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      Neisseria gonorrhoeae: Drug Resistance, Mouse Models, and Vaccine Development

      1 , 2 , 3 , 1 , 4
      Annual Review of Microbiology
      Annual Reviews

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          Abstract

          Gonorrhea, an obligate human infection, is on the rise worldwide and gonococcal strains resistant to many antibiotics are emerging. Appropriate antimicrobial treatment and prevention, including effective vaccines, are urgently needed. To guide investigation, an experimental model of genital tract infection has been developed in female mice to study mechanisms by which Neisseria gonorrhoeae evades host-derived antimicrobial factors and to identify protective and immunosuppressive pathways. Refinements of the animal model have also improved its use as a surrogate host of human infection and accelerated the testing of novel therapeutic and prophylactic compounds against gonococcal infection. Reviewed herein are the (a) history of antibiotic usage and resistance against gonorrhea and the consequences of resistance mechanisms that may increase gonococcal fitness and therefore the potential for spread, (b) use of gonococcal infection in the animal model system to study mechanisms of pathogenesis and host defenses, and (c) current status of vaccine development.

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          Most cited references113

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          The complex role of estrogens in inflammation.

          There is still an unresolved paradox with respect to the immunomodulating role of estrogens. On one side, we recognize inhibition of bone resorption and suppression of inflammation in several animal models of chronic inflammatory diseases. On the other hand, we realize the immunosupportive role of estrogens in trauma/sepsis and the proinflammatory effects in some chronic autoimmune diseases in humans. This review examines possible causes for this paradox. This review delineates how the effects of estrogens are dependent on criteria such as: 1) the immune stimulus (foreign antigens or autoantigens) and subsequent antigen-specific immune responses (e.g., T cell inhibited by estrogens vs. activation of B cell); 2) the cell types involved during different phases of the disease; 3) the target organ with its specific microenvironment; 4) timing of 17beta-estradiol administration in relation to the disease course (and the reproductive status of a woman); 5) the concentration of estrogens; 6) the variability in expression of estrogen receptor alpha and beta depending on the microenvironment and the cell type; and 7) intracellular metabolism of estrogens leading to important biologically active metabolites with quite different anti- and proinflammatory function. Also mentioned are systemic supersystems such as the hypothalamic-pituitary-adrenal axis, the sensory nervous system, and the sympathetic nervous system and how they are influenced by estrogens. This review reinforces the concept that estrogens have antiinflammatory but also proinflammatory roles depending on above-mentioned criteria. It also explains that a uniform concept as to the action of estrogens cannot be found for all inflammatory diseases due to the enormous variable responses of immune and repair systems.
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            Antimicrobial resistance in Neisseria gonorrhoeae in the 21st century: past, evolution, and future.

            Neisseria gonorrhoeae is evolving into a superbug with resistance to previously and currently recommended antimicrobials for treatment of gonorrhea, which is a major public health concern globally. Given the global nature of gonorrhea, the high rate of usage of antimicrobials, suboptimal control and monitoring of antimicrobial resistance (AMR) and treatment failures, slow update of treatment guidelines in most geographical settings, and the extraordinary capacity of the gonococci to develop and retain AMR, it is likely that the global problem of gonococcal AMR will worsen in the foreseeable future and that the severe complications of gonorrhea will emerge as a silent epidemic. By understanding the evolution, emergence, and spread of AMR in N. gonorrhoeae, including its molecular and phenotypic mechanisms, resistance to antimicrobials used clinically can be anticipated, future methods for genetic testing for AMR might permit region-specific and tailor-made antimicrobial therapy, and the design of novel antimicrobials to circumvent the resistance problems can be undertaken more rationally. This review focuses on the history and evolution of gonorrhea treatment regimens and emerging resistance to them, on genetic and phenotypic determinants of gonococcal resistance to previously and currently recommended antimicrobials, including biological costs or benefits; and on crucial actions and future advances necessary to detect and treat resistant gonococcal strains and, ultimately, retain gonorrhea as a treatable infection. Copyright © 2014, American Society for Microbiology. All Rights Reserved.
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              Is Neisseria gonorrhoeae initiating a future era of untreatable gonorrhea?: detailed characterization of the first strain with high-level resistance to ceftriaxone.

              Recently, the first Neisseria gonorrhoeae strain (H041) that is highly resistant to the extended-spectrum cephalosporin (ESC) ceftriaxone, the last remaining option for empirical first-line treatment, was isolated. We performed a detailed characterization of H041, phenotypically and genetically, to confirm the finding, examine its antimicrobial resistance (AMR), and elucidate the resistance mechanisms. H041 was examined using seven species-confirmatory tests, antibiograms (30 antimicrobials), porB sequencing, N. gonorrhoeae multiantigen sequence typing (NG-MAST), multilocus sequence typing (MLST), and sequencing of ESC resistance determinants (penA, mtrR, penB, ponA, and pilQ). Transformation, using appropriate recipient strains, was performed to confirm the ESC resistance determinants. H041 was assigned to serovar Bpyust, MLST sequence type (ST) ST7363, and the new NG-MAST ST4220. H041 proved highly resistant to ceftriaxone (2 to 4 μg/ml, which is 4- to 8-fold higher than any previously described isolate) and all other cephalosporins, as well as most other antimicrobials tested. A new penA mosaic allele caused the ceftriaxone resistance. In conclusion, N. gonorrhoeae has now shown its ability to also develop ceftriaxone resistance. Although the biological fitness of ceftriaxone resistance in N. gonorrhoeae remains unknown, N. gonorrhoeae may soon become a true superbug, causing untreatable gonorrhea. A reduction in the global gonorrhea burden by enhanced disease control activities, combined with wider strategies for general AMR control and enhanced understanding of the mechanisms of emergence and spread of AMR, which need to be monitored globally, and public health response plans for global (and national) perspectives are important. Ultimately, the development of new drugs for efficacious gonorrhea treatment is necessary.
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                Author and article information

                Journal
                Annual Review of Microbiology
                Annu. Rev. Microbiol.
                Annual Reviews
                0066-4227
                1545-3251
                September 08 2017
                September 08 2017
                : 71
                : 1
                : 665-686
                Affiliations
                [1 ]Division of Infectious Diseases and Immunology, Department of Medicine, University of Massachusetts Medical School, Worcester, Massachusetts 01605-4321;,
                [2 ]Department of Microbiology and Immunology and Emory Antibiotic Resistance Center, Emory University School of Medicine, Atlanta, Georgia 30322
                [3 ]Laboratories of Bacterial Pathogenesis, Veterans Affairs Medical Center, Decatur, Georgia 30033;
                [4 ]Department of Microbiology and Immunology, F. Edward Hébert School of Medicine, Uniformed Services University, Bethesda, Maryland 20814-4799;
                Article
                10.1146/annurev-micro-090816-093530
                28886683
                13c2f86d-e51d-4c01-bc31-f1bf39c4de11
                © 2017

                http://www.annualreviews.org/licenses/tdm

                History

                Social policy & Welfare,General medicine,Environmental change,Infectious disease & Microbiology,Public health

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