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      Genetic Architecture of Group A Streptococcal Necrotizing Soft Tissue Infections in the Mouse

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          Abstract

          Host genetic variations play an important role in several pathogenic diseases, and we have previously provided strong evidences that these genetic variations contribute significantly to differences in susceptibility and clinical outcomes of invasive Group A Streptococcus (GAS) infections, including sepsis and necrotizing soft tissue infections (NSTIs). Our initial studies with conventional mouse strains revealed that host genetic variations and sex differences play an important role in orchestrating the severity, susceptibility and outcomes of NSTIs. To understand the complex genetic architecture of NSTIs, we utilized an unbiased, forward systems genetics approach in an advanced recombinant inbred (ARI) panel of mouse strains (BXD). Through this approach, we uncovered interactions between host genetics, and other non-genetic cofactors including sex, age and body weight in determining susceptibility to NSTIs. We mapped three NSTIs-associated phenotypic traits (i.e., survival, percent weight change, and lesion size) to underlying host genetic variations by using the WebQTL tool, and identified four NSTIs-associated quantitative genetic loci (QTL) for survival on mouse chromosome (Chr) 2, for weight change on Chr 7, and for lesion size on Chr 6 and 18 respectively. These QTL harbor several polymorphic genes. Identification of multiple QTL highlighted the complexity of the host-pathogen interactions involved in NSTI pathogenesis. We then analyzed and rank-ordered host candidate genes in these QTL by using the QTLminer tool and then developed a list of 375 candidate genes on the basis of annotation data and biological relevance to NSTIs. Further differential expression analyses revealed 125 genes to be significantly differentially regulated in susceptible strains compared to their uninfected controls. Several of these genes are involved in innate immunity, inflammatory response, cell growth, development and proliferation, and apoptosis. Additional network analyses using ingenuity pathway analysis (IPA) of these 125 genes revealed interleukin-1 beta network as key network involved in modulating the differential susceptibility to GAS NSTIs.

          Author Summary

          GAS bacteria are major human pathogens that are responsible for millions of infections worldwide, including severe and deadly NSTIs. Several studies have identified numerous GAS secreted virulence factors including proteases, DNases, and superantigens, which mediate several pathologic features of GAS NSTIs. However, the exact role of host genetic and/or nongenetic factors in GAS NSTIs has not been studied so far. To understand these contributions, we undertook the present study utilizing the ARI panel of BXD strains. We found that host genetic context and sex differences can modulate host-pathogen interplay and accordingly potentiate disease severity, manifestations, and outcomes. We also mapped the genetic susceptibility loci of GAS NSTIs to four mouse chromosomes, namely 2, 6, 7 and 18, harboring several polymorphic genes. We believe that these findings will be helpful in uncovering further regulatory events of host-mediated GAS pathogenesis that may occur once the pathogen becomes invasive.

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          Most cited references41

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          A new set of BXD recombinant inbred lines from advanced intercross populations in mice

          Background Recombinant inbred (RI) strains are an important resource for mapping complex traits in many species. While large RI panels are available for Arabidopsis, maize, C. elegans, and Drosophila, mouse RI panels typically consist of fewer than 30 lines. This is a severe constraint on the power and precision of mapping efforts and greatly hampers analysis of epistatic interactions. Results In order to address these limitations and to provide the community with a more effective collaborative RI mapping panel we generated new BXD RI strains from two independent advanced intercrosses (AI) between C57BL/6J (B6) and DBA/2J (D2) progenitor strains. Progeny were intercrossed for 9 to 14 generations before initiating inbreeding, which is still ongoing for some strains. Since this AI base population is highly recombinant, the 46 advanced recombinant inbred (ARI) strains incorporate approximately twice as many recombinations as standard RI strains, a fraction of which are inevitably shared by descent. When combined with the existing BXD RI strains, the merged BXD strain set triples the number of previously available unique recombinations and quadruples the total number of recombinations in the BXD background. Conclusion The combined BXD strain set is the largest mouse RI mapping panel. It is a powerful tool for collaborative analysis of quantitative traits and gene function that will be especially useful to study variation in transcriptome and proteome data sets under multiple environments. Additional strains also extend the value of the extensive phenotypic characterization of the previously available strains. A final advantage of expanding the BXD strain set is that both progenitors have been sequenced, and approximately 1.8 million SNPs have been characterized. This provides unprecedented power in screening candidate genes and can reduce the effective length of QTL intervals. It also makes it possible to reverse standard mapping strategies and to explore downstream effects of known sequence variants.
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            Molecular insight into invasive group A streptococcal disease.

            Streptococcus pyogenes is also known as group A Streptococcus (GAS) and is an important human pathogen that causes considerable morbidity and mortality worldwide. The GAS serotype M1T1 clone is the most frequently isolated serotype from life-threatening invasive (at a sterile site) infections, such as streptococcal toxic shock-like syndrome and necrotizing fasciitis. Here, we describe the virulence factors and newly discovered molecular events that mediate the in vivo changes from non-invasive GAS serotype M1T1 to the invasive phenotype, and review the invasive-disease trigger for non-M1 GAS. Understanding the molecular basis and mechanism of initiation for streptococcal invasive disease may expedite the discovery of novel therapeutic targets for the treatment and control of severe invasive GAS diseases.
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              Epidermal barrier formation and recovery in skin disorders.

              Skin is at the interface between the complex physiology of the body and the external, often hostile, environment, and the semipermeable epidermal barrier prevents both the escape of moisture and the entry of infectious or toxic substances. Newborns with rare congenital barrier defects underscore the skin's essential role in a terrestrial environment and demonstrate the compensatory responses evoked ex utero to reestablish a barrier. Common inflammatory skin disorders such as atopic dermatitis and psoriasis exhibit decreased barrier function, and recent studies suggest that the complex response of epidermal cells to barrier disruption may aggravate, maintain, or even initiate such conditions. Either aiding barrier reestablishment or dampening the epidermal stress response may improve the treatment of these disorders. This Review discusses the molecular regulation of the epidermal barrier as well as causes and potential treatments for defects of barrier formation and proposes that medical management of barrier disruption may positively affect the course of common skin disorders.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS Pathog
                PLoS Pathog
                plos
                plospath
                PLoS Pathogens
                Public Library of Science (San Francisco, CA USA )
                1553-7366
                1553-7374
                11 July 2016
                July 2016
                : 12
                : 7
                : e1005732
                Affiliations
                [1 ]Department of Molecular Genetics, Biochemistry and Microbiology, College of Medicine, University of Cincinnati, Cincinnati, Ohio, United States of America
                [2 ]Department of Biomedical Sciences, School of Medicine and Health Sciences, University of North Dakota, Grand Forks, North Dakota, United States of America
                [3 ]Karolinska Institutet, Centre for Infectious Medicine, Karolinska University Hospital, Stockholm, Sweden
                [4 ]Department of Anaesthesia, Rigshospitalet, Copenhagen, Denmark
                New York Medical College, UNITED STATES
                Author notes

                The authors have declared that no competing interests exist.

                Conceived and designed the experiments: KCK SM MS ANT MK. Performed the experiments: KCK SM JA NS SN. Analyzed the data: KCK SM JA JH NS SN. Contributed reagents/materials/analysis tools: JH OH. Wrote the paper: KCK SM JH NS ANT MK.

                [¤a]

                Current Address: Department of Medicine/Division of Cardiology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California, United States of America

                [¤b]

                Current Address: Department of Biological Sciences, California State Polytechnic University, Pomona, Pomona, California, United States of America

                ‡ JA and JH also contributed equally to this work.

                Author information
                http://orcid.org/0000-0002-4895-2495
                http://orcid.org/0000-0002-4632-265X
                Article
                PPATHOGENS-D-15-02749
                10.1371/journal.ppat.1005732
                4939974
                27399650
                df0aed68-b5bb-4a2f-8ffc-a71c6f74d5c6
                © 2016 Chella Krishnan et al

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 30 November 2015
                : 7 June 2016
                Page count
                Figures: 13, Tables: 4, Pages: 27
                Funding
                Funded by: funder-id http://dx.doi.org/10.13039/501100004963, Seventh Framework Programme;
                Award ID: 305340
                Award Recipient :
                Funded by: funder-id http://dx.doi.org/10.13039/501100004963, Seventh Framework Programme;
                Award ID: 305340
                Award Recipient :
                Funded by: The Swedish Research Council
                Award Recipient :
                Funded by: The Swedish Research Council
                Award Recipient :
                Funded by: The Swedish Research Council
                Award Recipient :
                This study was funded by European Union (Seventh Framework Program) under the grant agreement number 305340 to ANT MK; and the Swedish Research Council under grant number 20150338 to MS ANT MK. The funders had no role in the study design, data collection and analysis, and in the preparation of the manuscript.
                Categories
                Research Article
                Biology and Life Sciences
                Genetics
                Genetic Loci
                Quantitative Trait Loci
                Biology and Life Sciences
                Evolutionary Biology
                Population Genetics
                Haplotypes
                Biology and Life Sciences
                Genetics
                Population Genetics
                Haplotypes
                Biology and Life Sciences
                Population Biology
                Population Genetics
                Haplotypes
                Research and Analysis Methods
                Model Organisms
                Animal Models
                Mouse Models
                Biology and Life Sciences
                Genetics
                Gene Expression
                Medicine and Health Sciences
                Surgical and Invasive Medical Procedures
                Biopsy
                Biology and Life Sciences
                Genetics
                Gene Expression
                Gene Regulation
                Biology and Life Sciences
                Genetics
                Phenotypes
                Medicine and Health Sciences
                Dermatology
                Skin Infections
                Medicine and Health Sciences
                Infectious Diseases
                Skin Infections
                Custom metadata
                Most of the relevant data are within the paper and its Supporting Information files. Original datasets can be obtained at Gene Network (GN) website ( www.genenetwork.org) by using the associated identification numbers: (i) corrected relative survival index (GN Trait ID: 17524), (ii) corrected percent weight change kinetics for days 1-4 and their principal component (PC1) (GN Trait ID: 17520 – 17523 and 17527), and (iii) corrected maximum lesion area (GN Trait ID: 17525).

                Infectious disease & Microbiology
                Infectious disease & Microbiology

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