key proteins from reaching the sites of DNA damage.

Chlamydia Damage to Cells Is Similar to that Which Leads to Cancer

Thus Chlamydia-infected, damaged cells that did not go down the cell suicide route continued to proliferate, passing on the DNA damage, and also spurred by some extra pro-survival signals activated in the host cell by the pathogen.

The result is an increasing population of rogue host cells that have escaped the normal mechanisms that ensure faulty DNA is not replicated: a hallmark of cancer.

The discovery is important because if it is established that an infection leads to cancer, then vaccination to prevent the infection, or antibiotics to eliminate it, may also prevent the cancer.

Such preventive methods are already working with other cancer-causing agents such as Human Papilloma Virus (HPV) and Helicobacter pylori, which can cause cervical and gastric cancer, respectively.

However, the path from infection to cancer needs to be firmly established before such a strategy can be considered in the case of Chlamydia.

Source: https://www.medicalnewstoday.com/articles/262350.php

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Hopes for Gonorrhea Vaccine

Beginning in 2004 and lasting through 2006, a mass vaccination campaign inoculated most of the New Zealand population: about 90%, including 81% of those under age 20. New Zealand scientists then published their results for the impact of the vaccine on the outbreak.

"The emergence of completely drug-resistant gonorrhoea is a major concern," Dr. Helen Petousis-Harris, lead author of the new study and a senior lecturer at the University of Auckland, wrote in an email.

Evidence from a mass vaccination campaign for an outbreak of bacterial meningitis in New Zealand had unexpected results: reduced rates of the sexually transmitted disease gonorrhea, a study published Monday in the journal The Lancet finds. It is the first time a vaccine has shown any protection against gonorrhea.

In recent years, gonorrhea has shown increasing antibiotic resistance, with some patients unable to be treated with any available drug. Because of this, the World Health Organization includes gonorrhea in its list of bacteria that pose the greatest threat to human health.

She explained that "even moderate protection" against the sexually transmitted disease could have significant impact because the bacteria that cause it "are very tricky." They develop resistance to drugs by transferring genes in atypical ways and recombining with related bacterial species.

Meningococcal disease, the bacterial form of meningitis, is a serious infection of the meninges, the membrane covering the brain. It's transmitted from person to person, usually in close contact, such as kissing, sneezing or coughing, or living in close quarters with an infected person.

A vaccine targeting the specific strain of bacteria causing meningococcal disease in the New Zealand outbreak was eventually "developed in a collaboration between Chiron Vaccines, the National Institute of Public Health of Norway (NIPH) and the New Zealand government," according to Mary Anne Rhyne, director of corporate communications at GlaxoSmithKline, the pharmaceutical company that inherited the vaccine from Chiron through a series of corporate acquisitions.

The vaccine targeted the vesicle, or sac, on the outer membrane of the bacteria.

"I wondered, in looking at their results from the outbreak, if there was any possibility that this vaccine might have had any other effects," said Black, who focused on the country's gonorrhea statistics in particular.

Neisseria gonorrhoeae bacteria (which cause gonorrhea) and Neisseria meningitidis bacteria (which cause meningococcal disease) are "two related organisms. They're cousins, if you will," he said, explaining that the genetic makeup of the two is "85 to 90% similar."

Petousis-Harris and her co-researchers, who had access to a database recording events during the meningococcal B outbreak, set to work testing his hypothesis.

"We compared the vaccination rates in two groups of people," Petousis-Harris explained. One group had gonorrhea, and the other group had chlamydia, both of which are spread through sexual contact.

If the vaccine had an effect against gonorrhea because it is an organism related to meningococcal disease, the researchers hypothesized, then no effect should be seen against chlamydia, an unrelated organism.

"This is exactly what we saw," Petousis-Harris wrote in an email. "We found that people with gonorrhoea were less likely to be vaccinated than people with chlamydia," indicating that the vaccine protected against gonorrhea but not chlamydia.

The researchers also discovered that vaccinated people were significantly less likely to become infected with gonorrhea than people who had not received the vaccine: 41% vs. 51%.

Taking other factors into account, including ethnicity and gender, the researchers concluded that having received the meningococcal vaccine reduced the incidence of gonorrhea by about 31%.

"Given the emergence of drug resistance, a vaccine may be our only avenue," Petousis-Harris said.

Source: https://edition.cnn.com/2017/07/10/health/gonorrhea-vaccine-study/index.html