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Lynn E. Connolly

Bio: Lynn E. Connolly is an academic researcher from University of Washington. The author has contributed to research in topics: Tuberculosis & Mycobacterium tuberculosis. The author has an hindex of 5, co-authored 5 publications receiving 1095 citations.

Papers
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Journal ArticleDOI
01 Apr 2011-Cell
TL;DR: The existence of multidrug-tolerant organisms that arise within days of infection, are enriched in the replicating intracellular population, and are amplified and disseminated by the tuberculous granuloma are described.

447 citations

01 Jan 2007
TL;DR: A flowthrough fish facility is constructed for the large-scale longitudinal study of M. marinum-induced tuberculosis in adult zebrafish where both innate and adaptive immunity are operant, demonstrating that the control of fish tuberculosis is dependent on adaptive immunity.
Abstract: ABSTRACT The zebrafish, a genetically tractable model vertebrate, is naturally susceptible to tuberculosis caused by Mycobacterium marinum, a close genetic relative of the causative agent of human tuberculosis, Mycobacterium tuberculosis. We previously developed a zebrafish embryo-M. marinum infection model to study host-pathogen interactions in the context of innate immunity. Here, we have constructed a flowthrough fish facility for the large-scale longitudinal study of M. marinum-induced tuberculosis in adult zebrafish where both innate and adaptive immunity are operant. We find that zebrafish are exquisitely susceptible to M. marinum strain M. Intraperitoneal injection of five organisms produces persistent granulomatous tuberculosis, while the injection of ∼9,000 organisms leads to acute, fulminant disease. Bacterial burden, extent of disease, pathology, and host mortality progress in a time- and dose-dependent fashion. Zebrafish tuberculous granulomas undergo caseous necrosis, similar to human tuberculous granulomas. In contrast to mammalian tuberculous granulomas, zebrafish lesions contain few lymphocytes, calling into question the role of adaptive immunity in fish tuberculosis. However, like rag1 mutant mice infected with M. tuberculosis, we find that rag1 mutant zebrafish are hypersusceptible to M. marinum infection, demonstrating that the control of fish tuberculosis is dependent on adaptive immunity. We confirm the previous finding that M. marinum ΔRD1 mutants are attenuated in adult zebrafish and extend this finding to show that ΔRD1 predominantly produces nonnecrotizing, loose macrophage aggregates. This observation suggests that the macrophage aggregation defect associated with ΔRD1 attenuation in zebrafish embryos is ongoing during adult infection.

273 citations

Journal ArticleDOI
TL;DR: In this article, a large-scale longitudinal study of M. marinum-induced tuberculosis in adult zebrafish where both innate and adaptive immunity are operant was conducted. And they found that the adaptive immunity is dependent on adaptive immunity.
Abstract: The zebrafish, a genetically tractable model vertebrate, is naturally susceptible to tuberculosis caused by Mycobacterium marinum, a close genetic relative of the causative agent of human tuberculosis, Mycobacterium tuberculosis. We previously developed a zebrafish embryo-M. marinum infection model to study host-pathogen interactions in the context of innate immunity. Here, we have constructed a flowthrough fish facility for the large-scale longitudinal study of M. marinum-induced tuberculosis in adult zebrafish where both innate and adaptive immunity are operant. We find that zebrafish are exquisitely susceptible to M. marinum strain M. Intraperitoneal injection of five organisms produces persistent granulomatous tuberculosis, while the injection of approximately 9,000 organisms leads to acute, fulminant disease. Bacterial burden, extent of disease, pathology, and host mortality progress in a time- and dose-dependent fashion. Zebrafish tuberculous granulomas undergo caseous necrosis, similar to human tuberculous granulomas. In contrast to mammalian tuberculous granulomas, zebrafish lesions contain few lymphocytes, calling into question the role of adaptive immunity in fish tuberculosis. However, like rag1 mutant mice infected with M. tuberculosis, we find that rag1 mutant zebrafish are hypersusceptible to M. marinum infection, demonstrating that the control of fish tuberculosis is dependent on adaptive immunity. We confirm the previous finding that M. marinum DeltaRD1 mutants are attenuated in adult zebrafish and extend this finding to show that DeltaRD1 predominantly produces nonnecrotizing, loose macrophage aggregates. This observation suggests that the macrophage aggregation defect associated with DeltaRD1 attenuation in zebrafish embryos is ongoing during adult infection.

270 citations

Journal ArticleDOI
TL;DR: It is argued that understanding and countering general bacterial mechanisms of phenotypic antibiotic resistance may hold the key to reducing the duration of treatment of all recalcitrant bacterial infections, including tuberculosis.
Abstract: The authors argue that understanding and countering general bacterial mechanisms of phenotypic antibiotic resistance may hold the key to reducing the duration of treatment of all recalcitrant bacterial infections, including tuberculosis.

202 citations


Cited by
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Journal ArticleDOI
TL;DR: This Review surveys the achievements and potential of zebrafish for modelling human diseases and for drug discovery and development.
Abstract: Despite the pre-eminence of the mouse in modelling human disease, several aspects of murine biology limit its routine use in large-scale genetic and therapeutic screening. Many researchers who are interested in an embryologically and genetically tractable disease model have now turned to zebrafish. Zebrafish biology allows ready access to all developmental stages, and the optical clarity of embryos and larvae allow real-time imaging of developing pathologies. Sophisticated mutagenesis and screening strategies on a large scale, and with an economy that is not possible in other vertebrate systems, have generated zebrafish models of a wide variety of human diseases. This Review surveys the achievements and potential of zebrafish for modelling human diseases and for drug discovery and development.

1,998 citations

Journal ArticleDOI
TL;DR: This Opinion article describes recent studies of tolerance, resistance and persistence, outlining how a clear and distinct definition for each phenotype can be developed from these findings and proposes a framework for classifying the drug response of bacterial strains according to these definitions that is based on the measurement of the minimum inhibitory concentration.
Abstract: Antibiotic tolerance is associated with the failure of antibiotic treatment and the relapse of many bacterial infections. However, unlike resistance, which is commonly measured using the minimum inhibitory concentration (MIC) metric, tolerance is poorly characterized, owing to the lack of a similar quantitative indicator. This may lead to the misclassification of tolerant strains as resistant, or vice versa, and result in ineffective treatments. In this Opinion article, we describe recent studies of tolerance, resistance and persistence, outlining how a clear and distinct definition for each phenotype can be developed from these findings. We propose a framework for classifying the drug response of bacterial strains according to these definitions that is based on the measurement of the MIC together with a recently defined quantitative indicator of tolerance, the minimum duration for killing (MDK). Finally, we discuss genes that are associated with increased tolerance - the 'tolerome' - as targets for treating tolerant bacterial strains.

1,019 citations

Journal ArticleDOI
01 Aug 2010-Gut
TL;DR: The most commonly recommended triple Helicobacter pylori regimen (proton pump inhibitor (PPI), amoxicillin and clarithromycin) now provides unacceptably low treatment success as discussed by the authors.
Abstract: With few exceptions, the most commonly recommended triple Helicobacter pylori regimen (proton pump inhibitor (PPI), amoxicillin and clarithromycin) now provides unacceptably low treatment success. A review of worldwide results suggests that successful eradication using a triple regimen is not consistently observed in any population. Clinicians should use ‘only use what works locally’ and ignore consensus statements and society guidelines if they are not consistent with local results. Clinical trials should be result based, with the goal of identifying regimens with >90–95% success. New treatments should be only be compared with the currently locally effective treatment (>90%) or a historical untreated control (which has been shown to reliably yield 0% eradication); trials using placebos or treatments known to be inferior are with rare exceptions unethical. If a highly effective regimen is not available locally, we recommend trying a 14 day concomitant quadruple treatment regimen containing a PPI, amoxicillin, clarithromycin and a nitroimidazole; 10 day sequential treatment (PPI plus amoxicillin for 5 days followed by a PPI, clarithromycin and a nitroimidazole for 5 days); or 14 day bismuth-containing quadruple treatments. Treatments needing further evaluation include those containing furazolidone or nitazoxanide, hybrids of sequential–concomitant therapies and amoxicillin–PPI dual therapy with PPI doses such that they maintain intragastric pH >6.

896 citations

Journal ArticleDOI
09 Jan 2009-Cell
TL;DR: In this paper, the authors use quantitative intravital microscopy to reveal distinct steps of granuloma formation and assess their consequence for infection, showing that pathogenic mycobacteria exploit the granulomas during the innate immune phase for local expansion and systemic dissemination.

821 citations

Journal ArticleDOI
TL;DR: Current concepts and recent advances in TB drug discovery and development are covered, including an update of ongoing TB treatment trials, newer clinical trial designs, TB biomarkers and adjunct host-directed therapies.
Abstract: Despite the introduction 40 years ago of the inexpensive and effective four-drug (isoniazid, rifampicin, pyrazinamide and ethambutol) treatment regimen, tuberculosis (TB) continues to cause considerable morbidity and mortality worldwide. For the first time since the 1960s, new and novel drugs and regimens for all forms of TB are emerging. Such regimens are likely to utilize both repurposed drugs and new chemical entities, and several of these regimens are now progressing through clinical trials. This article covers current concepts and recent advances in TB drug discovery and development, including an update of ongoing TB treatment trials, newer clinical trial designs, TB biomarkers and adjunct host-directed therapies.

765 citations