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Search Results: 1 - 10 of 477471 matches for " James A. Musser "
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Full-Exon Resequencing Reveals Toll-Like Receptor Variants Contribute to Human Susceptibility to Tuberculosis Disease
Xin Ma, Yuhua Liu, Brian B. Gowen, Edward A. Graviss, Andrew G. Clark, James M. Musser
PLOS ONE , 2007, DOI: 10.1371/journal.pone.0001318
Abstract: Tuberculosis (TB) is the leading cause of death worldwide due to an infectious agent. Data have accumulated over decades suggesting that variability in human susceptibility to TB disease has a genetic component. Toll-like receptors (TLRs) play a critical role in initiating the innate immune response to many pathogens in mouse models, but little is known about their role in human infections. Human TLRs have been reported to recognize mycobacterial antigens and initiate an immune response. We tested the hypothesis that amino acid-altering polymorphisms in five TLRs were associated with susceptibility to TB disease using a population-based case-control study with 1,312 adult TB patients and controls. Full-coding region sequencing of the five TLR genes in all 1,312 subjects yielded a data set in excess of 16 Mb. Rare nonsynonymous polymorphisms in TLR6-TLR1-TLR10 were significantly overrepresented among African-American TB cases compared with ethnically-matched control subjects. Common nonsynonymous polymorphisms in TLR6-TLR1-TLR10 also were significantly associated with TB disease in certain ethnic groups. Among African Americans, homozygotes for the common-variant haplotype TLR1-248S, TLR1-602I, and TLR6-249S had a significantly increased TB disease risk. A transmission/disequilibrium test on an independent sample found that the TLR1-248S variant was preferentially transmitted to diseased children, thereby confirming disease association. These results are consistent with recent reports implicating TLR1 variants, including TLR1-602, in significantly altered innate immune responses. Also consistent with disease association, rare TLR6 variants were defective in their ability to mediate NF-κB signal transduction in transfected human cells. Taken together, the data suggest that variant TLRs contribute to human susceptibility to TB disease. Extensive full-exon resequencing was critical for revealing new information about the role of TLRs in human-pathogen interactions and the genetic basis of innate immune function.
Genome-Wide Analysis of Group A Streptococci Reveals a Mutation That Modulates Global Phenotype and Disease Specificity
Paul Sumby,Adeline R Whitney,Edward A Graviss,Frank R DeLeo,James M Musser
PLOS Pathogens , 2006, DOI: 10.1371/journal.ppat.0020005
Abstract: Many human pathogens produce phenotypic variants as a means to circumvent the host immune system and enhance survival and, as a potential consequence, exhibit increased virulence. For example, it has been known for almost 90 y that clinical isolates of the human bacterial pathogen group A streptococci (GAS) have extensive phenotypic heterogeneity linked to variation in virulence. However, the complete underlying molecular mechanism(s) have not been defined. Expression microarray analysis of nine clinical isolates identified two fundamentally different transcriptomes, designated pharyngeal transcriptome profile (PTP) and invasive transcriptome profile (ITP). PTP and ITP GAS differed in approximately 10% of the transcriptome, including at least 23 proven or putative virulence factor genes. ITP organisms were recovered from skin lesions of mice infected subcutaneously with PTP GAS and were significantly more able to survive phagocytosis and killing by human polymorphonuclear leukocytes. Complete genome resequencing of a mouse-derived ITP GAS revealed that the organism differed from its precursor by only a 7-bp frameshift mutation in the gene (covS) encoding the sensor kinase component of a two-component signal transduction system implicated in virulence. Genetic complementation, and sequence analysis of covR/S in 42 GAS isolates confirmed the central role of covR/S in transcriptome, exoproteome, and virulence modulation. Genome-wide analysis provides a heretofore unattained understanding of phenotypic variation and disease specificity in microbial pathogens, resulting in new avenues for vaccine and therapeutics research.
A Combination of Independent Transcriptional Regulators Shapes Bacterial Virulence Gene Expression during Infection
Samuel A. Shelburne,Randall J. Olsen,Bryce Suber,Pranoti Sahasrabhojane,Paul Sumby,Richard G. Brennan,James M. Musser
PLOS Pathogens , 2010, DOI: 10.1371/journal.ppat.1000817
Abstract: Transcriptional regulatory networks are fundamental to how microbes alter gene expression in response to environmental stimuli, thereby playing a critical role in bacterial pathogenesis. However, understanding how bacterial transcriptional regulatory networks function during host-pathogen interaction is limited. Recent studies in group A Streptococcus (GAS) suggested that the transcriptional regulator catabolite control protein A (CcpA) influences many of the same genes as the control of virulence (CovRS) two-component gene regulatory system. To provide new information about the CcpA and CovRS networks, we compared the CcpA and CovR transcriptomes in a serotype M1 GAS strain. The transcript levels of several of the same genes encoding virulence factors and proteins involved in basic metabolic processes were affected in both ΔccpA and ΔcovR isogenic mutant strains. Recombinant CcpA and CovR bound with high-affinity to the promoter regions of several co-regulated genes, including those encoding proteins involved in carbohydrate and amino acid metabolism. Compared to the wild-type parental strain, ΔccpA and ΔcovRΔccpA isogenic mutant strains were significantly less virulent in a mouse myositis model. Inactivation of CcpA and CovR alone and in combination led to significant alterations in the transcript levels of several key GAS virulence factor encoding genes during infection. Importantly, the transcript level alterations in the ΔccpA and ΔcovRΔccpA isogenic mutant strains observed during infection were distinct from those occurring during growth in laboratory medium. These data provide new knowledge regarding the molecular mechanisms by which pathogenic bacteria respond to environmental signals to regulate virulence factor production and basic metabolic processes during infection.
How to approach genome wars in sepsis?
Jack Hawiger, James M Musser
Critical Care , 2011, DOI: 10.1186/cc10482
Abstract: Sepsis is one of the most difficult and costly problems to treat and prevent. It is caused by systemic or localized infections that damage the integrity of microcirculation in multiple organs. In sepsis, severe endothelial dysfunction underlies ischemic injury to the lungs, kidney, heart, brain, and other organs, leading to over 200,000 deaths annually among the estimated 700,000 to 900,000 patients in US hospitals. Mortality due to sepsis varies, peaking early in the first year of life (for example, neonatal sepsis), remaining at 10% in children, and then steadily climbing to 38.4% at age 85 [1]. The US hospitalization rates for sepsis among persons aged 65 to 74 and 75 to 84 years increased 57% and 52%, respectively, between 2000 and 2007 [2]. In 2008, the most expensive hospital stays in the United States exceeding $500,000 per hospitalization were due to sepsis (average 22 days) [3]. These most recent statistics indicate that current US annual expenditures for patients with sepsis are probably much higher than previous estimates of $17 billion [1], probably exceeding two-thirds of the entire 2011 budget of $30.7 billion for biomedical research funded by the National Institutes of Health. Even worse, sepsis survivors suffer incapacitating cognitive impairment and functional disability, posing tremendous emotional and financial challenges [4]. Sepsis undermines advances in medical and surgical management of multiple diseases [1]. While the worldwide Surviving Sepsis Campaign has developed excellent standards of care [5], the only US Food and Drug Administration-approved drug for adult severe sepsis - recombinant human activated protein C - was introduced a decade ago [6].A report entitled 'Blood Systems Response to Sepsis' published online by the National Heart Lung and Blood Institute (NHLBI) Division of Blood Diseases and Resources addresses the challenge of sepsis and its long-term sequelae [7]. An interdisciplinary panel of experts analyzed the problem of seps
Analysis of growth-phase regulated genes in Streptococcus agalactiae by global transcript profiling
Izabela Sitkiewicz, James M Musser
BMC Microbiology , 2009, DOI: 10.1186/1471-2180-9-32
Abstract: The S. agalactiae transcriptome is dynamic in response to growth conditions. Several genes and regulons involved in virulence factor production and utilization of alternate carbon sources were differentially expressed throughout growth.These data provide new information about the magnitude of plasticity of the S. agalactiae transcriptome and its adaptive response to changing environmental conditions. The resulting information will greatly assist investigators studying S. agalactiae physiology and pathogenesis.Bacteria employ multiple mechanisms to control gene expression and react to their constantly changing environment. These processes are especially critical for bacterial pathogens to survive and cause disease in humans and other hosts. Global control of gene expression is achieved using alternative sigma factors, two-component systems (TCSs), small regulatory RNAs, regulators such as RelA and LuxS, or concerted action of regulons (for a review see [1-6] and references therein). Gram positive pathogens such as group A Streptococcus (S. pyogenes, GAS) and group B Streptococcus (S. agalactiae, GBS) lack (or have limited number) of alternative sigma factors of fully confirmed function [7-9]. Analyses of global transcription in GAS under various growth conditions including saliva, blood, and tissue has shown that environmental response regulation is achieved using other mechanisms such RNA stability [10], "stand alone" regulators such as mga [11], or TCSs [12-15]. These transcriptome analyses have been especially useful in providing new information about microbial physiology and leads for pathogenesis research. However, the transcriptional response of GBS to changing growth conditions has not been fully analyzed, only single reports were recently published [16]. GBS is an important human and cow pathogen, responsible for thousands of severe invasive infections in man and large economic loss attributable to bovine mastitis (see [17,18] and references therein).One of t
Distinct Single Amino Acid Replacements in the Control of Virulence Regulator Protein Differentially Impact Streptococcal Pathogenesis
Nicola Horstmann,Pranoti Sahasrabhojane,Bryce Suber,Muthiah Kumaraswami,Randall J. Olsen,Anthony Flores,James M. Musser,Richard G. Brennan,Samuel A. Shelburne III
PLOS Pathogens , 2011, DOI: 10.1371/journal.ppat.1002311
Abstract: Sequencing of invasive strains of group A streptococci (GAS) has revealed a diverse array of single nucleotide polymorphisms in the gene encoding the control of virulence regulator (CovR) protein. However, there is limited information regarding the molecular mechanisms by which CovR single amino acid replacements impact GAS pathogenesis. The crystal structure of the CovR C-terminal DNA-binding domain was determined to 1.50 ? resolution and revealed a three-stranded β-sheet followed by a winged helix-turn-helix DNA binding motif. Modeling of the CovR protein-DNA complex indicated that CovR single amino acid replacements observed in clinical GAS isolates could directly alter protein-DNA interaction and impact protein structure. Isoallelic GAS strains that varied by a single amino acid replacement in the CovR DNA binding domain had significantly different transcriptomes compared to wild-type and to each other. Similarly, distinct recombinant CovR variants had differential binding affinity for DNA from the promoter regions of several virulence factor-encoding genes. Finally, mice that were challenged with GAS CovR isoallelic strains had significantly different survival times, which correlated with the transcriptome and protein-DNA binding studies. Taken together, these data provide structural and functional insights into the critical and distinct effects of variation in the CovR protein on GAS pathogenesis.
Contribution of Exogenous Genetic Elements to the Group A Streptococcus Metagenome
Stephen B. Beres, James M. Musser
PLOS ONE , 2007, DOI: 10.1371/journal.pone.0000800
Abstract: Variation in gene content among strains of a bacterial species contributes to biomedically relevant differences in phenotypes such as virulence and antimicrobial resistance. Group A Streptococcus (GAS) causes a diverse array of human infections and sequelae, and exhibits a complex pathogenic behavior. To enhance our understanding of genotype-phenotype relationships in this important pathogen, we determined the complete genome sequences of four GAS strains expressing M protein serotypes (M2, M4, and 2 M12) that commonly cause noninvasive and invasive infections. These sequences were compared with eight previously determined GAS genomes and regions of variably present gene content were assessed. Consistent with the previously determined genomes, each of the new genomes is ~1.9 Mb in size, with ~10% of the gene content of each encoded on variably present exogenous genetic elements. Like the other GAS genomes, these four genomes are polylysogenic and prophage encode the majority of the variably present gene content of each. In contrast to most of the previously determined genomes, multiple exogenous integrated conjugative elements (ICEs) with characteristics of conjugative transposons and plasmids are present in these new genomes. Cumulatively, 242 new GAS metagenome genes were identified that were not present in the previously sequenced genomes. Importantly, ICEs accounted for 41% of the new GAS metagenome gene content identified in these four genomes. Two large ICEs, designated 2096-RD.2 (63 kb) and 10750-RD.2 (49 kb), have multiple genes encoding resistance to antimicrobial agents, including tetracycline and erythromycin, respectively. Also resident on these ICEs are three genes encoding inferred extracellular proteins of unknown function, including a predicted cell surface protein that is only present in the genome of the serotype M12 strain cultured from a patient with acute poststreptococcal glomerulonephritis. The data provide new information about the GAS metagenome and will assist studies of pathogenesis, antimicrobial resistance, and population genomics.
Remodeling of the Streptococcus agalactiae Transcriptome in Response to Growth Temperature
Laurent Mereghetti, Izabela Sitkiewicz, Nicole M. Green, James M. Musser
PLOS ONE , 2008, DOI: 10.1371/journal.pone.0002785
Abstract: Background To act as a commensal bacterium and a pathogen in humans and animals, Streptococcus agalactiae (group B streptococcus, GBS) must be able to monitor and adapt to different environmental conditions. Temperature variation is a one of the most commonly encountered variables. Methodology/Principal Findings To understand the extent to which GBS modify gene expression in response to temperatures encountered in the various hosts, we conducted a whole genome transcriptome analysis of organisms grown at 30°C and 40°C. We identified extensive transcriptome remodeling at various stages of growth, especially in the stationary phase (significant transcript changes occurred for 25% of the genes). A large proportion of genes involved in metabolism was up-regulated at 30°C in stationary phase. Conversely, genes up-regulated at 40°C relative to 30°C include those encoding virulence factors such as hemolysins and extracellular secreted proteins with LPXTG motifs. Over-expression of hemolysins was linked to larger zones of hemolysis and enhanced hemolytic activity at 40°C. A key theme identified by our study was that genes involved in purine metabolism and iron acquisition were significantly up-regulated at 40°C. Conclusion/Significance Growth of GBS in vitro at different temperatures resulted in extensive remodeling of the transcriptome, including genes encoding proven and putative virulence genes. The data provide extensive new leads for molecular pathogenesis research.
Identification of an Unusual Pattern of Global Gene Expression in Group B Streptococcus Grown in Human Blood
Laurent Mereghetti, Izabela Sitkiewicz, Nicole M. Green, James M. Musser
PLOS ONE , 2009, DOI: 10.1371/journal.pone.0007145
Abstract: Because passage of the bacterium to blood is a crucial step in the pathogenesis of many group B Streptococcus (GBS) invasive infections, we recently conducted a whole-genome transcriptome analysis during GBS incubation ex vivo with human blood. In the current work, we sought to analyze in detail the difference in GBS gene expression that occurred in one blood sample (donor A) relative to other blood samples. We incubated GBS strain NEM316 with fresh heparinized human blood obtained from healthy volunteers, and analyzed GBS genome expression and cytokine production. Principal component analysis identified extensive clustering of the transcriptome data among all samples at time 0. In striking contrast, the whole bacterial gene expression in the donor A blood sample was significantly different from the gene expression in all other blood samples studied, both after 30 and 90 min of incubation. More genes were up-regulated in donor A blood relative to the other samples, at 30 min and 90 min. Furthermore, there was significant variation in transcript levels between donor A blood and other blood samples. Notably, genes with the highest transcript levels in donor A blood were those involved in carbohydrate metabolism. We also discovered an unusual production of proinflammatory and immunomodulatory cytokines: MIF, tPAI-1 and IL-1β were produced at higher levels in donor A blood relative to the other blood samples, whereas GM-CSF, TNF-α, IFN-γ, IL-7 and IL-10 remained at lower levels in donor A blood. Potential reasons for our observations are that the immune response of donor A significantly influenced the bacterial transcriptome, or both GBS gene expression and immune response were influenced by the metabolic status of donor A.
Extensive Adaptive Changes Occur in the Transcriptome of Streptococcus agalactiae (Group B Streptococcus) in Response to Incubation with Human Blood
Laurent Mereghetti, Izabela Sitkiewicz, Nicole M. Green, James M. Musser
PLOS ONE , 2008, DOI: 10.1371/journal.pone.0003143
Abstract: To enhance understanding of how Streptococcus agalactiae (group B streptococcus, GBS) adapts during invasive infection, we performed a whole-genome transcriptome analysis after incubation with whole human blood. Global changes occurred in the GBS transcriptome rapidly in response to blood contact following shift from growth in a rich laboratory medium. Most (83%) of the significantly altered transcripts were down-regulated after 30 minutes of incubation in blood, and all functional categories of genes were abundantly represented. We observed complex dynamic changes in the expression of transcriptional regulators and stress response genes that allow GBS to rapidly adapt to blood. The transcripts of relatively few proven virulence genes were up-regulated during the first 90 minutes. However, a key discovery was that genes encoding proteins involved in interaction with the host coagulation/fibrinolysis system and bacterial-host interactions were rapidly up-regulated. Extensive transcript changes also occurred for genes involved in carbohydrate metabolism, including multi-functional proteins and regulators putatively involved in pathogenesis. Finally, we discovered that an incubation temperature closer to that occurring in patients with severe infection and high fever (40°C) induced additional differences in the GBS transcriptome relative to normal body temperature (37°C). Taken together, the data provide extensive new information about transcriptional adaptation of GBS exposed to human blood, a crucial step during GBS pathogenesis in invasive diseases, and identify many new leads for molecular pathogenesis research.
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