In the Shadow of Gonococcus: A Tale of Love and Admiration for the STI Field

Sexually transmitted diseases (STDs), previously known as venereal diseases, are as old as humanity. Do you call it STD or STI (sexually transmitted infection)1? Why not call it SSM (sexually shared microbiota)2? Regardless of what you call it, it is not every day you meet someone who admires STI and fell in love with the gonococcus (GC). The title of my reflection may not be surprising to those who know me well and are familiar with my passion and enthusiasm for the work I do. As a microbiologist, I have had the privilege of working with many clinically important bacteria and thought that my research would focus mostly on antimicrobial resistance (AMR) of bacteria causing community- and hospital-acquired infections. As serendipity would have it, I got involved in STI research while I was working on my doctoral research on multidrug-resistant Klebsiella pneumoniae isolated from urinary tract infections. Not everyone believes in love at first sight. When I first saw gonococcus in its fluorescent glory (Fig. 1), I had to get to know it better. My first project when I joined the University of Washington Neisseria Reference Laboratory in early 2000s was full of intrigue and beauty as I spent long hours making DNA agarose plugs, performing restriction enzyme digest, and running pulsed field gel electrophoresis to reveal the gorgeous gonococcus fingerprints of a cluster of isolates from an outbreak of fluoroquinolone resistance and gonorrhea treatment failure in Seattle.Figure 1: Immunofluorescence antibody staining of gonococcus, an endocervical Neisseria gonorrhoeae strain.Dare to love the gonococcus! It is insane, or is it? Neisseria gonorrhoeae is a strict human pathogen discovered by Albert Ludwig Sigesmund Neisser in 1879.3 I love the gonococcus because of its fascinating biology, pathogenesis including immune evasion, and importantly, its recalcitrant plasticity and remarkable resilient ability to sequentially develop resistance to all antimicrobials recommended for gonorrhea treatment. Since the 1940s, GC has serially developed resistance to changing first-line therapies, including sulfonamides, penicillins, tetracyclines, fluoroquinolones, and most recently extended-spectrum cephalosporins. Disturbingly, several countries have identified gonococci exhibiting high-level resistance to ceftriaxone, the last remaining highly effective treatment option for gonorrhea. The long-standing Gonococcal Isolate Surveillance Project was instrumental to the Centers for Disease Control and Prevention (CDC) recognizing GC as 1 of the 5 urgent antibiotic resistance threats in the United States in 2013 and 2019. I am thrilled by the progress in the US GC AMR surveillance, which was expanded in 2016 to build local capacity to perform timely and actionable antimicrobial susceptibility testing by the gradient strip method and established the Antibiotic Resistance Laboratory Network for surveillance of GC AMR through agar dilution antimicrobial susceptibility testing and whole genome sequencing.4 Data generated from the Gonococcal Isolate Surveillance Project/Antimicrobial Resistance Laboratory Network laboratories have been used to inform and guide revisions to the gonorrhea treatment guidelines. In 2022, CDC made a huge investment that involved more than 24 partners implementing collaborations in more than 42 countries to launch the Global Antibiotic Resistance Laboratory and Response Network including the expansion of the World Health Organization–CDC Enhanced Gonococcal Antimicrobial Surveillance Programme to resource-limited countries such as Zimbabwe, Malawi, and Côte d'Ivoire. Data from Enhanced Gonococcal Antimicrobial Surveillance Programme sites will improve our understanding of dissemination of GC AMR in geographically diverse areas where there is currently limited or no GC AMR data and inform national and international gonorrhea treatment guidelines. Although this is a commendable step in the right direction, there are still many countries that still rely on syndromic STI management and do not have the laboratory infrastructure for GC AMR surveillance. Although it is imperative to continue expanding and enhancing surveillance of GC AMR and gonorrhea treatment failures globally, our reliance on nucleic acid amplification tests for gonorrhea diagnosis, rather than isolation of GC by culture, will continue to make it impossible to conduct population-level surveillance of GC AMR until we can implement rigorous molecular AMR assays for detection of genetic determinants of GC AMR. Culture-independent genome sequencing of remnant nucleic acid amplification test specimens for molecular surveillance of GC AMR will significantly enhance the culture-based surveillance of GC AMR. Containment of ever more resistant, untreatable gonorrhea necessitates global cooperation in tracking national and international emergence of GC AMR and its transmission globally. As we look to the future, a holistic and comprehensive approach to combating GC AMR requires a better understanding of how GC AMR develops and is transmitted within the human microbiota. This is particularly important for pharyngeal gonorrhea, which often is asymptomatic, considered to be difficult to treat and associated with cephalosporin resistance. Moreover, drug levels in the oropharynx are often lower than at other sites of N. gonorrhoeae infection, and it is a reasonable hypothesis that the oropharynx often harbors diverse microbiota that facilitates horizontal genetic exchange of AMR determinants. Ongoing studies in my laboratory will contribute to our understanding of the dynamics of AMR among GC and the other bacteria that inhabit the human oropharynx. This knowledge will provide important insights into how AMR-GC develops, critically valuable information in developing strategies to contain the threat of AMR-GC and for development of novel antimicrobials. As we celebrate the 50th anniversary of our beloved and esteemed journal, I reflect on my admiration for the field of STI that I cherish so much. We owe a big shout-out to all the giants and leaders of STI who worked tirelessly to give STI the visibility and recognition it deserves. To the next generation of STI leaders, I salute your courage to keep moving the field of STI to greater heights. In STI, I have found not just mentors but friends, champions, and “sponsors” who want the best for the field and everyone working in it. I owe a great deal of admiration to the field of STI that supported me and continue to nurture my career development. Only in this amazing field of STI do I feel at home and feel connected to STI colleagues all over the world. To my beloved STD journal, I remember the nervous anticipation of submitting my first article for consideration,5 I now regularly coauthor articles in STD6,7 and feel honored to be on the journal's Editorial Board. As I reflect on my admiration for the STI field, I must convey my heartfelt appreciation to the American Sexually Transmitted Diseases Association (ASTDA) that has played a significant role in my scientific leadership development through participation in the Annual ASTDA Workshop8 and serving on the ASTDA Board of Directors. Reflecting on the impactful value that our field of STI brings to the world, I must acknowledge everyone working on STIs for all your amazing studies that have significantly contributed to advancing our understanding of the diagnosis, epidemiology, pathogenesis, treatment, surveillance, control, and prevention of STIs in the United States and globally. Looking at an STI through the magnifying lens of a microbiologist, STI pathogens, especially the gonococcus, have always held a special place in my heart, and I am grateful to have trained and continue to work as a faculty at the University of Washington. In closing, I am indebted to the field of STI and to my favorite bug, gonococcus. I am grateful to have had the serendipitous opportunity to join the University of Washington Neisseria Reference Laboratory over 2 decades ago, and I have since then loved working with GC and I look forward to more years of productive GC research till retirement do us part.