Editing Neisseria gonorrhoeae (section)

== 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 pathway|Entner-Doudoroff]] (ED) and [[Pentose phosphate pathway|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 pathway|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 transaminase|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 a number of 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<sup>+</sup> by directly transferring electrons to ubiquinone.<ref name="Green_2022" />

Conversely, acetyl-CoA that does not enter the CAC but enters the [[Phosphate acetyltransferase|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 cycle|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  [[capnophile]]s, meaning they require higher-than-normal concentrations of carbon dioxide (CO<sub>2</sub>) to grow , either in the form of CO<sub>2</sub> or bicarbonate (HCO<sub>3</sub><sup>−</sup>) 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 CO<sub>2</sub> productions in the exponential phase. Assimilation of this CO<sub>2</sub> 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 [[Nicotinamide adenine dinucleotide|NAD<sup>+</sup>]]-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 [[Coenzyme Q10|ubiquinone]]. While these enzymes do not directly pump protons (H<sup>+</sup> 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 colonize 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 ''ccb<sub>3</sub>'' -type cytochrome oxidase. In addition to [[aerobic respiration]], gonococci can also perform [[anaerobic respiration]] via the reduction of nitrite (NO<sub>2</sub>) to nitric oxide (NO) as well as reduction of NO to nitrous oxide (N<sub>2</sub>O).<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>

There are several enzymes that contribute electrons to the intramembranous ubiquinone pool, the first step in the ETC. These include the membrane bound LDHs (LldD and LdhD), [[Respiratory complex I|NADH:ubiquinone oxidoreductase]] (aka NADH dehydrogenase; Nuo complex I), Na<sup>+</sup>-translocating NADH dehydrogenase (Nqr), [[succinate dehydrogenase]] (SDH), and the membrane-bound NAD<sup>+</sup>-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 [[Coenzyme Q – cytochrome c reductase|cytochrome ''bc<sub>1</sub>'' complex]] or can be directly transferred to NO as a terminal electron acceptor by [[Nitric-oxide reductase|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 | pages = 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 ''bc<sub>1</sub>'' complex along two alternative pathways via the reduction of either cytochrome ''c<sub>4</sub>'' or ''c<sub>5</sub>''. Both of these cytochromes  transfer electrons to the terminal cytochrome ''ccb<sub>3</sub>'' oxidase for the reduction of O<sub>2</sub> to form H<sub>2</sub>O under aerobic conditions.<ref name="Green_2022" /><ref name="Li_2010" />

Gonococci are also reduce NO<sub>2</sub> 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 N<sub>2</sub>O in a partial denitrification pathway.<ref name="Green_2022" /><ref name="Li_2010" /><ref name="Aspholm_2010" /> The ''ccb<sub>3</sub>'' oxidase of ''N. gonorrhoeae'', dissimilarly to other members of the ''Neisseria'' genus, is a tri-heme protein that can transfer electrons not only to O<sub>2</sub> (conserved across ''Neisseria'' species) but also to AniA for NO<sub>2</sub> reduction. This is in addition to the typical process of receiving electrons transferred from cytochrome ''c<sub>5</sub>''.<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<sup>+</sup> 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 ''bc<sub>1</sub>'' complex, and cytochrome ''ccb<sub>3</sub>''.<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 [[ATP synthase|F<sub>1</sub>F<sub>0</sub> 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<sup>+</sup> 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 ''bc<sub>1</sub>'' complex, and cytochrome ''ccb<sub>3</sub>''.<ref name="Green_2022" /><ref name="Aspholm_2010" /><ref name="Cytochrome bc1 complexes of microor"/> Subsequently, ATP synthesis is performed by the [[ATP synthase|F<sub>1</sub>F<sub>0</sub> 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 are able to 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 [[siderophore]]s, 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 | pages = 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 [[siderocalin]]s that are able to chelate siderophores to as a further method of inhibiting pathogenic bacterial growth. These are sometimes ineffective against ''N. gonorrhoeae'', which is able to colonize intracellularly, particularly in phagocytic cells such as [[macrophage]]s and neutrophils. Increases in host intracellular iron also down regulates some of the intracellular pathogen-killing mechanisms; coincidentally, pathogenic ''Neisseria'' are able to alter several host cell mechanisms that ultimately allow the pathogen to take most of the available iron away from the host immune cell.<ref name="Stoudenmire_2022" />

=== Surface molecules ===
On its surface, ''N. gonorrhoeae'' bears hair-like [[Pilus|pili]], surface proteins with various functions, and sugars called [[Lipopolysaccharide|lipooligosaccharide]]. The pili mediate adherence, movement, and DNA exchange. The opacity-associated (Opa) proteins interact with the immune system, as do the [[Porin (protein)|porins]]. Lipooligosaccharide is an [[endotoxin]] that provokes an immune response. All of these are [[antigen]]ic 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 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 ====
[[File:Type IV Pilus Twitching Motility Steps.svg|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 [[polymer]]ic protein filaments called [[Type IV pilus|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 | 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 (biology)|substrate]]. Subsequent pilus retraction drags the cell forward. The resulting movement is referred to as twitching motility. ''N. gonorrhoeae'' is able to 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 [[Newton (unit)|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 are able to 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 are 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 system|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 | doi-broken-date = 1 November 2024 }}</ref>

In addition to gene rearrangement, it is also [[Natural competence|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 mutation|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|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 [[Transcytosis|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 is able to 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 =  | pages = 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 an important 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>
[[File:Neisseria gonorrhoeae Growth on New York City Agar Plate.jpg|thumb|right|The growth of ''N. gonorrhoeae'' colonies on New York City agar, a specialized and selective medium for gonococci]]