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      Is gonococcal disease preventable? The importance of understanding immunity and pathogenesis in vaccine development

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          Abstract

          Gonorrhea is a major, global public health problem for which there is no vaccine. The continuing emergence of antibiotic-resistant strains raises concerns that untreatable Neisseria gonorrhoeae may become widespread in the near future. Consequently, there is an urgent need for increased efforts towards the development of new anti-gonococcal therapeutics and vaccines, as well as suitable models for potential pre-clinical vaccine trials. Several current issues regarding gonorrhea are discussed herein , including the global burden of disease, the emergence of antibiotic-resistance, the status of vaccine development and, in particular, a focus on the model systems available to evaluate drug and vaccine candidates. Finally, alternative approaches to evaluate vaccine candidates are presented. Such approaches may provide valuable insights into the protective mechanisms, and correlates of protection, required to prevent gonococcal transmission, local infection and disease sequelae.

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          Most cited references160

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          Of mice and not men: differences between mouse and human immunology.

          Mice are the experimental tool of choice for the majority of immunologists and the study of their immune responses has yielded tremendous insight into the workings of the human immune system. However, as 65 million years of evolution might suggest, there are significant differences. Here we outline known discrepancies in both innate and adaptive immunity, including: balance of leukocyte subsets, defensins, Toll receptors, inducible NO synthase, the NK inhibitory receptor families Ly49 and KIR, FcR, Ig subsets, the B cell (BLNK, Btk, and lambda5) and T cell (ZAP70 and common gamma-chain) signaling pathway components, Thy-1, gammadelta T cells, cytokines and cytokine receptors, Th1/Th2 differentiation, costimulatory molecule expression and function, Ag-presenting function of endothelial cells, and chemokine and chemokine receptor expression. We also provide examples, such as multiple sclerosis and delayed-type hypersensitivity, where complex multicomponent processes differ. Such differences should be taken into account when using mice as preclinical models of human disease.
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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
                Crit Rev Microbiol
                Crit. Rev. Microbiol
                IMBY
                imby20
                Critical Reviews in Microbiology
                Taylor & Francis
                1040-841X
                1549-7828
                1 November 2016
                23 January 2016
                : 42
                : 6
                : 928-941
                Affiliations
                [ a ]Department of Pediatrics, The Research Institute at Nationwide Children's Hospital and The Ohio State University Columbus, OH, USA
                [ b ]Institute for Glycomics, Griffith University , Gold Coast, Australia
                [ c ]Department of Microbiology, The University of Iowa , Iowa City, IA, USA
                Author notes
                Address for correspondence: Dr. Kate L. Seib, Institute for Glycomics, Griffith University , Gold Coast, Australia. E-mail: k.seib@ 123456griffith.edu.au
                Jennifer L. Edwards, The Research Institute at Nationwide Children’s Hospital , Columbus, OH, USA. E-mail: Jennifer.Edwards@ 123456nationwidechildrens.org
                Article
                1105782
                10.3109/1040841X.2015.1105782
                4958600
                26805040
                e28b1eb8-8326-4054-a984-02500b149fe1
                © 2016 The Author(s). Published by Taylor & Francis.

                This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License ( http://creativecommons.org/Licenses/by-nc-nd/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited, and is not altered, transformed, or built upon in any way.

                History
                : 31 July 2015
                : 1 October 2015
                : 6 October 2015
                Page count
                Pages: 14
                Categories
                Review
                Review Article

                candidate vaccine antigens,gonorrhea,infection models,multi-drug resistance,neisseria gonorrhoeae

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