Neisseria gonorrhoeae

{{Short description|Species of bacterium}} {{Use dmy dates|date=February 2020}} {{cs1 config|name-list-style=vanc|display-authors=6}} {{Speciesbox | image = Gonococcal urethritis PHIL 4085 lores.jpg | image_alt = Gram-stain of gonococcal urethritis. Note distribution in neutrophils and presence of both intracellular and extracellular bacteria. (CDC) | image_caption = Gram-stain of gonococcal urethritis. Note distribution in neutrophils and presence of both intracellular and extracellular bacteria. (CDC) | genus = Neisseria | species = gonorrhoeae | authority = (Zopf 1885) Trevisan 1885<ref>{{cite web | title = Genus ''Neisseria'' | work = List of Prokaryotic Names with Standing in Nomenclature (LPSN) | vauthors = Euzéby JP, Parte AC | url = https://lpsn.dsmz.de/genus/neisseria | access-date = 7 July 2017 }}</ref> | synonyms = * ''Micrococcus'' der Gonorrhoe Neisser 1879<ref>{{cite journal | vauthors = Neisser A |title=Ueber eine der Gonorrhoe eigentümliche Micrococusform |trans-title=About a micrococus form peculiar to gonorrhea |language=de |journal=Centralblatt für die medizinischen Wissenschaften |volume=17 |issue=28 |year=1879 |pages=497–500 |url=https://archive.org/stream/centralblattfrd25unkngoog#page/n503/mode/1up }}</ref> * ''Gonococcus neisseri'' Lindau 1898 | synonyms_ref = }}

'''''Neisseria gonorrhoeae''''', also known as '''''gonococcus''''' (singular) or '''''gonococci''''' (plural), is a species of Gram-negative diplococci bacteria first isolated by Albert Neisser in 1879.<ref name="O'Donnell_2009">{{Cite book | chapter = Bacterial Cause of PID: Gonorrhoeae | chapter-url=https://books.google.com/books?id=JNlRYSC9gScC&q=Galen+coined+the+term+gonorrhea&pg=PA43|title=Pelvic Inflammatory Disease| vauthors = O'Donnell JA, Gelone SP |date=2009|publisher=Infobase Publishing|isbn=978-1-4381-0159-0 |language=en}}</ref> An obligate human pathogen, it primarily colonizes the mucosal lining of the urogenital tract; however, it is also capable of adhering to the mucosa of the nose,<ref name="pmid37558089">{{cite journal |vauthors=Inaba S, Aizawa Y, Kataoka S, Saitoh A |title=Purulent nasal discharge due to gonococcal nasopharyngitis in a neonate |journal=Journal of Infection and Chemotherapy |volume=29 |issue=12 |pages=1164–1166 |date=December 2023 |pmid=37558089 |doi=10.1016/j.jiac.2023.08.005|doi-access=free }}</ref> pharynx, rectum, and conjunctiva.<ref name="pmid37711920">{{cite journal |vauthors=Mahapure K, Singh A |title=A Review of Recent Advances in Our Understanding of Neisseria gonorrhoeae |journal=Cureus |volume=15 |issue=8 |article-number=e43464 |date=August 2023 |pmid=37711920 |pmc=10498933 |doi=10.7759/cureus.43464 |doi-access=free |url=}}</ref> It causes the sexually transmitted genitourinary infection gonorrhea<ref name=Sherris>{{cite book | veditors = Ryan KJ, Ray CG |title=Sherris Medical Microbiology | edition = 4th | publisher = McGraw Hill | year = 2004 | isbn = 978-0-8385-8529-0 |url=https://books.google.com/books?id=RRRrAAAAMAAJ }}{{page needed|date=February 2015}}</ref> as well as other forms of gonococcal disease including disseminated gonococcemia, septic arthritis, and gonococcal ophthalmia neonatorum.

''N. gonorrhoeae'' is oxidase positive and a microaerophile that is capable of surviving phagocytosis and growing inside neutrophils.<ref name="Sherris" /> Culturing it requires carbon dioxide supplementation and enriched agar (chocolate agar) with various antibiotics (Thayer–Martin). It exhibits antigenic variation through genetic recombination of its pili and surface proteins that interact with the immune system.<ref name="O'Donnell_2009" />

Sexual transmission is through vaginal, anal, or oral sex.<ref name="www.cdc.gov_2017"/> Sexual transmission may be prevented through the use of barrier protection.<ref name="CDC" /> Perinatal transmission may occur during childbirth, though it is preventable through antibiotic treatment of the mother before birth and application of antibiotic eye gel on the eyes of the newborn.<ref name="CDC" /> Gonococcal infections do not result in protective immunity; therefore, individuals may be infected multiple times. Reinfection is possible due to ''N. gonorrhoeae's'' ability to evade the immune system by varying its surface proteins.<ref name="Hill_2016"/>

Asymptomatic infection is common in both males and females.<ref name="CDC" /><ref>{{Cite web|url=https://www.uspreventiveservicestaskforce.org/Page/Document/RecommendationStatementFinal/chlamydia-and-gonorrhea-screening|title=Final Recommendation Statement: Chlamydia and Gonorrhea: Screening | work = U.S. Preventive Services Task Force |language=en|access-date=2017-12-07}}</ref> Untreated infection may spread to the rest of the body (disseminated gonorrhea infection), especially the joints (septic arthritis). Untreated infection in women may cause pelvic inflammatory disease and possible infertility due to the resulting scarring.<ref name="Lev13th2" /> Gonorrhoea is diagnosed through cultures, Gram staining, or nucleic acid tests (i.e. polymerase chain reaction) of urine samples, urethral swabs, or cervical swabs.<ref name="Ng_2005">{{cite journal | vauthors = Ng LK, Martin IE | title = The laboratory diagnosis of Neisseria gonorrhoeae | journal = The Canadian Journal of Infectious Diseases & Medical Microbiology | volume = 16 | issue = 1 | pages = 15–25 | date = January 2005 | pmid = 18159523 | pmc = 2095009 | doi = 10.1155/2005/323082 | doi-access = free }}</ref><ref name="Gonococcal Infections_2018">{{Cite web | url=https://www.cdc.gov/std/tg2015/gonorrhea.htm | title=Gonococcal Infections - 2015 STD Treatment Guidelines| date=2018-01-04}}</ref> Chlamydia co-testing and testing for other STIs is recommended due to high rates of co-infection.<ref name="Humana Press_2012">{{Cite book|title=Diagnosis of sexually transmitted diseases: methods and protocols| veditors = MacKenzie CR, Henrich B |date=2012|publisher=Humana Press|isbn=978-1-61779-936-5 |oclc=781681739}}</ref>

Antibiotic resistance in ''N. gonorrhoeae'' is a growing public health concern, especially given its propensity to develop resistance easily.<ref name="Quillin_2018">{{cite journal |vauthors=Quillin SJ, Seifert HS |date=April 2018 |title=Neisseria gonorrhoeae host adaptation and pathogenesis |journal=Nature Reviews. Microbiology |volume=16 |issue=4 |pages=226–240 |doi=10.1038/nrmicro.2017.169 |pmc=6329377 |pmid=29430011}}</ref> This ability of ''N. gonorrhoeae'' to rapidly adapt to novel antimicrobial treatments has been seen several times since the 1930s, making numerous treatment plans obsolete. Some strains have exhibited resistance to the current ceftriaxone treatments.<ref>{{cite journal | vauthors = Costa-Lourenço AP, Barros Dos Santos KT, Moreira BM, Fracalanzza SE, Bonelli RR | title = Antimicrobial resistance in Neisseria gonorrhoeae: history, molecular mechanisms and epidemiological aspects of an emerging global threat | journal = Brazilian Journal of Microbiology | volume = 48 | issue = 4 | pages = 617–628 | date = 2017-10-01 | pmid = 28754299 | pmc = 5628311 | doi = 10.1016/j.bjm.2017.06.001 }}</ref>

== Microbiology == thumb|A Gram stain of a urethral exudate showing typical intracellular Gram-negative diplococci, which is diagnostic for gonococcal urethritis<ref name="pmid33929174">{{cite journal |vauthors=Sell J, Nasir M, Courchesne C |title=Urethritis: Rapid Evidence Review |journal=American Family Physician |volume=103 |issue=9 |pages=553–558 |date=May 2021 |pmid=33929174 |doi= |url=}}</ref> ''Neisseria'' species are fastidious, Gram-negative cocci (though some species are rod-shaped and occur in pairs or short chains) that require nutrient supplementation to grow in laboratory cultures.<ref>{{cite book |doi=10.1016/b978-0-323-04579-7.00168-4 |chapter=Neisseria |title=Infectious Diseases |date=2010 |pages=1676–1689 |isbn=978-0-323-04579-7 | vauthors = Van Putten J, Tønjum T }}</ref> They are facultative intracellular pathogens, meaning they can persist and colonize within host cells but can also multiply outside the host cellular environment.<ref name="Green_2022" /><ref>{{cite journal | vauthors = Silva MT | title = Classical labeling of bacterial pathogens according to their lifestyle in the host: inconsistencies and alternatives | journal = Frontiers in Microbiology | volume = 3 | page = 71 | date = 2012 | pmid = 22393329 | pmc = 3289908 | doi = 10.3389/fmicb.2012.00071 | doi-access = free }}</ref><ref name="Yeshanew_2018">{{cite journal | vauthors = Yeshanew AG, Geremew RA | title = Neisseria Gonorrhoae and their antimicrobial susceptibility patterns among symptomatic patients from Gondar town, north West Ethiopia | journal = Antimicrobial Resistance and Infection Control | volume = 7 | issue = 1 | article-number = 85 | date = 2018-07-17 | pmid = 30026943 | pmc = 6050735 | doi = 10.1186/s13756-018-0376-3 | doi-access = free }}</ref> They typically appear in pairs (diplococci), resembling the shape of coffee beans.<ref name="Yeshanew_2018" /> Members of this genus do not form endospores and are nonmotile, except for pathogenic species, which are capable of moving using twitching motility;<ref>{{cite book |doi=10.1016/B978-0-7020-6285-8.00179-9 |quote=Endospores and exotoxins are not found and flagella are absent. Some Neisseria spp., including N. gonorrhoeae and N. meningitidis, may show surface-bound twitching motility due to pilus retraction. |chapter=Neisseria |title=Infectious Diseases |date=2017 |pages=1553–1564.e1 |isbn=978-0-7020-6285-8 | vauthors = Tønjum T, Van Putten J }}</ref> most are also obligate aerobes.<ref>{{cite book |doi=10.1016/b978-012304220-0/50013-3 |chapter=Neisseria |title=Principles of Bacterial Pathogenesis |date=2001 |pages=559–618 |isbn=978-0-12-304220-0 | vauthors = Gray-Owen SD, Dehio C, Rudel T, Naumann M, Meyer TF }}</ref><ref>{{cite journal | vauthors = Eriksson J, Eriksson OS, Maudsdotter L, Palm O, Engman J, Sarkissian T, Aro H, Wallin M, Jonsson AB | title = Characterization of motility and piliation in pathogenic Neisseria | journal = BMC Microbiology | volume = 15 | issue = 1 | article-number = 92 | date = April 2015 | pmid = 25925502 | pmc = 4449605 | doi = 10.1186/s12866-015-0424-6 | doi-access = free }}</ref> Of the 17 species that colonize humans, only two are pathogenic: ''N. gonorrhoeae,'' which causes gonorrhea, and ''N. meningitidis'', a leading cause of bacterial meningitis.<ref name="pmid32534649">{{cite journal | vauthors = Ladhani SN, Lucidarme J, Parikh SR, Campbell H, Borrow R, Ramsay ME | title = Meningococcal disease and sexual transmission: urogenital and anorectal infections and invasive disease due to Neisseria meningitidis | journal = Lancet | volume = 395 | issue = 10240 | pages = 1865–1877 | date = June 2020 | pmid = 32534649 | doi = 10.1016/S0140-6736(20)30913-2 | s2cid = 219701418 }}</ref><ref>{{Cite book |title=Principles of bacterial pathogenesis |date=2001 |publisher=Academic Press |isbn=978-0-12-304220-0 | veditors = Groisman EA |location=San Diego, Calif}}</ref>

=== Culture and identification === [[File:GC Culture.jpg|thumb|alt=Colonies of Neisseria gonorrhoeae on agar bacterial culture plates|Thayer–Martin agar is selective for growth of ''Neisseria'' species. Further testing (oxidase, carbohydrate use, and PCR) can be used to differentiate ''N. gonorrhoeae'' from ''N. meningitidis.q'']] ''N. gonorrhoeae'' can be isolated on Thayer–Martin agar (or VPN) agar in an atmosphere enriched with 3-7% carbon dioxide.<ref name="Ng_2005" /> Thayer–Martin agar is a chocolate agar plate (heated blood agar) containing nutrients and antimicrobials (vancomycin, colistin, nystatin, and trimethoprim). This agar preparation facilitates the growth of ''Neisseria'' species while inhibiting the growth of contaminating bacteria and fungi. Martin Lewis and New York City agar are other types of selective chocolate agar commonly used for ''Neisseria'' growth.<ref name="Ng_2005" /> ''N. gonorrhoeae'' is oxidase positive (possessing cytochrome c oxidase) and catalase positive (able to convert hydrogen peroxide to oxygen).<ref name="Ng_2005" /> When incubated with the carbohydrates lactose, maltose, sucrose, and glucose, ''N. gonorrhoeae'' will oxidize only the glucose.<ref name="Ng_2005" />

== Metabolism ==

=== Carbon === Unlike other ''Neisseria'' species that can also metabolize maltose, ''N. gonorrhoeae'' is capable of using only glucose, pyruvate, and lactate as central carbon sources, and glucose is catabolized via both the Entner-Doudoroff (ED) and pentose phosphate (PP) pathways, and the ED pathway is the primary oxidative method.<ref name="Green_2022" /><ref name="Morse_1980">{{cite book | vauthors = Morse SA, Cacciapuoti AF, Lysko PG | title = Advances in Microbial Physiology Volume 20 | chapter = Physiology of Neisseria gonorrhoeae | volume = 20 | pages = 251–320 | date = 1980-01-01 | pmid = 43667 | doi = 10.1016/s0065-2911(08)60209-x | publisher = Academic Press | isbn = 978-0-12-027720-9 | veditors = Rose AH, Morris JG }}</ref> Use of these pathways is necessary as ''N. gonorrhoeae'' is incapable of glucose catabolism via the Embden-Meyerhof-Parnas (EMP) pathway due its lack of the phosphofructokinase (PFK) gene; however, the fructose 1,6-bisphosphatase enzyme is present to allow for gluconeogenesis to occur.<ref name="Green_2022" />

Glucose is first metabolized through the ED pathway to produce pyruvate and glyceraldehyde 3-phosphate, the latter of which can then further metabolized by enzymes of the EMP pathway to yield another molecule of pyruvate.<ref name="Morse_1974">{{cite journal | vauthors = Morse SA, Stein S, Hines J | title = Glucose metabolism in Neisseria gonorrhoeae | journal = Journal of Bacteriology | volume = 120 | issue = 2 | pages = 702–714 | date = November 1974 | pmid = 4156358 | pmc = 245830 | doi = 10.1128/jb.120.2.702-714.1974 }}</ref> The resultant pyruvate molecules are then converted into acetyl-CoA, which can then be incorporated as a substrate for the citric acid cycle (CAC) to yield high-energy electron carriers that will be used by the electron transport chain (ETC) for ATP production; however, the CAC is largely used for generating biosynthetic precursors rather than for catabolic purposes.<ref name="Green_2022" /><ref name="Hebeler_1976">{{cite journal | vauthors = Hebeler BH, Morse SA | title = Physiology and metabolism of pathogenic neisseria: tricarboxylic acid cycle activity in Neisseria gonorrhoeae | journal = Journal of Bacteriology | volume = 128 | issue = 1 | pages = 192–201 | date = October 1976 | pmid = 824268 | pmc = 232843 | doi = 10.1128/jb.128.1.192-201.1976 }}</ref> This is due in part to inhibited expression of several CAC enzymes in the presence of glucose, pyruvate, or lactate. These enzymes, namely citrate synthase, aconitase, and isocitrate dehydrogenase, are needed for the incorporation of acetate. Instead, a partial CAC has been observed, where α-ketoglutarate is formed by glutamate dehydrogenase or transamination of oxaloacetate and glutamate by aspartate aminotransferase (yielding aspartate and α-ketoglutarate).<ref name="Morse_1980" /><ref name="Hebeler_1976" /> The CAC then continues from there to yield oxaloacetate, which is an important precursor molecule for several biosynthetic pathways.<ref name="Hebeler_1976" /> Another differentiating aspect of the gonococcal CAC is the lack of malate dehydrogenase, which is instead replaced by a membrane-bound malate:quinone-oxidoreductase that operates independently of NAD+ by directly transferring electrons to ubiquinone.<ref name="Green_2022" />

Conversely, acetyl-CoA that does not enter the CAC but enters the phosphotransacetylase-acetate kinase (PTA-AckA) pathway, where it can be converted into acetate by phosphorylation (to form acetyl phosphate and release coenzyme A) and dephosphorylation to form ATP.<ref>{{cite journal | vauthors = Ingram-Smith C, Martin SR, Smith KS | title = Acetate kinase: not just a bacterial enzyme | journal = Trends in Microbiology | volume = 14 | issue = 6 | pages = 249–253 | date = June 2006 | pmid = 16678422 | doi = 10.1016/j.tim.2006.04.001 }}</ref> While this acetate can enter the CAC for further oxidation, this does not occur so long as other carbon sources such as glucose or lactate are present, in which case it is excreted from the cell or incorporated for lipid synthesis.<ref name="Morse_1974" /><ref>{{cite journal | vauthors = Leighton MP, Kelly DJ, Williamson MP, Shaw JG | title = An NMR and enzyme study of the carbon metabolism of Neisseria meningitidis | journal = Microbiology | volume = 147 | issue = Pt 6 | pages = 1473–1482 | date = June 2001 | pmid = 11390678 | doi = 10.1099/00221287-147-6-1473 | doi-access = free }}</ref> ''N. gonorrhoeae'' lack the glyoxylate shunt, preventing them from using acetate to form CAC intermediates to replenish the cycle.<ref name="Morse_1974" /><ref name="Morse_1980" />

A significant portion of the glyceraldehyde 3-phosphate formed in gonococci is recycled via the gluconeogenic pathway to reform glucose 6-phosphate, as well as the intermediate fructose 6-phosphate. Both of these can then be used for pentose synthesis in the PP pathway via the oxidative and non-oxidative pathways, respectively, for subsequent nucleotide formation as well as energy production.<ref name="Morse_1980" />

''N. gonorrhoeae'', like other pathogenic members of the genus ''Neisseria'', are capnophiles, meaning they require higher-than-normal concentrations of carbon dioxide (CO2) to grow, either in the form of CO2 or bicarbonate (HCO3−) depending on the bacterial strain. This requirement must be met exogenously during the lag and stationary growth phases, though it appears to be met through high metabolic CO2 productions in the exponential phase. Assimilation of this CO2 in ''Neisseria'' species is done by carbonic anhydrase and phosphoenolpyruvate enzymes in the periplasmic space and the cytoplasm, respectively.<ref name="Morse_1980" />

Lactate catabolism is also of particular importance for gonococci, both for pathogenicity and for growth.<ref name="Green_2022" /> External lactate is transported in to the cell via lactate permease (LctP).<ref name="Green_2022" /> The ''N. gonorrhoeae'' genome encodes for three lactate dehydrogenase (LDH) enzymes for that allow for metabolism of both ''L''-lactate and ''D''-lactate: a cytoplasmic NAD+-dependent ''D''-lactate dehydrogenase (LdhA), which is responsible for and two membrane-bound LDHs, one specific to ''L''-lactate (LldD) and the other specific to ''D''-lactate (LdhD).<ref name="Green_2022" /><ref name="Atack_2014">{{cite journal | vauthors = Atack JM, Ibranovic I, Ong CL, Djoko KY, Chen NH, Vanden Hoven R, Jennings MP, Edwards JL, McEwan AG | title = A role for lactate dehydrogenases in the survival of Neisseria gonorrhoeae in human polymorphonuclear leukocytes and cervical epithelial cells | journal = The Journal of Infectious Diseases | volume = 210 | issue = 8 | pages = 1311–1318 | date = October 2014 | pmid = 24737798 | pmc = 4215069 | doi = 10.1093/infdis/jiu230 }}</ref> The membrane-bound LDHs have been determined to be flavoprotein-containing respiratory enzymes that directly oxidize lactate to reduce ubiquinone. While these enzymes do not directly pump protons (H+ ions) into the periplasmic space, it is proposed that the reduction of ubiquinone by these enzymes is capable of feeding into the larger ETC.<ref name="Atack_2014" />

=== Electron transport chain and oxidative phosphorylation === As an obligate human pathogen and a facultative anaerobic capnophile, ''Neisseria gonorrhoeae'' typically colonizes mucosal surfaces in microaerobic environments, such as those in the genitourinary tract.<ref name="Green_2022" /> Growth in areas where oxygen concentrations are limited requires a terminal oxidase with a high affinity for oxygen; in gonococci, oxygen reduction is performed by a ''ccb3'' -type cytochrome oxidase. In addition to aerobic respiration, gonococci can also perform anaerobic respiration via the reduction of nitrite (NO2) to nitric oxide (NO) as well as reduction of NO to nitrous oxide (N2O).<ref name="Green_2022" /><ref name="Li_2010">{{cite journal | vauthors = Li Y, Hopper A, Overton T, Squire DJ, Cole J, Tovell N | title = Organization of the electron transfer chain to oxygen in the obligate human pathogen Neisseria gonorrhoeae: roles for cytochromes c4 and c5, but not cytochrome c2, in oxygen reduction | journal = Journal of Bacteriology | volume = 192 | issue = 9 | pages = 2395–2406 | date = May 2010 | pmid = 20154126 | pmc = 2863483 | doi = 10.1128/JB.00002-10 }}</ref>

Several enzymes contribute electrons to the intramembranous ubiquinone pool, the first step in the ETC. These include the membrane-bound LDHs (LldD and LdhD), NADH:ubiquinone oxidoreductase (aka NADH dehydrogenase; Nuo complex I), Na+-translocating NADH dehydrogenase (Nqr), succinate dehydrogenase (SDH), and the membrane-bound NAD+-independent malate:quinone-oxidoreductase (MqR).<ref name="Green_2022" />

Following the initial transfer of electrons to ubiquinone, proposed schematics for the organization of the gonococcal ETC suggest the electrons can be further passed down the chain by reduction of the cytochrome ''bc1'' complex or can be directly transferred to NO as a terminal electron acceptor by NO reductase (NorB).<ref name="Green_2022" /><ref name="Aspholm_2010">{{cite journal | vauthors = Aspholm M, Aas FE, Harrison OB, Quinn D, Vik A, Viburiene R, Tønjum T, Moir J, Maiden MC, Koomey M | title = Structural alterations in a component of cytochrome c oxidase and molecular evolution of pathogenic Neisseria in humans | journal = PLOS Pathogens | volume = 6 | issue = 8 | article-number = e1001055 | date = August 2010 | pmid = 20808844 | pmc = 2924362 | doi = 10.1371/journal.ppat.1001055 | doi-access = free }}</ref> In the case of the former, electrons can then be passed from the ''bc1'' complex along two alternative pathways via the reduction of either cytochrome ''c4'' or ''c5''. Both of these cytochromes transfer electrons to the terminal cytochrome ''ccb3'' oxidase for the reduction of O2 to form H2O under aerobic conditions.<ref name="Green_2022" /><ref name="Li_2010" />

Gonococci also reduce NO2 via an inducible outer membrane-attached copper-containing nitrite reductase (AniA, a member of the NirK protein family) under anaerobic conditions, though this process has also been noted in microaerobic conditions as a means of supplementing growth.<ref name="Aspholm_2010" /> This leads to the formation of NO that is subsequently reduced to N2O in a partial denitrification pathway.<ref name="Green_2022" /><ref name="Li_2010" /><ref name="Aspholm_2010" /> The ''ccb3'' oxidase of ''N. gonorrhoeae'', dissimilarly to other members of the ''Neisseria'' genus, is a tri-heme protein that can transfer electrons not only to O2 (conserved across ''Neisseria'' species) but also to AniA for NO2 reduction. This is in addition to the typical process of receiving electrons transferred from cytochrome ''c5''.<ref name="Aspholm_2010" /><ref>{{cite journal |last1=Hopper |first1=Amanda |last2=Tovell |first2=Nicholas |last3=Cole |first3=Jeffrey |title=A physiologically significant role in nitrite reduction of the CcoP subunit of the cytochrome oxidase cbb 3 from Neisseria gonorrhoeae |journal=FEMS Microbiology Letters |date=December 2009 |volume=301 |issue=2 |pages=232–240 |doi=10.1111/j.1574-6968.2009.01824.x |pmid=19889029 }}</ref>

The general purpose of the ETC is the formation of the electrochemical gradient of hydrogen ions (H+ or protons), resulting from concentration differences across the plasma membrane, needed to power ATP production in a process known as oxidative phosphorylation.<ref name="Bacterial electron transport chains">{{cite journal | vauthors = Anraku Y | title = Bacterial electron transport chains | journal = Annual Review of Biochemistry | volume = 57 | issue = 1 | pages = 101–132 | date = June 1988 | pmid = 3052268 | doi = 10.1146/annurev.bi.57.070188.000533 }}</ref> In gonococci, movement of protons into the periplasmic space is accomplished by the Nuo complex I, the cytochrome ''bc1'' complex, and cytochrome ''ccb3''.<ref name="Green_2022" /><ref name="Aspholm_2010" /><ref name="Cytochrome bc1 complexes of microor">{{cite journal | vauthors = Trumpower BL | title = Cytochrome bc1 complexes of microorganisms | journal = Microbiological Reviews | volume = 54 | issue = 2 | pages = 101–129 | date = June 1990 | pmid = 2163487 | pmc = 372766 | doi = 10.1128/mr.54.2.101-129.1990 }}</ref> Subsequently, ATP synthesis is performed by the F1F0 ATP synthase, a two-part protein complex present in gonococci as well as numerous other species across phylogenetic domains.<ref name="UniProt">{{Cite web |title=UniProt |url=https://www.uniprot.org/uniprotkb/Q5F4Z4/entry |access-date=2024-11-18 |website=www.uniprot.org}}</ref> This complex couples proton translocation back into the cytoplasm along its gradient with mechanical rotation to generate ATP.<ref name="Mechanism of the F1F0-type ATP">{{cite journal | vauthors = Capaldi RA, Aggeler R | title = Mechanism of the F(1)F(0)-type ATP synthase, a biological rotary motor | journal = Trends in Biochemical Sciences | volume = 27 | issue = 3 | pages = 154–160 | date = March 2002 | pmid = 11893513 | doi = 10.1016/s0968-0004(01)02051-5 }}</ref>

=== Iron === The general purpose of the ETC is the formation of the electrochemical gradient of hydrogen ions (H+ or protons), resulting from concentration differences across the plasma membrane, needed to power ATP production in a process known as oxidative phosphorylation.<ref name="Bacterial electron transport chains"/> In gonococci, movement of protons into the periplasmic space is accomplished by the Nuo complex I, the cytochrome ''bc1'' complex, and cytochrome ''ccb3''.<ref name="Green_2022" /><ref name="Aspholm_2010" /><ref name="Cytochrome bc1 complexes of microor"/> Subsequently, ATP synthesis is performed by the F1F0 ATP synthase, a two-part protein complex present in gonococci as well as numerous other species across phylogenetic domains.<ref name="UniProt"/> This complex couples proton translocation back into the cytoplasm along its gradient with mechanical rotation to generate ATP.<ref name="Mechanism of the F1F0-type ATP"/>

To acquire the necessary iron, gonococci produce TonB-dependent transporters (TDTs) on the surface of their outer membrane that can directly extract iron, along with other metals, from their respective carrier proteins. Some of these include transferrin binding proteins A (TbpA) and B (TbpB), lactoferrin-binding proteins A (LbpA) and B (LbpB), and hemoglobin/hemoglobin-haptoglobin binding proteins HpuB and HpuA.<ref name="Green_2022" /><ref name="Stoudenmire_2022" /> In addition to these proteins, gonococci are also capable of using siderophores, or compounds that are capable of chelating iron in the environment, that are produced by other bacteria; however, gonococcal cells are incapable of synthesizing siderophores themselves. These xenosiderophores are taken up by the TDT FetA through the outer membrane and then brought into the cell by the ''fetBCDEF'' transporter system.<ref name="Green_2022" /><ref name="Stoudenmire_2022">{{cite journal | vauthors = Stoudenmire JL, Greenawalt AN, Cornelissen CN | title = Stealthy microbes: How ''Neisseria gonorrhoeae'' hijacks bulwarked iron during infection | journal = Frontiers in Cellular and Infection Microbiology | volume = 12 | article-number = 1017348 | date = 2022-09-15 | pmid = 36189345 | pmc = 9519893 | doi = 10.3389/fcimb.2022.1017348 | doi-access = free }}</ref>

Along with the sequestration defence that can be further upregulated by host inflammation, humans also produce siderocalins that can chelate siderophores as a further method of inhibiting pathogenic bacterial growth. These are sometimes ineffective against ''N. gonorrhoeae'', which can colonize intracellularly, particularly in phagocytic cells such as macrophages and neutrophils. Increases in host intracellular iron also downregulate some of the intracellular pathogen-killing mechanisms; coincidentally, pathogenic ''Neisseria'' can alter several host cell mechanisms that ultimately allow the pathogen to take most of the available iron from the host immune cell.<ref name="Stoudenmire_2022" />

=== Surface molecules === On its surface, ''N. gonorrhoeae'' bears hair-like pili, surface proteins with various functions, and sugars called lipooligosaccharide. The pili mediate adherence, movement, and DNA exchange. The opacity-associated (Opa) proteins interact with the immune system, as do the porins. Lipooligosaccharide is an endotoxin that provokes an immune response. All of these are antigenic and exhibit antigenic variation. The pili, Opa proteins, porins, and even the lipooligosaccharide have mechanisms to inhibit the immune response, making asymptomatic infection possible.<ref name="Edwards_2004">{{cite journal | vauthors = Edwards JL, Apicella MA | title = The molecular mechanisms used by Neisseria gonorrhoeae to initiate infection differ between men and women | journal = Clinical Microbiology Reviews | volume = 17 | issue = 4 | pages = 965–81, table of contents | date = October 2004 | pmid = 15489357 | pmc = 523569 | doi = 10.1128/CMR.17.4.965-981.2004 }}</ref>

==== Opa proteins ==== Phase-variable opacity-associated (Opa) adhesin proteins are used by ''N. gonorrhoeae'' as part of evading the immune response in a host cell. At least 12 Opa proteins are known, and the many variations of surface proteins make recognizing ''N. gonorrhoeae'' and mounting a defense by immune cells more difficult.<ref>{{cite web | title = STI Awareness: Gonorrhea | publisher = Planned Parenthood Advocates of Arizona | url = http://blog.advocatesaz.org/2011/04/11/sti-awareness-gonorrhea/ | archive-url = https://web.archive.org/web/20121103212554/http://blog.advocatesaz.org/2011/04/11/sti-awareness-gonorrhea/ | archive-date = 3 November 2012 | date = 11 April 2011 | access-date = 31 August 2011 }}</ref> Opa proteins are in the outer membrane and facilitate a response when the bacteria interacts with a variety of host cells. These proteins bind to various epithelial cells, and allow ''N. gonorrhoeae'' to increase the length of infection as well as increase the amount of invasion into other host cells.<ref>{{cite journal | vauthors = Sadarangani M, Pollard AJ, Gray-Owen SD | title = Opa proteins and CEACAMs: pathways of immune engagement for pathogenic Neisseria | journal = FEMS Microbiology Reviews | volume = 35 | issue = 3 | pages = 498–514 | date = May 2011 | pmid = 21204865 | doi = 10.1111/j.1574-6976.2010.00260.x }}</ref>

==== Type IV pili ==== thumb|511x511px|''Neisseria gonorrhoeae'' use their type IV pili as a motility structure. These are the steps for the type IV pilus twitching motility mechanism. Dynamic polymeric protein filaments called type IV pili allow ''N. gonorrhoeae'' to do many bacterial processes, including adhesion to surfaces, transformation competence, twitching motility, and immune response evasions.<ref name="Green_2022">{{cite book |doi=10.1016/bs.ampbs.2022.01.002 |title=Neisseria gonorrhoeae physiology and pathogenesis |series=Advances in Microbial Physiology |date=2022 |volume=80 |pages=35–83 |pmid=35489793 |isbn=978-0-323-98869-8 | vauthors = Green LR, Cole J, Parga EF, Shaw JG }}</ref> To enter the host the bacteria uses the pili to adhere to and penetrate mucosal surfaces. The pili are a pivotal virulence factor for ''N. gonorrhoeae''; without them, the bacterium is unable to promote colonization.<ref name="Hu_2020">{{cite journal | vauthors = Hu LI, Yin S, Ozer EA, Sewell L, Rehman S, Garnett JA, Seifert HS | title = Discovery of a New Neisseria gonorrhoeae Type IV Pilus Assembly Factor, TfpC | journal = mBio | volume = 11 | issue = 5 | date = October 2020 | pmid = 33109763 | doi = 10.1128/mBio.02528-20 | doi-access = free| veditors = Justice S | pmc = 7593972 }}</ref> For motility, individual bacteria use their pili in a manner that resembles a grappling hook: first, they are extended from the cell surface and attach to a substrate. Subsequent pilus retraction drags the cell forward. The resulting movement is referred to as twitching motility. ''N. gonorrhoeae'' can pull 100,000 times its own weight,<ref name="Merz_2000">{{cite journal | vauthors = Merz AJ, So M, Sheetz MP | title = Pilus retraction powers bacterial twitching motility | journal = Nature | volume = 407 | issue = 6800 | pages = 98–102 | date = September 2000 | pmid = 10993081 | doi = 10.1038/35024105 | bibcode = 2000Natur.407...98M }}</ref> and the pili used to do so are amongst the strongest biological motors known to date, exerting one nanonewton.<ref name="Merz_2000" /> The PilF and PilT ATPase proteins are responsible for powering the extension and retraction of the type IV pilus, respectively. The adhesive functions of the gonococcal pilus play a role in microcolony aggregation and biofilm formation. These pili are also used to avoid immune responses from the cell they are invading by having their type IV pili antigenically vary. The main pilus filament is replaced by variable DNA sequences very frequently.<ref name="Green_2022" /> By doing this process rapidly, they can create a diversity of pili on their surface and evade the host cell's immune response.<ref name="Hu_2020" />

==== Lipooligosaccharide ==== Lipooligosaccharide is a low-weight version of lipopolysaccharide present on the surfaces of most other Gram-negative bacteria. It is a sugar (saccharide) side chain attached to lipid A (thus "lipo-") in the outer membrane coating the cell wall of the bacteria. The root "oligo" refers to the fact that it is a few sugars shorter than the typical lipopolysaccharide.<ref name="Sherris" /> As an endotoxin, it provokes inflammation. The shedding of lipooligosaccharide by the bacteria is sometimes responsible for issues associated with pelvic inflammatory disease.<ref name="Sherris" /> Although it functions primarily as an endotoxin, lipooligosaccharide may disguise itself with host sialic acid and block initiation of the complement cascade.<ref name="Sherris" />

=== Antigenic variation === ''N. gonorrhoeae'' evades the immune system through a process called antigenic variation.<ref>{{cite journal | vauthors = Stern A, Brown M, Nickel P, Meyer TF | title = Opacity genes in Neisseria gonorrhoeae: control of phase and antigenic variation | journal = Cell | volume = 47 | issue = 1 | pages = 61–71 | date = October 1986 | pmid = 3093085 | doi = 10.1016/0092-8674(86)90366-1 | s2cid = 21366517 }}</ref> This process allows ''N. gonorrhoeae'' to recombine its genes and alter the antigenic determinants that adorn its surface,<ref name="Sherris" /> such as the Type IV pili.<ref>{{cite journal |vauthors=Cahoon LA, Seifert HS |date=September 2011 |title=Focusing homologous recombination: pilin antigenic variation in the pathogenic Neisseria |journal=Molecular Microbiology |volume=81 |issue=5 |pages=1136–1143 |doi=10.1111/j.1365-2958.2011.07773.x |pmc=3181079 |pmid=21812841}}</ref> Simply stated, the chemical composition of molecules are changed due to changes at the genetic level.<ref name="Hill_2016"/> ''N. gonorrhoeae'' is able to vary the composition of its pili and lipooligosaccharide. Of these, the pili exhibit the most antigenic variation due to chromosomal rearrangement.<ref name="Lev13th2" /><ref name="Sherris" /> The ''pilS'' gene is an example of this ability to rearrange, as its combination with the ''pilE'' gene is estimated to produce over 100 variants of the PilE protein.<ref name="Hill_2016" /> These changes allow for adjustment to local environmental differences at the site of infection, evasion of recognition by targeted antibodies, and inhibit the formation of an effective vaccine.<ref name="Hill_2016">{{cite journal | vauthors = Hill SA, Masters TL, Wachter J | title = Gonorrhea - an evolving disease of the new millennium | journal = Microbial Cell | volume = 3 | issue = 9 | pages = 371–389 | date = September 2016 | pmid = 28357376 | pmc = 5354566 | doi = 10.15698/mic2016.09.524 }}</ref>

In addition to gene rearrangement, it is also naturally competent, meaning it can acquire extracellular DNA from the environment via its type IV pilus, specifically proteins PilQ and PilT.<ref>{{cite journal | vauthors = Obergfell KP, Seifert HS | title = Mobile DNA in the pathogenic ''Neisseria'' | journal = Microbiology Spectrum | volume = 3 | issue = 3 | date = February 2015 | pmid = 25866700 | pmc = 4389775 | doi = 10.1128/microbiolspec.MDNA3-0015-2014 }}</ref> These processes allow ''N. gonorrhoeae'' to acquire and spread new genes, disguise itself with different surface proteins, and prevent the development of immunological memory – an ability which has contributed to antibiotic resistance and impeded vaccine development.<ref>{{cite journal | vauthors = Aas FE, Wolfgang M, Frye S, Dunham S, Løvold C, Koomey M | title = Competence for natural transformation in Neisseria gonorrhoeae: components of DNA binding and uptake linked to type IV pilus expression | journal = Molecular Microbiology | volume = 46 | issue = 3 | pages = 749–760 | date = November 2002 | pmid = 12410832 | doi = 10.1046/j.1365-2958.2002.03193.x | s2cid = 21854666 | doi-access = free }}</ref>

=== Phase variation === Phase variation is similar to antigenic variation, but instead of changes at the genetic level altering the composition of molecules, these genetic changes result in the activation or deactivation of a gene.<ref name="Hill_2016" /> Phase variation most often arises from a frameshift in the expressed gene.<ref name="Hill_2016" /> The Opa proteins of ''N. gonorrhoeae'' rely strictly on phase variation.<ref name="Hill_2016" /> Every time the bacteria replicate, they may switch multiple Opa proteins on or off through slipped-strand mispairing. That is, the bacteria introduce frameshift mutations that bring genes in or out of frame. The result is that different Opa genes are translated every time.<ref name="Sherris" /> Pili are varied by antigenic variation, but also phase variation.<ref name="Hill_2016" /> Frameshifts occur in both the ''pilE'' and ''pilC'' genes, effectively turning off the expression of pili in situations when they are not needed, such as during intracellular colonization as opposed to extracellular mucosal cell surface adhesion.<ref name="Hill_2016" />

===Survival of gonococci=== After gonococci invade and transcytose the host epithelial cells, they land in the submucosa, where neutrophils promptly consume them.<ref name="Sherris" /> The pili and Opa proteins on the surface may interfere with phagocytosis,<ref name="Lev13th2" /> but most gonococci end up in neutrophils. The exudates from infected individuals contain many neutrophils with ingested gonococci. Neutrophils release an oxidative burst of reactive oxygen species in their phagosomes to kill the gonococci.<ref>{{cite journal | vauthors = Simons MP, Nauseef WM, Apicella MA | title = Interactions of Neisseria gonorrhoeae with adherent polymorphonuclear leukocytes | journal = Infection and Immunity | volume = 73 | issue = 4 | pages = 1971–1977 | date = April 2005 | pmid = 15784537 | pmc = 1087443 | doi = 10.1128/iai.73.4.1971-1977.2005 }}</ref> However, a significant fraction of the gonococci can resist killing through the action of their catalase,<ref name="Sherris" /> which breaks down reactive oxygen species and can reproduce within the neutrophil phagosomes.<ref name="pmid30627130">{{cite journal | vauthors = Escobar A, Rodas PI, Acuña-Castillo C | title = Macrophage-''Neisseria gonorrhoeae'' Interactions: A Better Understanding of Pathogen Mechanisms of Immunomodulation | journal = Frontiers in Immunology | volume = 9 | issue = | page = 3044 | date = 2018 | pmid = 30627130 | pmc = 6309159 | doi = 10.3389/fimmu.2018.03044 | doi-access = free }}</ref>

The bacterial RecA protein, which mediates repair of DNA damage, plays a crucial role in gonococcal survival.<ref>{{cite journal | vauthors = Stohl EA, Seifert HS | title = Neisseria gonorrhoeae DNA recombination and repair enzymes protect against oxidative damage caused by hydrogen peroxide | journal = Journal of Bacteriology | volume = 188 | issue = 21 | pages = 7645–7651 | date = November 2006 | pmid = 16936020 | pmc = 1636252 | doi = 10.1128/JB.00801-06 }}</ref> ''N. gonorrhoeae'' may replace DNA damaged in neutrophil phagosomes with DNA from neighboring gonococci.<ref>{{cite journal | vauthors = Michod RE, Bernstein H, Nedelcu AM | title = Adaptive value of sex in microbial pathogens | journal = Infection, Genetics and Evolution | volume = 8 | issue = 3 | pages = 267–285 | date = May 2008 | pmid = 18295550 | doi = 10.1016/j.meegid.2008.01.002 | bibcode = 2008InfGE...8..267M }}</ref> The process in which recipient gonococci integrate DNA from neighboring gonococci into their genome is called transformation.<ref name="pmid27825443">{{cite journal | vauthors = Blokesch M | title = Natural competence for transformation | journal = Current Biology | volume = 26 | issue = 21 | pages = R1126–R1130 | date = November 2016 | pmid = 27825443 | doi = 10.1016/j.cub.2016.08.058 | doi-access = free | bibcode = 2016CBio...26R1126B }}</ref> thumb|right|The growth of ''N. gonorrhoeae'' colonies on New York City agar, a specialized and selective medium for gonococci

== Genome == The genomes of several strains of ''N''. ''gonorrhoeae ''have been sequenced. Most of them are about 2.1 Mb in size and encode 2,100 to 2,600 proteins (although most seem to be in the lower range).<ref>{{cite web|title=''Neisseria gonorrhoeae'' genome statistics|url=https://www.broadinstitute.org/annotation/genome/neisseria_gonorrhoeae/GenomeStats.html|publisher=Broad Institute|access-date=8 April 2017}}</ref> For instance, strain NCCP11945 consists of one circular chromosome (2,232,025 bp) encoding 2,662 predicted open reading frames (ORFs) and one plasmid (4,153 bp) encoding 12 predicted ORFs. The estimated coding density over the entire genome is 87%, and the average G+C content is 52.4%, values that are similar to those of strain FA1090. The NCCP11945 genome encodes 54 tRNAs and four copies of 16S-23S-5S rRNA operons.<ref name="Chung2008">{{cite journal | vauthors = Chung GT, Yoo JS, Oh HB, Lee YS, Cha SH, Kim SJ, Yoo CK | title = Complete genome sequence of Neisseria gonorrhoeae NCCP11945 | journal = Journal of Bacteriology | volume = 190 | issue = 17 | pages = 6035–6036 | date = September 2008 | pmid = 18586945 | pmc = 2519540 | doi = 10.1128/JB.00566-08 }}</ref>

=== Horizontal gene transfer === Horizontal gene transfer, also termed lateral gene transfer, is the sharing of genetic information amongst living organisms.<ref>{{cite journal | vauthors = Burmeister AR | title = Horizontal Gene Transfer | journal = Evolution, Medicine, and Public Health | volume = 2015 | issue = 1 | pages = 193–194 | date = July 2015 | pmid = 26224621 | pmc = 4536854 | doi = 10.1093/emph/eov018 }}</ref> This transmission of information is a driving force of antibiotic resistance in ''N. gonorrhoeae''.<ref>{{cite journal | vauthors = Unemo M, Shafer WM | title = Antibiotic resistance in Neisseria gonorrhoeae: origin, evolution, and lessons learned for the future | journal = Annals of the New York Academy of Sciences | volume = 1230 | issue = 1 | pages = E19–E28 | date = August 2011 | pmid = 22239555 | pmc = 4510988 | doi = 10.1111/j.1749-6632.2011.06215.x | bibcode = 2011NYASA1230E..19U }}</ref><ref name="Spencer-Smith_2016">{{cite journal | vauthors = Spencer-Smith R, Roberts S, Gurung N, Snyder LA | title = DNA uptake sequences in ''Neisseria gonorrhoeae'' as intrinsic transcriptional terminators and markers of horizontal gene transfer | journal = Microbial Genomics | volume = 2 | issue = 8 | article-number = e000069 | date = August 2016 | pmid = 28348864 | pmc = 5320588 | doi = 10.1099/mgen.0.000069 | doi-access = free }}</ref> Studies have identified that ''N. gonorrhoeae'' has obtained methods of antimicrobial resistance by way of horizontal gene transfer from other ''Neisseria'' species including ''N.'' ''lactamica'', ''N. macacae'', and ''N. mucosa.'' <ref>{{cite journal | vauthors = Manoharan-Basil SS, González N, Laumen JG, Kenyon C | title = Horizontal Gene Transfer of Fluoroquinolone Resistance-Conferring Genes From Commensal ''Neisseria'' to ''Neisseria gonorrhoeae'': A Global Phylogenetic Analysis of 20,047 Isolates | journal = Frontiers in Microbiology | volume = 13 | article-number = 793612 | date = 2022-03-17 | pmid = 35369513 | pmc = 8973304 | doi = 10.3389/fmicb.2022.793612 | doi-access = free }}</ref>

Transformation in ''N. gonorrhoeae'' is performed by the type IV pilus, where the DNA is bound and brought into the cell, followed by processing and homologous recombination.<ref>{{cite journal | vauthors = Hamilton HL, Dillard JP | title = Natural transformation of Neisseria gonorrhoeae: from DNA donation to homologous recombination | journal = Molecular Microbiology | volume = 59 | issue = 2 | pages = 376–385 | date = January 2006 | pmid = 16390436 | doi = 10.1111/j.1365-2958.2005.04964.x }}</ref>

Found in some genomes of ''Neisseria gonorrhoeae'', the gonococcal genetic island (GGI), a genomic island (GI) specific to gonococci, has been identified as a mobile genetic element that is horizontally acquired.<ref name="Cehovin_2017">{{cite journal | vauthors = Cehovin A, Lewis SB | title = Mobile genetic elements in Neisseria gonorrhoeae: movement for change | journal = Pathogens and Disease | volume = 75 | issue = 6 | date = August 2017 | pmid = 28645177 | doi = 10.1093/femspd/ftx071 }}</ref><ref>{{cite journal | vauthors = Kravtsov D, Gryadunov D, Shaskolskiy B | title = Gonococcal Genetic Island in the Global ''Neisseria gonorrhoeae'' Population: A Model of Genetic Diversity and Association with Resistance to Antimicrobials | journal = Microorganisms | volume = 11 | issue = 6 | page = 1547 | date = June 2023 | pmid = 37375049 | pmc = 10301925 | doi = 10.3390/microorganisms11061547 | doi-access = free }}</ref> GGI is involved with antimicrobial resistance, transmission of genetic information, and iron acquisition.<ref name="Cehovin_2017" /> The genes within the gonococcal genetic island encode for the infamous type IV secretion system (T4SS), which is responsible for DNA secretion and is essential for biofilm formation.<ref name="Cehovin_2017" /><ref>{{cite journal | vauthors = Zweig M, Schork S, Koerdt A, Siewering K, Sternberg C, Thormann K, Albers SV, Molin S, van der Does C | title = Secreted single-stranded DNA is involved in the initial phase of biofilm formation by Neisseria gonorrhoeae | journal = Environmental Microbiology | volume = 16 | issue = 4 | pages = 1040–1052 | date = April 2014 | pmid = 24119133 | doi = 10.1111/1462-2920.12291 | bibcode = 2014EnvMi..16.1040Z | url = https://backend.orbit.dtu.dk/ws/files/90448694/emi12291.pdf }}</ref>

In 2011, researchers at Northwestern University found evidence of a human DNA fragment in a ''N. gonorrhoeae'' genome, the first example of horizontal gene transfer from humans to a bacterial pathogen.<ref>{{cite journal | vauthors = Anderson MT, Seifert HS | title = Neisseria gonorrhoeae and humans perform an evolutionary LINE dance | journal = Mobile Genetic Elements | volume = 1 | issue = 1 | pages = 85–87 | date = May 2011 | pmid = 22016852 | pmc = 3190277 | doi = 10.4161/mge.1.1.15868 }}</ref><ref name=anderson2011>{{cite journal | vauthors = Anderson MT, Seifert HS | title = Opportunity and means: horizontal gene transfer from the human host to a bacterial pathogen | journal = mBio | volume = 2 | issue = 1 | pages = e00005–e00011 | year = 2011 | pmid = 21325040 | pmc = 3042738 | doi = 10.1128/mBio.00005-11 | doi-access = free}}</ref>

== Disease == {{main|Gonorrhoea}}

=== Symptoms === Symptoms of infection with ''N. gonorrhoeae'' differ depending on the site of infection and many infections are asymptomatic independent of sex.<ref>{{cite journal | vauthors = Detels R, Green AM, Klausner JD, Katzenstein D, Gaydos C, Handsfield H, Pequegnat W, Mayer K, Hartwell TD, Quinn TC | title = The incidence and correlates of symptomatic and asymptomatic Chlamydia trachomatis and Neisseria gonorrhoeae infections in selected populations in five countries | journal = Sexually Transmitted Diseases | volume = 38 | issue = 6 | pages = 503–509 | date = June 2011 | pmid = 22256336 | pmc = 3408314 | doi = 10.1097/OLQ.0b013e318206c288 }}</ref><ref name="Edwards_2004" /><ref name="www.cdc.gov_2017">{{Cite web|url=https://www.cdc.gov/std/gonorrhea/stdfact-gonorrhea-detailed.htm|title=Detailed STD Facts - Gonorrhea|date=2017-09-26|website=www.cdc.gov|language=en-us|access-date=2017-12-07}}</ref> Depending on the route of transmission, ''N. gonorrhoeae'' may cause infection of the throat (pharyngitis) or infection of the anus/rectum (proctitis).<ref name="Sherris2" /><ref name="Lev13th2" />

{{Anchor|Gonococcemia}}Disseminated gonococcal infections can occur when ''N. gonorrhoeae'' enters the bloodstream ('''gonococcemia'''), often spreading to the joints and causing a rash (dermatitis-arthritis syndrome).<ref name="Sherris2" /> Dermatitis-arthritis syndrome results in joint pain (arthritis), tendon inflammation (tenosynovitis), and painless non-pruritic (non-itchy) dermatitis.<ref name="Lev13th2" /> Disseminated infection and pelvic inflammatory disease in women tend to begin after menses due to reflux during menses, facilitating spread.<ref name="Sherris2" /> In rare cases, disseminated infection may cause infection of the meninges of the brain and spinal cord (meningitis) or infection of the heart valves (endocarditis).<ref name="Sherris2" /><ref name="www.cdc.gov" />

==== Male ==== In symptomatic men, the primary symptom of genitourinary infection is urethritis – burning with urination (dysuria), increased urge to urinate, and a pus-like (purulent) discharge from the penis. The discharge may be foul-smelling.<ref name="Sherris2">{{cite book|url=https://books.google.com/books?id=RRRrAAAAMAAJ|title=Sherris Medical Microbiology|publisher=McGraw Hill|year=2004|isbn=978-0-8385-8529-0| veditors = Ryan KJ, Ray CG |edition=4th }}{{page needed|date=February 2015}}</ref> If untreated, scarring of the urethra may result in difficulty urinating. Infection may spread from the urethra in the penis to nearby structures, including the testicles (epididymitis/orchitis), or to the prostate (prostatitis).<ref name="Sherris2" /><ref name="Lev13th2">{{cite book | vauthors = Levinson W |title=Review of medical microbiology and immunology |date=2014 |publisher=McGraw-Hill Education |isbn=978-0-07-181811-7 |oclc=871305336 }}{{page needed|date=September 2021}}</ref><ref>{{cite web|url=https://www.std-gov.org/stds/gonorrhea.htm|title=Gonorrhea (the clap) Symptoms|publisher=std-gov.org|date=2015-04-02}}</ref>

==== Female ==== thumb|Gram stain of a vaginal swab showing gonococci (in pairs - arrow) inside polymorphonuclear granulocytes

In symptomatic women, the primary symptoms of genitourinary infection are increased vaginal discharge, burning with urination (dysuria), increased urge to urinate, pain with intercourse, or menstrual abnormalities. Pelvic inflammatory disease results if ''N. gonorrhoeae'' ascends into the pelvic peritoneum (via the cervix, endometrium, and fallopian tubes). The resulting inflammation and scarring of the fallopian tubes can lead to infertility and an increased risk of ectopic pregnancy.<ref name="Sherris2" /> Pelvic inflammatory disease develops in 10 to 20% of the females infected with ''N. gonorrhoeae''.<ref name="Sherris2" />

==== Neonates (perinatal infection) ==== In perinatal infection, the primary manifestation is infection of the eye (neonatal conjunctivitis or ophthalmia neonatorum) when the newborn is exposed to ''N. gonorrhoeae'' in the birth canal. The eye infection can lead to corneal scarring or perforation, ultimately resulting in blindness. If the newborn is exposed during birth, conjunctivitis occurs within 2–5 days after birth and is severe.<ref name="Sherris2" /><ref name="www.cdc.gov">{{Cite web|url=https://www.cdc.gov/std/tg2015/gonorrhea.htm|title=Gonococcal Infections - 2015 STD Treatment Guidelines|website=www.cdc.gov|language=en-us|access-date=2017-12-07}}</ref> Gonococcal ophthalmia neonatorum, once common in newborns, is prevented by the application of erythromycin (antibiotic) gel to the eyes of babies at birth as a public health measure. Silver nitrate is no longer used in the United States.<ref name="www.cdc.gov" /><ref name="Sherris2" />

===Transmission=== ''N. gonorrhoeae'' is most often transmitted through vaginal, oral, or anal sex; nonsexual transmission is unlikely in adult infection.<ref name="www.cdc.gov_2017"/> It can also be transmitted to a newborn during passage through the birth canal if the mother has an untreated genitourinary infection. Given the high rate of asymptomatic infection, it is recommended that pregnant women be tested for gonococcal infection before birth.<ref name="www.cdc.gov_2017"/> Communal baths, shared towels or fabrics, rectal thermometers, and improper hand hygiene by caregivers have been identified as potential means of transmission in pediatric settings.<ref>{{cite journal | vauthors = Goodyear-Smith F | title = What is the evidence for non-sexual transmission of gonorrhoea in children after the neonatal period? A systematic review | journal = Journal of Forensic and Legal Medicine | volume = 14 | issue = 8 | pages = 489–502 | date = November 2007 | pmid = 17961874 | doi = 10.1016/j.jflm.2007.04.001 }}</ref>

Traditionally, the bacterium was thought to move attached to spermatozoa, but this hypothesis did not explain female-to-male transmission of the disease. A recent study suggests that rather than "surf" on wiggling sperm, ''N. gonorrhoeae'' bacteria use pili to anchor onto proteins in the sperm and move through coital fluid.<ref name="Anderson2014">{{cite journal | vauthors = Anderson MT, Dewenter L, Maier B, Seifert HS | title = Seminal plasma initiates a Neisseria gonorrhoeae transmission state | journal = mBio | volume = 5 | issue = 2 | pages = e01004–e01013 | date = March 2014 | pmid = 24595372 | pmc = 3958800 | doi = 10.1128/mBio.01004-13 | doi-access = free}}</ref>

=== Infection === Successful transmission is followed by adherence to the epithelial cells found at the infected mucosal site by the bacterium's type IV pili. The pili's ability to attach and subsequently retract pulls ''N. gonorrhoeae'' towards the epithelial membrane at the surface of the mucosal cell.<ref name="Quillin_2018" /> Post attachment, ''N. gonorrhoeae'' replicates its genome and divides to form microcolonies.<ref name="Quillin_2018" /> Gonococcal infection is sometimes aided by the membrane cofactor protein, CD46, as it has been known to act as a receptor for gonococcal pilus.<ref name="Edwards_2004" /> Additionally, interaction with pili has been shown to cause cytoskeletal rearrangement of the host cell, further demonstrating that gonococcal pili engagement disrupts the response of the host cell and increases the likelihood of successful infection.<ref name="Edwards_2004" /> During growth and colonization, ''N. gonorrhoeae'' stimulates the release of pro-inflammatory cytokines and chemokines from host immune cells that result in the recruitment of neutrophils to the area.<ref name="Hill_2016" /> These phagocytic cells typically take in foreign pathogens and destroy them; however, ''N. gonorrhoeae'''s ability to manipulate the host cell response allows the pathogen to survive within these immune cells and evade elimination.<ref name="Hill_2016" />

==== Laboratory diagnosis ==== The primary detection methods for ''Neisseria gonorrhoeae'' are nucleic acid amplification tests, which are the most sensitive techniques available.<ref name="Meyer_2020">{{cite journal | vauthors = Meyer T, Buder S | title = The Laboratory Diagnosis of ''Neisseria gonorrhoeae'': Current Testing and Future Demands | journal = Pathogens | volume = 9 | issue = 2 | page = 91 | date = January 2020 | pmid = 32024032 | pmc = 7169389 | doi = 10.3390/pathogens9020091 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Cosentino LA, Campbell T, Jett A, Macio I, Zamborsky T, Cranston RD, Hillier SL | title = Use of nucleic acid amplification testing for diagnosis of anorectal sexually transmitted infections | journal = Journal of Clinical Microbiology | volume = 50 | issue = 6 | pages = 2005–2008 | date = June 2012 | pmid = 22493338 | pmc = 3372150 | doi = 10.1128/JCM.00185-12 }}</ref> Other methods of detection include microscopy and culture.<ref name="Meyer_2020" />

=== Prevention === Transmission is reduced by using latex barriers (e.g., condoms or dental dams) during sex and by limiting sexual partners.<ref name="CDC">{{cite web | url = https://www.cdc.gov/std/tg2015/clinical.htm | archive-url = https://web.archive.org/web/20151222183741/https://www.cdc.gov/std/tg2015/clinical.htm | archive-date = 22 December 2015 | title = 2015 Sexually Transmitted Diseases Treatment Guidelines | work = CDC | publisher = Centers for Disease Control and Prevention, U.S. Department of Health & Human Services}}</ref> Condoms and dental dams should be used during oral and anal sex as well. Spermicides, vaginal foams, and douches are not effective methods for transmission prevention.<ref name="Sherris" />

==== Vaccine ==== A vaccine against ''N. gonorrhoeae'' is becoming more necessary due to the growing incidence of cases, increasing antimicrobial resistance, and its impact on reproductive health.<ref name="www.cdc.gov_2">{{Cite web |title=Gonococcal Infections Among Adolescents and Adults - STI Treatment Guidelines |url=https://www.cdc.gov/std/treatment-guidelines/gonorrhea-adults.htm |access-date=2024-11-19 |website=www.cdc.gov|date=5 December 2022 }}</ref> There are problems that have hampered vaccine development including: the absence of immunity post-infection, exclusively human hosts, and antigenic and phase variation of potential vaccine targets.<ref name="Williams_2024">{{cite journal | vauthors = Williams E, Seib KL, Fairley CK, Pollock GL, Hocking JS, McCarthy JS, Williamson DA | title = ''Neisseria gonorrhoeae'' vaccines: a contemporary overview | journal = Clinical Microbiology Reviews | volume = 37 | issue = 1 | pages = e0009423 | date = March 2024 | pmid = 38226640 | pmc = 10938898 | doi = 10.1128/cmr.00094-23 | veditors = Forrest GN }}</ref> Currently, there are several ''N. gonorrhoeae'' vaccines in development, including an outer membrane vesicle vaccine.<ref name="Williams_2024" /> This includes the NGoXIM, the native OMV, and Bexsero/4CMenB vaccine candidates, which are all in the late clinical stages of development.<ref>{{ClinicalTrialsGov|NCT05630859|Safety and Efficacy of GSK Neisseria Gonorrhoeae GMMA (NgG) Investigational Vaccine When Administered to Healthy Adults 18 to 50 Years of Age.}}</ref> The creation of a vaccine for ''N. gonorrhoeae'' has several potential public health impacts. In one estimate, a vaccine for the heterosexual population given before sexual activity occurs showed that the prevalence of ''N. gonorrhoeae'' could be reduced by up to 90% after 20 years.<ref name="Williams_2024" /> In 2023, the FDA gave fast-track designation to a gonorrhoea vaccine candidate from GSK<ref>{{cite press release |title=GSK receives US FDA Fast Track designation for investigational vaccine against gonorrhoea |url=https://www.gsk.com/en-gb/media/press-releases/gsk-receives-us-fda-fast-track-designation-for-investigational-vaccine-against-gonorrhoea/ |archive-url=https://web.archive.org/web/20250724003851/https://www.gsk.com/en-gb/media/press-releases/gsk-receives-us-fda-fast-track-designation-for-investigational-vaccine-against-gonorrhoea/ |archive-date=24 July 2025 |publisher=GSK |date=27 June 2023 |access-date=24 July 2025}}</ref> . NHS England has also launched the world's first vaccination program against gonorrhea, using a vaccine against ''Neisseria meningitidis'' which was found to be partially effective against ''N. gonorrhoeae'' <ref>{{cite news |last1=Rogers |first1=Andrew |last2=Gallagher |first2=James |title=World-first gonorrhoea vaccine launched by NHS England as infections soar |url=https://www.bbc.com/news/articles/cded26z16leo |archive-url=https://web.archive.org/web/20250724004403/https://www.bbc.com/news/articles/cded26z16leo |archive-date=24 July 2025 |work=BBC News |date=21 May 2025 |access-date=24 July 2025}}</ref><ref>{{cite web |title=Gonorrhoea vaccine |url=https://vaccineknowledge.ox.ac.uk/gonorrhoea-vaccine#Key-vaccine-facts |archive-url=https://web.archive.org/web/20250724003258/https://vaccineknowledge.ox.ac.uk/gonorrhoea-vaccine |archive-date=24 July 2025 |website=Vaccine Knowledge Project |publisher=Oxford Vaccine Group, University of Oxford |date=20 June 2025 |access-date=24 July 2025 }}</ref> .

===Treatment=== Currently, the CDC recommends a single dose of the injectable cephalosporin, ceftriaxone, as the first line of defense against gonococcal infections.<ref>{{Cite web |last=CDC |date=2024-05-16 |title=Drug-Resistant Gonorrhea |url=https://www.cdc.gov/gonorrhea/hcp/drug-resistant/index.html#:~:text=Currently,%20just%20one%20regimen%20is,to%20cephalosporins%20and%20other%20drugs. |access-date=2024-11-20 |website=Gonorrhea |language=en-us}}</ref> Individuals weighing less than 150 kg are typically prescribed a ceftriaxone concentration of 500 mg, while individuals who weigh over 150 kg are typically prescribed a dose of 1 g. Although ceftriaxone is not the only cephalosporin that has been effective at treating gonorrhoeae, it is the most advantageous.<ref name="www.cdc.gov_2" /> In the event of a cephalosporin allergy, the CDC recommends a dual treatment of gentamicin and azithromycin. Each drug should be administered as a single dose, with the gentamicin entering intramuscularly at a concentration of 240 mg, along with 2 g of azithromycin taken orally.<ref name="www.cdc.gov_2" /> If an individual is not allergic to cephalosporins but ceftriaxone is unavailable, an alternative treatment is a single dose of 800 mg cefixime consumed orally.<ref name="www.cdc.gov_2" /> In all of these cases, combination therapy and co-treatment for chlamydia is recommended, as simultaneous infections are common.<ref>{{cite journal | vauthors = St Cyr S, Barbee L, Workowski KA, Bachmann LH, Pham C, Schlanger K, Torrone E, Weinstock H, Kersh EN, Thorpe P | title = Update to CDC's Treatment Guidelines for Gonococcal Infection, 2020 | language = en-us | journal = MMWR. Morbidity and Mortality Weekly Report | volume = 69 | issue = 50 | pages = 1911–1916 | date = December 2020 | pmid = 33332296 | doi = 10.15585/mmwr.mm6950a6 | pmc = 7745960 }}</ref> ==== Antibiotic resistance ==== Antibiotic resistance in gonorrhea was first identified in the 1940s. Gonorrhea was treated with penicillin, but doses had to be progressively increased to remain effective. By the 1970s, penicillin-and tetracycline-resistant gonorrhea emerged in the Pacific Basin. These resistant strains then spread to Hawaii, California, the rest of the United States, Australia and Europe. Fluoroquinolones were the next line of defense, but soon resistance to this antibiotic emerged, as well. Since 2007, standard treatment has been third-generation cephalosporins, such as ceftriaxone, which are considered to be our "last line of defense".<ref>{{cite news|url=https://www.bbc.co.uk/news/health-15238613|title=UK doctors advised gonorrhoea has turned drug resistant|date=10 October 2011|work=BBC News}}</ref><ref name="blog.advocatesaz.org">{{cite web | url = http://blog.advocatesaz.org/2012/03/06/sti-awareness-antibiotic-resistant-gonorrhea | archive-url = https://web.archive.org/web/20121105124828/http://blog.advocatesaz.org/2012/03/06/sti-awareness-antibiotic-resistant-gonorrhea/ | archive-date = 5 November 2012 | title = STI Awareness: Antibiotic-Resistant Gonorrhea | publisher = Planned Parenthood Advocates of Arizona | date = 6 March 2012 | access-date = 6 March 2012 }}</ref> Recently, a high-level ceftriaxone-resistant strain of gonorrhea called {{vanchor|H041}} was discovered in Japan. Lab tests found it to be resistant to high concentrations of ceftriaxone, as well as most of the other antibiotics tested. Within ''N. gonorrhoeae'', genes exist that confer resistance to every single antibiotic used to cure gonorrhea, but thus far, they do not coexist within a single gonococcus. However, because of ''N. gonorrhoeae''{{'}}s high affinity for horizontal gene transfer, antibiotic-resistant gonorrhea is seen as an emerging public health threat.<ref name="blog.advocatesaz.org" />

Before 2007, fluoroquinolones were a common treatment recommendation for gonorrhoeae. The CDC stopped suggesting these systemic bacterial agents once a resistant strain of ''N. gonorrhoeae'' emerged in the United States. The removal of fluoroquinolones as a potential treatment left cephalosporins as the only viable antimicrobial option for gonorrhea treatment. Wary of further gonococcal resistance, the CDC's recommendations shifted in 2010 to a dual therapy strategy—cephalosporin with either azithromycin or doxycycline. Despite these efforts, resistant ''N. gonorrhoeae'' had been reported in five continents by 2011, further limiting treatment options and recommendations. Antimicrobial resistance is not universal and ''N. gonorrhoeae'' strains in the United States continue to respond to a combination regimen of ceftriaxone and azithromycin.<ref name="pmid35015033">{{cite journal |vauthors=Tuddenham S, Hamill MM, Ghanem KG |title=Diagnosis and Treatment of Sexually Transmitted Infections: A Review |journal=JAMA |volume=327 |issue=2 |pages=161–172 |date=January 2022 |pmid=35015033 |doi=10.1001/jama.2021.23487 |url=}}</ref>

=== Serum resistance === As a Gram negative bacterium, ''N. gonorrhoeae'' requires defense mechanisms to protect itself against the complement system (or complement cascade), whose components are found with human serum.<ref name="Edwards_2004"/> There are three different pathways that activate this system however, they all result in the activation of complement protein 3 (C3).<ref name="Janeway Jr_2001">{{cite book |last1=Charles A Janeway |first1=Jr |last2=Travers |first2=Paul |last3=Walport |first3=Mark |last4=Shlomchik |first4=Mark J. |title=Immunobiology: The Immune System in Health and Disease. 5th edition |date=2001 |publisher=Garland Science |chapter-url=https://www.ncbi.nlm.nih.gov/books/NBK27100/ |chapter=The complement system and innate immunity }}</ref> A cleaved portion of this protein, C3b, is deposited on pathogenic surfaces and results in opsonization as well as the downstream activation of the membrane attack complex.<ref name="Janeway Jr_2001"/> ''N. gonorrhoeae'' has several mechanisms to avoid this action.<ref name="Quillin_2018"/> As a whole, these mechanisms are referred to as serum resistance.<ref name="Quillin_2018"/>

== History ==

=== Name origin === ''Neisseria gonorrhoeae'' is named for Albert Neisser, who isolated it as the causative agent of the disease gonorrhea in 1878.<ref name="Quillin_2018"/><ref name="O'Donnell_2009" /> Galen (130 AD) coined the term "gonorrhea" from the Greek ''gonos'' which means "seed" and ''rhoe'' which means "flow".<ref>{{Cite web|url=https://www.etymonline.com/word/gonorrhea|title=gonorrhea {{!}} Origin and meaning of gonorrhea by Online Etymology Dictionary|website=www.etymonline.com|language=en|access-date=2017-12-05}}</ref><ref name="Hill_2016"/> Thus, gonorrhea means "flow of seed", a description referring to the white penile discharge, assumed to be semen, seen in male infection.<ref name="Quillin_2018" />

=== Discovery === In 1878, Albert Neisser isolated and visualized ''N. gonorrhoeae'' diplococci in samples of pus from 35 men and women with the classic symptoms of genitourinary infection with gonorrhea – two of whom also had infections of the eyes.<ref name="Hill_2016" /> In 1882, Leistikow and Loeffler were able to grow the organism in culture.<ref name="Quillin_2018" /> Then in 1883, Max Bockhart proved conclusively that the bacterium isolated by Albert Neisser was the causative agent of the disease known as gonorrhea by inoculating the penis of a healthy man with the bacteria.<ref name="Hill_2016" /> The man developed the classic symptoms of gonorrhea days after, satisfying the last of Koch's postulates. Until this point, researchers debated whether syphilis and gonorrhea were manifestations of the same disease or two distinct entities.<ref name="Singal">{{cite book | vauthors = Singal A, Grover C |title=Comprehensive Approach to Infections in Dermatology |date=2016 |publisher=JP Medical |isbn=978-93-5152-748-0 |page=470 }}</ref><ref name="Hill_2016" /> One such 18th-century researcher, John Hunter, tried to settle the debate in 1767<ref name="Hill_2016" /> by inoculating a man with pus taken from a patient with gonorrhea. He erroneously concluded that syphilis and gonorrhea were indeed the same disease when the man developed the copper-colored rash that is classic for syphilis.<ref name="Janeway Jr_2001"/><ref name="Singal"/> Although many sources repeat that Hunter inoculated himself,<ref name="Janeway Jr_2001" /><ref name="Quillin_2018" /> others have argued that it was another man.<ref>{{cite journal | vauthors = Gladstein J | title = Hunter's chancre: did the surgeon give himself syphilis? | journal = Clinical Infectious Diseases | volume = 41 | issue = 1 | pages = 128; author reply 128-128; author reply 129 | date = July 2005 | pmid = 15937780 | doi = 10.1086/430834 | doi-access = free }}</ref> After Hunter's experiment other scientists sought to disprove his conclusions by inoculating other male physicians, medical students,<ref name="Quillin_2018" /> and incarcerated men with gonorrheal pus, who all developed the burning and discharge of gonorrhea. One researcher, Ricord, took the initiative to perform 667 inoculations of gonorrheal pus on patients of a mental hospital, with zero cases of syphilis.<ref name="Hill_2016" /><ref name="Quillin_2018" /> Notably, the advent of penicillin in the 1940s made effective treatments for gonorrhea available.<ref>{{cite journal |last1=Jose |first1=Predesh Parasseril |last2=Vivekanandan |first2=Vatsan |last3=Sobhanakumari |first3=Kunjumani |title=Gonorrhea: Historical outlook |journal=Journal of Skin and Sexually Transmitted Diseases |date=15 October 2020 |volume=2 |pages=110–114 |article-number=110 |doi=10.25259/JSSTD_4_2020 |doi-access=free }}</ref>

== See also == * ''Neisseria meningitidis''

== References == {{Reflist|30em}}

== External links == {{Scholia|topic}} {{Refbegin}} * {{cite web |vauthors=Todar K |title=Pathogenic Neisseriae: Gonorrhea, Neonatal Ophthalmia and Meningococcal Meningitis |work=Todar's Online Textbook of Bacteriology |url=http://www.textbookofbacteriology.net/neisseria.html |access-date=12 October 2008 |archive-date=16 October 2022 |archive-url=https://web.archive.org/web/20221016211251/https://textbookofbacteriology.net/neisseria.html }} * {{EMedicine|article|218059|Gonorrhea}} * {{cite web |title=''Neisseria gonorrhoeae'' |work=NCBI Taxonomy Browser |url=https://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&id=485 |id=485 }} {{Refend}} * [http://bacdive.dsmz.de/index.php?search=10470&submit=Search Type strain of ''Neisseria gonorrhoeae'' at Bac''Dive'' – the Bacterial Diversity Metadatabase]

Category:Bacteria described in 1885 Category:Gonorrhea Category:Gram-negative bacteria Category:Pathogenic bacteria Category:Neisseriales Category:Taxa named by Friedrich Wilhelm Zopf