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, 16 (4), 226-240

Neisseria Gonorrhoeae Host Adaptation and Pathogenesis


Neisseria Gonorrhoeae Host Adaptation and Pathogenesis

Sarah Jane Quillin et al. Nat Rev Microbiol.


The host-adapted human pathogen Neisseria gonorrhoeae is the causative agent of gonorrhoea. 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. 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. This knowledge will facilitate disease prevention, surveillance and control, improve diagnostics and may help to facilitate the development of effective vaccines or new therapeutics. In this Review, we discuss sex-related symptomatic gonorrhoeal disease and provide an overview of the bacterial factors that are important for the different stages of pathogenesis, including transmission, colonization and immune evasion, and we discuss the problem of antibiotic resistance.


Figure 1:
Figure 1:. Overview of Neisseria gonorrhoeae infection
During initial infection, N. gonorrhoeae adheres to host epithelial cells through Type IV pili (step 1), which retract and enable epithelial interactions with other prominent surface structures,. After initial adherence, N. gonorrhoeae replicates and forms microcolonies (step 2), and possibly biofilms,, and likely competes with the resident microbiota. When colonizing the epithelium, N. gonorrhoeae is capable of invasion and transcytosis. During these initial stages in infection, N. gonorrhoeae releases fragments of peptidoglycan, lipooligosaccharide (LOS), and outer membrane vesicles(OMVs),, (step 3) that activate Toll-like receptor (TLR) and nucleotide-binding oligomerization domain-like receptor (NOD) signaling in epithelial cells, macrophages, and dendritic cells (DCs),,. NOD and TLR signaling from these cells leads to activation of inflammatory transcription factors and the release of cytokines and chemokines (step 4). N. gonorrhoeae also releases heptose-1,7-bisphosphate (HBP) that activates TRAF-interacting protein with forkhead-associated domain (TIFA) immunity (step 5). The release of pro-inflammatory cytokines and chemokines by these innate immune signaling pathways creates cytokine and chemokine gradients that recruit large numbers of polymorphonuclear leukocytes (PMNs) neutrophils to the site of infection (step 6), where they interact with and phagocytose N. gonorrhoeae. The influx of neutrophils comprises a purulent exudate that then facilitates tranmission (step 7).
Figure 2:
Figure 2:. Overview of Neisseria gonorrhoeae pathogenesis factors
As a host-restricted pathogen, N. gonorrhoeae encodes a relatively small repertoire of pathogenesis and colonization factors compared to other gram-negative bacteria. a) N. gonorrhoeae uses an array of surface structures to adhere to host cells, occasionally invade host cells, and evade the immune system,,. These surface structures include Type IV pili, LOS, porin, and Opa proteins. b) Efflux pumps protect N. gonorrhoeae from antimicrobials and fatty acid stress, and membrane transporters allow N. gonorrhoeae to coopt nutrients from the surrounding environment,,-. Pump FarAB controls fatty acid transport, while pump MtrCDE controls antimicrobial peptides. Pumps LpbAB, HpuAB, and TbpAB contribute to iron transport and iron homeostasis. c) A set of transcriptional regulators, discussed in detail in the main text and Figure 3, induce transcriptional programs to adapt and respond to changing environmental conditions during infection,,-. The regulons that respond to iron levels, oxidative conditions, and oxygen concentration are co-regulated and interconnected. d) Protective enzymes like catalase and MsrAB detoxify reactive oxygen species (ROS), like superoxide anion O2, hydrogen peroxide H2O2, and hypochlorous acid HOCl, that are generated endogenously and by neutrophils.
Figure 3:
Figure 3:. Characterized transcriptional regulatory factors of Neisseria gonorrhoeae.
To adapt to a changing urogenital, rectal, and oropharyngeal environment during infection, N. gonorrhoeae has relatively only a few regulatory networks. N. gonorrhoeae has regulators that specifically respond to metal availability, antimicrobial peptides, oxygen availability, membrane stress, and protein misfolding. These systems are often overlapping, particularly at the level of iron and oxygen availability. Transcriptional regulator MpeR is known to repress the antimicrobial efflux pump operon repressor MtrR; both regulators mediate antimicrobial peptide efflux,. Two-component regulatory system composed of sensor histidine kinase and response regulator MisS-MisR respond to membrane perturbations and control membrane homeostasis. Oxygen-sensor FNR responds to oxygen concentrations and contributes to regulation of genes encoding AniA and NorB, which control a denitrification system required for anaerobic respiration,. Iron-response master regulator Fur responds to fluctuating iron levels and controls iron homeostasis under iron-replete and iron-starvation conditions. PerR responds to fluctuating zinc and manganese levels, controlling metal influx through MntABC and zinc and manganese homeostasis. RpoH responds to heat shock and protein misfolding and controls a regulon that maintains protein-folding homeostasis . OxyR responds to the presence of reactive oxygen species and maintains redox homeostasis.
Figure 4:
Figure 4:. Neisseria gonorrhoeae evades and modulates the innate and adaptive immune system.
a) During infection, both the alternative and classical complement pathways may be activated by N. gonorrhoeae. N. gonorrhoeae binds complement proteins to prevent opsonization and killing by membrane attack complexes, as well as siaylates its LOS to hide from the complement system. N. gonorrhoeae binds host Factor H and C4bp, becoming serum resistant by presenting as ‘self’ and shielding itself from complement recognition, N. gonorrhoeae also binds to the alternative complement pathway receptor CR3 and the receptor for iC3b, a process thought to aid in epithelial cell invasion. N. gonorrhoeae binds C3b through Lipid A on its LOS, rapidly inactivating C3b to iC3b through factor I. b) N. gonorrhoeae is able to survive in and around macrophages and neutrophils during infection, and modulate the immune activating properties of dendritic cells,,,,,,. In macrophages, N. gonorrhoeae is able to survive inside the phagosome and modulate apoptosis and production of inflammatory cytokines . The bacteria polarize macrophages, resulting in macrophages less capable of T cell activation, and similarly, dendritic cells exposed to N. gonorrhoeae are less capable of stimulating T cell proliferation. The interactions of N. gonorrhoeae and neutrophils is complex and is discussed in detail in the text. c) N. gonorrhoeae infection does not generate immunological memory, due to the ability of N. gonorrhoeae to antigenically and phase vary its surface structures including Type IV pili, Opa proteins, and LOS. In addition, N. gonorrhoeae modulates the adaptive immune response by suppressing T helper cell proliferation and subsequent activation through influencing cytokine production,,.
Figure 5:
Figure 5:. Antibiotic resistance in Neisseria gonorrhoeae a. Main resistance determinants of N. gonorrhoeae.
Transpeptidase penicillin binding protein 2 (PBP2), encoded by penA is a periplasmic transpeptidase and the main lethal target of cephalosporins; most resistant isolates contain mosaic mutations in penA. The efflux pump, MtrCDE, composed of subunits MtrE, MtrC, and MtrD, and its repressor MtrR contribute to N. gonorrhoeae resistance through antimicrobial efflux. The major porin protein, PorB, encoded by penB, is also a main resistance determinant that cannot manifest independently, but requires concomitant mutation in mtrR. b. Timeline of antibiotic resistance development. Since the treatment of N. gonorrhoeae with sulfonamides in the 1930s, N. gonorrhoeae have acquired genetic resistance determinants that prevent killing by all major classes of antibiotics that are used as first line methods of treatment for gonorrhea infection,,,. As shown in the timeline, each new class of antibiotics that served as first line treatment for N. gonorrhoeae have been stopped as all strains gained resistance. Recently, resistance was observed for the last available first line treatment for N. gonorrhoeae infection, the extended-spectrum cephalosporins. The ability of N. gonorrhoeae to evolve resistance has lead the World Health Organization and Center for Disease Control, United States to term it a ‘superbug’, and speculate that, if new therapies are not developed soon, we may face an era of untreatable antimicrobial resistant gonorrhea.

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