Early work in the human fallopian tube organ culture model established that GC could colonize explants and recapitulate the damage seen in patients with gonorrhea (22). Consistent with its proposed evolution from an ancestral commensal bacterium, N. gonorrhoeae has retained features that are common in commensals, but it has also developed unique features that are crucial to its pathogenesis. 189. The Molecular Mechanisms Used by Neisseria gonorrhoeae To Initiate Infection Differ between Men and Women | Clinical Microbiology Reviews. The gonococcus requires iron for growth and survival in vivo. Edwards JL, Brown EJ, Ault KA, Apicella MA.
doi: 10.1128/IAI.00012-06, 64. doi: 10.4049/jimmunol.174.12.7995, 143. Chief among them are the cellular events surrounding ciliated cell death and extrusion from the epithelium. The continued worldwide incidence of gonorrhoeal infection, coupled with the rising resistance to antimicrobials and the difficulties in controlling the disease in developing countries, highlights the need to better understand the molecular basis of N. gonorrhoeae infection. Zhu T, McClure R, Harrison OB, Genco C, Massari P. Vaccines (Basel). doi: 10.1093/infdis/143.3.413, 26. p. 597–602. (2009) 5:e1000625.
(2014) 20:377–89. Zielke RA, Wierzbicki IH, Weber JV, Gafken PR, Sikora AE. Flak TA, Heiss LN, Engle JT, Goldman WE.
Chen C, Song X, Wei W, Zhong H, Dai J, Lan Z, et al. Merz AJ, Rifenbery DB, Arvidson CG, So M. Traversal of a polarized epithelium by pathogenic Neisseriae: facilitation by type IV pili and maintenance of epithelial barrier function. However, the demonstrated ability of GC to disrupt epithelial integrity and invade through the epithelial layer (18, 21) likely puts the bacterium in proximity to TLR4 on fibroblasts. A. Pili 1. Infect Immun. doi: 10.1371/journal.pone.0087688, 147. Front Cell Infect Microbiol. Overview of Neisseria gonorrhoeae pathogenesis…, Figure 2:. Zhu W, Tomberg J, Knilans KJ, Anderson JE, McKinnon KP, Sempowski GD, et al. Mol Microbiol. Neisseria gonorrhoeae activates the proteinase cathepsin B to mediate the signaling activities of the NLRP3 and ASC-containing inflammasome. Another technology that could be used to replicate in vitro the biological complexity seen in vivo is organs-on-chips (OOCs), which come from a fusion of biological and engineering fields. Characterization of Toll-like receptors in the female reproductive tract in humans. During mouse infection, GC induces cytokines that indicate the presence of a T helper 17 (Th17) cell response (including the cytokine IL-17A) and not the cytokines expected from a Th1 response (153). J Biol Chem. McGee ZA, Jensen RL, Clemens CM, Taylor-Robinson D, Johnson AP, Gregg CR. doi: 10.1046/j.1365-2958.2000.01938.x, 187. (2012) 14:290–300. Laboratory diagnosis of Gonorrhoea. These cells are capable of differentiation on adipogenic, osteogenic, and chondrogenic pathways and produce cytokines such as GM-CSF, IL-4, IL-6, TNFα and IFNγ. (2011) the authors present a research article that describes a random mutagenesis screen…, Gonorrhea - an evolving disease of the new millennium, Lipooligosaccharide Structure is an Important Determinant in the Resistance of Neisseria Gonorrhoeae to Antimicrobial Agents of Innate Host Defense, The Gonococcal Genetic Island and Type IV Secretion in the Pathogenic Neisseria, Resistance of Neisseria Gonorrhoeae to Neutrophils. Opa proteins then act to influence the Th17/Th1 balance, suppressing Th1 and Th2 responses (155). doi: 10.1128/IAI.71.7.3901-3908.2003, 122.
Edwards VL, Wang LC, Dawson V, Stein DC, Song W. Neisseria gonorrhoeae breaches the apical junction of polarized epithelial cells for transmigration by activating EGFR.
To generate faithful reproductions of fallopian tube epithelia, both iPSCs (173) and adult stem cells from dissected fallopian tube (175) need to be grown as organoids. Tissue culture media such as Eagle's Minimal Essential Medium (MEM) is sufficient to support tissue survival, though gonococci grow poorly in this media (15). Microb Pathog. doi: 10.1073/pnas.1017300108, 170. Two types: types T1-T2 virulent and T3-T5 avirulent. The toxic effect of gonococcal LOS, like damage from gonococcal infection, also appeared to be a human-specific phenomenon, not affecting the ciliary activity of rabbit, pig, or cow oviducts (28). Consequences of the damage sustained on the fallopian tube epithelium include increased risk of ectopic pregnancy and tubal-factor infertility. Glaser AK, Reder NP, Chen Y, Mccarty EF, Yin C, Wei L, et al.
Harvey HA, Jennings MP, Campbell CA, Williams R, Apicella MA. Neisseria gonorrhoeae survives within and modulates apoptosis and inflammatory cytokine production of human macrophages. Induced pluripotent stem cell (iPSC) lines have been used to generate fallopian tube epithelium de novo (173). Neisseria gonorrhoeae selectively suppresses the development of Th1 and Th2 cells, and enhances Th17 cell responses, through TGF-beta-dependent mechanisms. You are currently offline. (2017) 215:452–5. I-domain-containing integrins serve as pilus receptors for Neisseria gonorrhoeae adherence to human epithelial cells.
Poole NM, Rajan A, Maresso AW. doi: 10.1371/journal.ppat.1000348, 70. PLoS ONE (2014) 9:e87688.
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The exact receptor that gonococcal pili engage during fallopian tube infection for either adherence or invasion is unknown.
The interaction of naturally elaborated blebs from serum-susceptible and serum-resistant strains of Neisseria gonorrhoeae with normal human serum. Though the male urethral infection model continues to provide many important insights into host and pathogen biology, this review will focus primarily on modeling infection of the human upper female reproductive tract as the male model has been reviewed elsewhere (12, 13).
Synthetic muramyl peptides, some of which are similar to those naturally released by gonococci, can be endocytosed by HEK293T cells to activate NOD1 and NOD2 (114). Cookson BT, Cho HL, Herwaldt LA, Goldman WE. Infect Immun. (2017) 8:14584. doi: 10.1038/ncomms14584, 182. doi: 10.1128/IAI.00101-08, 164. Cohen MS, Cannon JG.
Johnson AP, Taylor-Robinson D, McGee ZA. 2020 Jun 9;8:439. doi: 10.3389/fcell.2020.00439.
Experimental gonococcal genital tract infection and opacity protein expression in estradiol-treated mice. Neisseria gonorrhoeae Neisseria gonorrhoeae is a Gram-negative coccus, 0.6 to 1.0 µm in diameter, usually seen in pairs with adjacent flattened sides (Figure 1 Left and Fig 2 below). Mol Microbiol. (2017) 8:875. doi: 10.1038/s41467-017-00901-0, 160. Mol Microbiol. García KP, Rubilar PS, Vargas MF, Cardenas H, Rios MA, Orihuela PA, et al. Pardo-Saganta A, Tata PR, Law BM, Saez B, Chow RD, Prabhu M, et al.
Derbie A, Mekonnen D, Woldeamanuel Y, Abebe T. Antimicrob Resist Infect Control. These data suggest that whatever factors are driving Opa protein production at the endocervix, Opa proteins may be turned off or selected against when bacteria are infecting the fallopian tube. doi: 10.4049/jimmunol.168.5.2424, 126.
Host species-specific damage to oviduct mucosa by Neisseria gonorrhoeae lipopolysaccharide. doi: 10.1097/PGP.0000000000000095, 137. It is not known which CEACAM (or HSPG) is the most available target of Opa proteins in the fallopian tube, nor is it known what threshold level of expression is needed for Opa-CEACAM binding in any given tissue. Despite the lack of TLR4 expression in certain regions of the FRT, and a confirmed lack of expression in isolated vaginal, ectocervical and endocervical cells lines, GC is still able to activate NF-κB and induce proinflammatory cytokines in End-1 endocervical cells in the absence of TLR4 (125). 19. Received: 31 August 2018; Accepted: 02 November 2018; Published: 21 November 2018. The damage caused by gonococcal infection and the subsequent inflammatory response produce the condition known as pelvic inflammatory disease (PID). Its three-dimensional structure has allowed observations about the speed of cellular invasion, the process of transcytosis and colonization of the sub-epithelial space. doi: 10.1128/IAI.01267-10, 69. J Biomed Biotechnol. doi: 10.1136/sti.55.4.256, 25. (2014) 5:316. doi: 10.3389/fimmu.2014.00316. 1. Transfer of gonococcal urethritis from man to chimpanzee. GC, gonococcus; PMN, polymorphonuclear leukocyte (neutrophil); Mac, macrophage; DC, dendritic cell; TH, T helper cell; LOS, lipooligosaccharide; PG, peptidoglycan; HBP, heptose-1,7-bisphosphate; TLR, Toll-like receptor; MMP, matrix metalloproteinase; TJ, tight junction; AJ, adherens junction; NO•, nitric oxide. The majority of Opa proteins (which vary in number between gonococcal strains) bind to distinct CEACAMs, though at least one Opa binds instead to heparin-sulfate proteoglycans (HSPG) (88). Toussi DN, Carraway M, Wetzler LM, Lewis LA, Liu X, Massari P. The amino acid sequence of Neisseria lactamica PorB surface-exposed loops influences Toll-like receptor 2-dependent cell activation. Br J Exp Pathol. 2020 Jun 3;11:1299. doi: 10.3389/fmicb.2020.01299. During fallopian tube explant infections, GC were more often seen contacting (or in close proximity to) non-ciliated cells, which could facilitate the induction of a protective response. Shao R, Wang X, Wang W, Stener-Victorin E, Mallard C, Brännström M, Billig H. Fertil Steril.
J Exp Med. Variable localization of Toll-like receptors in human fallopian tube epithelial cells. . Gonococci most often colonize the mucous membrane of the genito -urinary tract or rectum.
Packiam M, Wu H, Veit SJ, Mavrogiorgos N, Jerse AE, Ingalls RR. As a bacterium adapted to life in a human host, the gonococcus presents a challenge to the development of model systems for probing host-microbe interactions. J Infect Dis. Characterization of the immune cell repertoire in the normal fallopian tube. PLoS One. Polymicrobial etiology of acute pelvic inflammatory disease. (2010b) 107:11056–61. Cell Microbiol. That finding was disputed by later work that surveyed the entire FRT and found detectable expression only in the fallopian tube (106).
PLoS ONE (2013) 8:e56705. For fallopian tubes in particular, the mixture of ciliated and non-ciliated cells, and the differences in their behavior during infection is key to the observed pathology.