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Serum Resistance

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As a gram negative bacteria, N. gonorrhoeae requires defense mechanisms to protect itself against the complement system (or complement cascade), whose components are found with human serum.[1] There are three different pathways that activate this system however, they all result in the activation of complement protein 3 (C3).[2] A cleaved portion of this protein, C3a is deposited on pathogenic surfaces and results in opsonization as well as the downstream activation of the membrane attack complex.[2] N. gonorrhoeae has several mechanisms to avoid this action.[3] As a whole, these mechanisms are referred to as serum resistance.[3]

Treatment

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The current treatment recommended by the CDC is a dual antibiotic therapy. This includes an injected single dose of ceftriaxone (a third-generation cephalosporin) along with azithromycin administered orally.[4] Azithromycin is preferred for additional coverage of gonorrhea that may be resistant to cephalosporins but susceptible to macrolides.[5][6] Sexual partners (defined by the CDC as sexual contact within the past 60 days)[7] should also be notified, tested, and treated.[6][4] It is important that if symptoms persist after receiving treatment of N. gonorrhoeae infection, a reevaluation should be pursued.[4]


Antigenic variation

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N. gonorrhoeae evades the immune system through a process called antigenic variation.[8] This process allows N. gonorrhoeae to recombine its genes and alter the antigenic determinants (sites where antibodies bind), such as the Type IV pili[9], that adorn its surface.[10] Simply stated, the chemical composition of molecules is changed due to changes at the genetic level.[11] N. gonorrhoeae is able to vary the composition of its pili, and LOS; of these, the pili exhibit the most antigenic variation due to chromosomal rearrangement.[12][10] 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.[13] These changes allow for adjustment to the differences in the local environment at the site of infection, evasion of recognition by targeted antibodies, and contribute to the lack of an effective vaccine.[14]

In addition to the ability to rearrange the genes it already has, it is also naturally competent to acquire new DNA (plasmids), via its type IV pilus, specifically proteins Pil Q and Pil T.[15] These processes allow N. gonorrhoeae to acquire/spread new genes, disguise itself with different surface proteins, and prevent the development of immunological memory – an ability which has led to antibiotic resistance and has also impeded vaccine development.[16]

Phase variation

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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 turning on or off of a gene.[17] These most often arise from a frameshift in the expressed gene.[17] The Opacity, or Opa, proteins of N. gonorrhoeae rely strictly on phase variation.[17] 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.[10] Pili are varied not only by antigenic variation, but also phase variation.[17] 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 after colonization when N. gonorrhoeae survives within cells as opposed to on their surface. [17]

Infection

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For N. gonorrhoeae, the first step after successful transmission is adherence to the epithelial cells found at the mucosal site that is infected.[18] The bacterium relies on type IV pili that attach and retract, pulling N. gonorrhoeae toward the epithelial membrane where its surface proteins, such as opacity proteins, can interact directly.[18] After adherence, N. gonorrhoeae replicates itself and forms microcolonies.[19] While colonizing, N. gonorrhoeae has the potential to transcytose across the epithelial barrier and work its way in to the bloodstream.[20] During growth and colonization, N. gonorrhoeae stimulates the release of cytokines and chemokines from host immune cells that are pro-inflammatory.[20] These pro-inflammatory molecules result in the recruitment of macrophages and neutrophils.[21] These phagocytic cells typically take in foreign pathogens and destroy them, but N. gonorrhoeae has evolved many mechanisms that allow it to survive within these immune cells and thwart the attempts at elimination. [21]

Disease

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Main article: Gonorrhoea

Symptoms of infection with N. gonorrhoeae differ depending on the site of infection and many infections are asymptomatic independent of sex.[22][23][24] 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.[25] 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).[25][26][27] Men who have had a gonorrhea infection have a significantly increased risk of having prostate cancer.[28] 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 increased risk of ectopic pregnancy.[25] Pelvic inflammatory disease develops in 10 to 20% of the females infected with N. gonorrhoeae.[25] It is important to note that depending on the route of transmission, N. gonorrhoeae may cause infection of the throat (pharyngitis) or infection of the anus/rectum (proctitis). [25][26]

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.[25][29] 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.[29][25]

Disseminated gonococcal infections can occur when N. gonorrhoeae enters the bloodstream, often spreading to the joints and causing a rash (dermatitis-arthritis syndrome).[25] Dermatitis-arthritis syndrome results in joint pain (arthritis), tendon inflammation (tenosynovitis), and painless non-pruritic (non-itchy) dermatitis.[26] Disseminated infection and pelvic inflammatory disease in women tend to begin after menses due to reflux during menses, facilitating spread.[25] 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).[25][29]

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  1. ^ Edwards, J. L.; Apicella, M. A. (2004-10-01). "The Molecular Mechanisms Used by Neisseria gonorrhoeae To Initiate Infection Differ between Men and Women". Clinical Microbiology Reviews. 17 (4): 965–981. doi:10.1128/cmr.17.4.965-981.2004. ISSN 0893-8512.
  2. ^ a b Charles A Janeway, Jr; Travers, Paul; Walport, Mark; Shlomchik, Mark J. (2001). "The complement system and innate immunity". Immunobiology: The Immune System in Health and Disease. 5th edition.
  3. ^ a b Quillin, Sarah Jane; Seifert, H Steven (2018-02-12). "Neisseria gonorrhoeae host adaptation and pathogenesis". Nature Reviews Microbiology. 16 (4): 226–240. doi:10.1038/nrmicro.2017.169. ISSN 1740-1526.
  4. ^ a b c "CDC - Gonorrhea Treatment". www.cdc.gov. 2017-10-31. Retrieved 2017-12-07.
  5. ^ Nwokolo, Nneka C; Dragovic, Bojana; Patel, Sheel; Tong, CY William; Barker, Gary; Radcliffe, Keith (2016-03-01). "2015 UK national guideline for the management of infection with Chlamydia trachomatis". International Journal of STD & AIDS. 27 (4): 251–267. doi:10.1177/0956462415615443. ISSN 0956-4624. PMID 26538553.
  6. ^ a b Cite error: The named reference :10 was invoked but never defined (see the help page).
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  8. ^ Stern, Anne; Brown, Melissa; Nickel, Peter; Meyer, Thomas F. (1986). "Opacity genes in Neisseria gonorrhoeae: Control of phase and antigenic variation". Cell. 47 (1): 61–71. doi:10.1016/0092-8674(86)90366-1. PMID 3093085.
  9. ^ Cahoon, Laty A.; Seifert, H. Steven (2011). "Focusing homologous recombination: Pilin antigenic variation in the pathogenic Neisseria". Molecular Microbiology. 81 (5): 1136–43. doi:10.1111/j.1365-2958.2011.07773.x. PMC 3181079. PMID 21812841.
  10. ^ a b c Cite error: The named reference Sherris was invoked but never defined (see the help page).
  11. ^ Hill, Stuart A.; Masters, Thao L.; Wachter, Jenny (2016-09-05). "Gonorrhea – an evolving disease of the new millennium". Microbial Cell. 3 (9): 371–389. doi:10.15698/mic2016.09.524. ISSN 2311-2638.
  12. ^ Cite error: The named reference Lev13th was invoked but never defined (see the help page).
  13. ^ Hill, Stuart A.; Masters, Thao L.; Wachter, Jenny (2016-09-05). "Gonorrhea – an evolving disease of the new millennium". Microbial Cell. 3 (9): 371–389. doi:10.15698/mic2016.09.524. ISSN 2311-2638. PMC 5354566. PMID 28357376.{{cite journal}}: CS1 maint: PMC format (link)
  14. ^ Hill, Stuart A.; Masters, Thao L.; Wachter, Jenny (2016-09-05). "Gonorrhea – an evolving disease of the new millennium". Microbial Cell. 3 (9): 371–389. doi:10.15698/mic2016.09.524. ISSN 2311-2638. PMC 5354566. PMID 28357376.{{cite journal}}: CS1 maint: PMC format (link)
  15. ^ Obergfell, KP; Seifert, HS (February 2015). "Mobile DNA in the Pathogenic Neisseria". Microbiology Spectrum. 3 (1): MDNA3–0015–2014. doi:10.1128/microbiolspec.MDNA3-0015-2014. PMC 4389775. PMID 26104562.
  16. ^ Aas, Finn Erik; Wolfgang, Matthew; Frye, Stephan; Dunham, Steven; Løvold, Cecilia; Koomey, Michael (2002). "Competence for natural transformation in Neisseria gonorrhoeae: Components of DNA binding and uptake linked to type IV pilus expression". Molecular Microbiology. 46 (3): 749–60. doi:10.1046/j.1365-2958.2002.03193.x. PMID 12410832.
  17. ^ a b c d e Hill, Stuart A.; Masters, Thao L.; Wachter, Jenny (2016-09-05). "Gonorrhea – an evolving disease of the new millennium". Microbial Cell. 3 (9): 371–389. doi:10.15698/mic2016.09.524. ISSN 2311-2638. PMC 5354566. PMID 28357376.{{cite journal}}: CS1 maint: PMC format (link)
  18. ^ a b Pearce, W A; Buchanan, T M (1978-04-01). "Attachment role of gonococcal pili. Optimum conditions and quantitation of adherence of isolated pili to human cells in vitro". Journal of Clinical Investigation. 61 (4): 931–943. doi:10.1172/jci109018. ISSN 0021-9738.
  19. ^ Higashi, D. L.; Lee, S. W.; Snyder, A.; Weyand, N. J.; Bakke, A.; So, M. (2007-08-06). "Dynamics of Neisseria gonorrhoeae Attachment: Microcolony Development, Cortical Plaque Formation, and Cytoprotection". Infection and Immunity. 75 (10): 4743–4753. doi:10.1128/iai.00687-07. ISSN 0019-9567.
  20. ^ a b Quillin, Sarah Jane; Seifert, H Steven (2018-02-12). "Neisseria gonorrhoeae host adaptation and pathogenesis". Nature Reviews Microbiology. 16 (4): 226–240. doi:10.1038/nrmicro.2017.169. ISSN 1740-1526.
  21. ^ a b Hill, Stuart A.; Masters, Thao L.; Wachter, Jenny (2016-09-05). "Gonorrhea – an evolving disease of the new millennium". Microbial Cell. 3 (9): 371–389. doi:10.15698/mic2016.09.524. ISSN 2311-2638.
  22. ^ Detels, Roger; Green, Annette M.; Klausner, Jeffrey D.; Katzenstein, David; Gaydos, Charlotte; Hadsfield, Hunter; Peqyegnat, Willo; Mayer, Kenneth; Hartwell, Tyler D.; Quinn, Thomas . (2011). "The Incidence and Correlates of Symptomatic and Asymptomatic Chlamydia trachomatis and Neisseria gonorrhoeae Infections in Selected Populations in Five Countries". Sex. Transm. Dis. 38 (6): 503–509. PMC 3408314. PMID 22256336.
  23. ^ Edwards, Jennifer L.; Apicella, Michael A. (October 2004). "The Molecular Mechanisms Used by Neisseria gonorrhoeae To Initiate Infection Differ between Men and Women". Clinical Microbiology Reviews. 17 (4): 965–981. doi:10.1128/CMR.17.4.965-981.2004. ISSN 0893-8512. PMC 523569. PMID 15489357.
  24. ^ "Detailed STD Facts - Gonorrhea". www.cdc.gov. 2017-09-26. Retrieved 2017-12-07.
  25. ^ a b c d e f g h i j Ryan, KJ; Ray, CG, eds. (2004). Sherris Medical Microbiology (4th ed.). McGraw Hill. ISBN 978-0-8385-8529-0.[page needed]
  26. ^ a b c Levinson, Warren. Review of medical microbiology and immunology (Thirteenth ed.). New York. ISBN 9780071818117. OCLC 871305336.
  27. ^ "Gonorrhea (the clap) Symptoms". www.std-gov.org.
  28. ^ Caini, Saverio; Gandini, Sara; Dudas, Maria; Bremer, Viviane; Severi, Ettore; Gherasim, Alin (2014). "Sexually transmitted infections and prostate cancer risk: A systematic review and meta-analysis". Cancer Epidemiology. 38 (4): 329–338. doi:10.1016/j.canep.2014.06.002. ISSN 1877-7821. PMID 24986642.
  29. ^ a b c "Gonococcal Infections - 2015 STD Treatment Guidelines". www.cdc.gov. Retrieved 2017-12-07.
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