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      Unraveling Neisseria meningitidis pathogenesis: from functional genomics to experimental models

      review-article
      a , 1
      F1000Research
      F1000Research
      Neisseria meningitidis, N. meningitidis, pathogenesis, genomics, omics

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          Abstract

          Neisseria meningitidis is a harmless commensal bacterium finely adapted to humans. Unfortunately, under “privileged” conditions, it adopts a “devious” lifestyle leading to uncontrolled behavior characterized by the unleashing of molecular weapons causing potentially lethal disease such as sepsis and acute meningitis. Indeed, despite the lack of a classic repertoire of virulence genes in N. meningitidis separating commensal from invasive strains, molecular epidemiology and functional genomics studies suggest that carriage and invasive strains belong to genetically distinct populations characterized by an exclusive pathogenic potential. In the last few years, “omics” technologies have helped scientists to unwrap the framework drawn by N. meningitidis during different stages of colonization and disease. However, this scenario is still incomplete and would benefit from the implementation of physiological tissue models for the reproduction of mucosal and systemic interactions in vitro. These emerging technologies supported by recent advances in the world of stem cell biology hold the promise for a further understanding of N. meningitidis pathogenesis.

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          Most cited references73

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          Epidemic meningitis, meningococcaemia, and Neisseria meningitidis.

          Meningococcus, an obligate human bacterial pathogen, remains a worldwide and devastating cause of epidemic meningitis and sepsis. However, advances have been made in our understanding of meningococcal biology and pathogenesis, global epidemiology, transmission and carriage, host susceptibility, pathophysiology, and clinical presentations. Approaches to diagnosis, treatment, and chemoprophylaxis are now in use on the basis of these advances. Importantly, the next generation of meningococcal conjugate vaccines for serogroups A, C, Y, W-135, and broadly effective serogroup B vaccines are on the horizon, which could eliminate the organism as a major threat to human health in industrialised countries in the next decade. The crucial challenge will be effective introduction of new meningococcal vaccines into developing countries, especially in sub-Saharan Africa, where they are urgently needed.
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            Meningococcal disease.

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              Microfluidic blood-brain barrier model provides in vivo-like barrier properties for drug permeability screening.

              Efficient delivery of therapeutics across the neuroprotective blood-brain barrier (BBB) remains a formidable challenge for central nervous system drug development. High-fidelity in vitro models of the BBB could facilitate effective early screening of drug candidates targeting the brain. In this study, we developed a microfluidic BBB model that is capable of mimicking in vivo BBB characteristics for a prolonged period and allows for reliable in vitro drug permeability studies under recirculating perfusion. We derived brain microvascular endothelial cells (BMECs) from human induced pluripotent stem cells (hiPSCs) and cocultured them with rat primary astrocytes on the two sides of a porous membrane on a pumpless microfluidic platform for up to 10 days. The microfluidic system was designed based on the blood residence time in human brain tissues, allowing for medium recirculation at physiologically relevant perfusion rates with no pumps or external tubing, meanwhile minimizing wall shear stress to test whether shear stress is required for in vivo-like barrier properties in a microfluidic BBB model. This BBB-on-a-chip model achieved significant barrier integrity as evident by continuous tight junction formation and in vivo-like values of trans-endothelial electrical resistance (TEER). The TEER levels peaked above 4000 Ω · cm(2) on day 3 on chip and were sustained above 2000 Ω · cm(2) up to 10 days, which are the highest sustained TEER values reported in a microfluidic model. We evaluated the capacity of our microfluidic BBB model to be used for drug permeability studies using large molecules (FITC-dextrans) and model drugs (caffeine, cimetidine, and doxorubicin). Our analyses demonstrated that the permeability coefficients measured using our model were comparable to in vivo values. Our BBB-on-a-chip model closely mimics physiological BBB barrier functions and will be a valuable tool for screening of drug candidates. The residence time-based design of a microfluidic platform will enable integration with other organ modules to simulate multi-organ interactions on drug response. Biotechnol. Bioeng. 2017;114: 184-194. © 2016 Wiley Periodicals, Inc.
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                Author and article information

                Journal
                F1000Res
                F1000Res
                F1000Research
                F1000Research
                F1000Research (London, UK )
                2046-1402
                26 July 2017
                2017
                : 6
                : 1228
                Affiliations
                [1 ]Toscana Life Sciences Foundation, Sienna, Italy
                Author notes

                Competing interests: The author declares that he has no competing interests.

                Author information
                https://orcid.org/0000-0002-9752-5844
                Article
                10.12688/f1000research.11279.1
                5531161
                28781769
                520c79ed-abdf-4b54-adea-79d701505bf6
                Copyright: © 2017 Soriani M

                This is an open access article distributed under the terms of the Creative Commons Attribution Licence, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 17 July 2017
                Funding
                The author(s) declared that no grants were involved in supporting this work.
                Categories
                Review
                Articles
                Airway/Respiratory Physiology
                Bacterial Infections
                Cell Adhesion
                Cellular Microbiology & Pathogenesis
                Genomics
                Immunity to Infections
                Immunomodulation
                Immunopharmacology & Hematologic Pharmacology
                Medical Microbiology
                Microbial Evolution & Genomics
                Morphogenesis & Cell Biology
                Preventive Medicine

                neisseria meningitidis,n. meningitidis,pathogenesis,genomics,omics

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