According to the findings of researchers working in the Institute for Biomedical Sciences at Georgia State University, generating a mutation that inhibits the process by which the bacterial pathogen Neisseria gonorrhoeae causes gonorrhea, a common sexually transmitted infection, could offer a new way to prevent and treat the disease. Gonorrhea is a common sexually transmitted infection.
The researchers came to the conclusion that it might be possible to reduce the risk of contracting gonorrhea by introducing a mutation into an essential component of the outer membrane transporter that N. gonorrhoeae uses to hijack human immunity proteins and strip them of metals. These results were recently published in the peer-reviewed journal mBio.
Gonorrhea, which affects more than 80 million people around the world every year, is a global threat to public health as a result of the growing incidence of antimicrobial drug resistance, rising treatment costs, and the absence of a protective vaccine. Gonorrhea can lead to serious health consequences if it is not treated, including pelvic inflammatory disease, ectopic pregnancy, infertility, and even life-threatening endocarditis and meningitis. Up to 80 percent of cases in women are asymptomatic. Gonorrhea can be spread from person to person through sexual contact.
The development of antimicrobial resistance to currently available drugs is making it increasingly difficult to find effective treatments for gonorrhea. Because N. gonorrhoeae alters the expression of important surface molecules and dampens the immune response, it is difficult to identify suitable vaccine targets. This is another challenge. In order to prevent invading pathogens from causing disease, human beings rely on a process known as nutritional immunity. This process reduces the availability of essential nutrients like iron and zinc, thereby starving the invading pathogens. Metal-binding proteins are responsible for the sequestration of metals and a reduction in the amount of free essential metal ions that are available for pathogens to thrive and spread disease.
In order to get around the host’s nutritional immunity mechanisms, N. gonorrhoeae inserts TonB-dependent transporters (TdTs) into its outer membrane. These transporters bind to the host’s nutritional immunity proteins and remove the metals they contain from those proteins. TdTs frequently play critical roles in the establishment of infections, which makes them promising targets for vaccines.
One of the TdTs, known as TdfJ, is able to recognize human S100A7, which is a zinc-binding protein that prevents the replication of pathogens by concealing zinc. TdfJ is utilized by N. gonorrhoeae in order to acquire zinc from S100A7 and incorporate it into its own structure. In extracellular loop 3 of the TdfJ protein, there is an alpha-helix finger. The interaction between gonococcal TbpA and human transferrin, which is necessary for the uptake of iron, is mediated by a similar alpha-helix found in loop 3 of another gonococcal TdT known as TbpA. This alpha-helix plays a crucial role in the interaction. In light of this information, the researchers formed a hypothesis that the TdfJ loop 3 helix (L3H) takes part in interactions with S100A7. They then generated a series of mutations in the TdfJ L3H in order to test whether or not these mutations prevented N. gonorrhoeae from acquiring zinc and, as a result, from causing disease.
“The prospect of untreatable gonococcal infections has spurred efforts to identify targets for novel therapeutic and prevention strategies,” said Dr. Cynthia Nau Cornelissen, senior author of the study, Distinguished University Professor, and director of the Center for Translational Immunology in the Department of Microbiology and Immunology at the University of Washington. “Members of the family of outer membrane TonB-dependent metal transporters have emerged as promising candidates because they play a critical role in establishing infection,” Cornelissen “According to the findings of our research, mutagenesis of key residues within the TdfJ L3H reduced S100A7 binding and zinc piracy by the gonococcus. The most profound effects were observed with substitutions at residues K261 and R262. When taken together, these findings point to the TdfJ L3H playing an important part in the process of evading the host’s nutritional immunity.”
In the study, the binding interaction between the zinc importer TdfJ and its human zinc source, S100A7, was characterized. Additionally, a key region of TdfJ that mediates this interaction was found in the protein.
“The binding interaction between gonococcal TdfJ and its human ligand S100A7 was described in detail for the first time by our research. In addition, we found a number of mutations in TdfJ loop 3 that change the way S100A7 binds to proteins and, as a result, zinc extraction “a statement made by Stavros A. Maurakis, who is the study’s primary author and who received his Ph.D. from Georgia State University’s Institute for Biomedical Sciences. “We may be able to help pave the way toward identifying effective prophylaxis and/or treatment for an important human disease with a more in-depth understanding of the intricate relationships between these bacterial nutrient receptors and their host nutrient sources,”
Stavros A. Maurakis, Julie L. Stoudenmire, and Cynthia Nau Cornelissen from Georgia State University’s Institute for Biomedical Sciences contributed to the study as co-authors. Jeffrey K. Rymer and Walter J. Chazin from Vanderbilt University also contributed to the study as co-authors.
The National Institutes of Health are the ones providing funding for this study (NIH).
