Creating a mutation that inhibits how the bacterial pathogen works Neisseria gonorrhoeae Gonorrhea, a common sexually transmitted infection, is offering a new way to prevent and treat the disease, according to researchers at Georgia State University’s Institute of Biomedical Sciences.
The researchers found that generating a mutation in a key part of the outer carrier membrane N. gonorrhoeae Uses to hijack and demineralize human immune proteins can help prevent gonorrhea. The results have been published in the journal mBio.
Gonorrhea, which infects more than 80 million people worldwide each year, is a global public health threat due to the increasing incidence of antimicrobial resistance, rising treatment costs and the lack of a preventive vaccine. Up to 80 percent of cases are in women without symptoms, and if left untreated, gonorrhea can lead to serious health consequences, including pelvic inflammatory disease, ectopic pregnancy, infertility, and even life-threatening endocarditis and meningitis.
Effective treatment options for gonorrhea are decreasing due to the development of antimicrobial resistance to existing drugs. Also, it is difficult to determine appropriate vaccine targets because N. gonorrhoeae It alters the expression of key surface molecules and attenuates the immune response. To prevent invading pathogens from causing disease, humans rely on a process called nutritional immunity to limit the availability of important nutrients such as iron and zinc and starve invaders. Metal-binding proteins trap metals and limit the amount of free essential metal ions that pathogens need to thrive and cause disease.
To overcome the host’s nutritional immune efforts, N. gonorrhoeae TonB-dependent transporters (TdTs) diffuse to its outer membrane to bind to dietary immune proteins and demineralize them. TdTs often play key roles in determining infection, making them promising targets for vaccines.
One TdT named TdfJ recognizes human S100A7, a zinc-binding protein that inhibits the replication of pathogens by masking zinc. N. gonorrhoeae TdfJ is used to extract zinc from S100A7 and assimilate the metal. TdfJ contains an alpha-helical finger in the extracellular loop 3. A similar alpha-helix in loop 3 of another gonococcal TdT, known as TbpA, plays a critical role in the interaction between TbpA and human transransrin, which is essential for iron absorption. Based on this information, the researchers hypothesized that the TdfJ loop 3 (L3H) helix participates in interactions with S100A7, and generated a series of mutations in TdfJ L3H to determine whether they blocked capacity N. gonorrhoeae To get zinc and thus cause disease.
“The possibility of untreatable gonococcal infection has stimulated efforts to identify targets for novel therapeutic and preventive strategies, and members of the TonB outer membrane-dependent metal transporter family have emerged as promising candidates as they play a critical role in the infection,” he said. Dr. Cynthia Now Corneliusen, first author of the study, Distinguished University Professor and Director of the Center for Transformational Immunology at the Georgia State Institute of Biomedical Sciences. “Our study revealed that mutations in key residues within TdfJ L3H reduced S100A7 binding and zinc piracy by gonococci, with the most profound effects seen with substitutions at residues K261 and R262. Together, these data suggest a key role for TdfJ L3H in sabotaging host nutritional immunity.” .
The study characterized the binding interaction between the TdfJ zinc importer and the human zinc source S100A7, and also identified a key region of TdfJ that mediates this interaction.
“We have detailed, for the first time, the binding interaction of gonococcal TdfJ and the human ligand S100A7. We also identified several mutations in the TdfJ 3 loop that alter S100A7 binding and subsequent zinc extraction,” said Stavros A. Morakis, first author of the study. and Ph.D. Graduated from the Institute of Biomedical Sciences in Georgia. “By having a more comprehensive understanding of the complex relationships between these bacterial nutrient receptors and their host nutrient sources, we may help pave the way toward identifying effective prevention and/or treatment for an important human disease.”
Study co-authors include Stavros A. Morakis, Julie L. Stadenmayer and Cynthia Now Cornelissen of the Georgia State Institute of Biomedical Sciences. and Jeffrey K. Rimmer and Walter J. Chasin of Vanderbilt University.
The study is funded by the National Institutes of Health (NIH).