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Dive into the research topics where Patrick M. Schlievert is active.

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Clinical Microbiology Reviews | 2000

Exotoxins of Staphylococcus aureus

Martin M. Dinges; Paul M. Orwin; Patrick M. Schlievert

This article reviews the literature regarding the structure and function of two types of exotoxins expressed by Staphylococcus aureus, pyrogenic toxin superantigens (PTSAgs) and hemolysins. The molecular basis of PTSAg toxicity is presented in the context of two diseases known to be caused by these exotoxins: toxic shock syndrome and staphylococcal food poisoning. The family of staphylococcal PTSAgs presently includes toxic shock syndrome toxin-1 (TSST-1) and most of the staphylococcal enterotoxins (SEs) (SEA, SEB, SEC, SED, SEE, SEG, and SEH). As the name implies, the PTSAgs are multifunctional proteins that invariably exhibit lethal activity, pyrogenicity, superantigenicity, and the capacity to induce lethal hypersensitivity to endotoxin. Other properties exhibited by one or more staphylococcal PTSAgs include emetic activity (SEs) and penetration across mucosal barriers (TSST-1). A detailed review of the molecular mechanisms underlying the toxicity of the staphylococcal hemolysins is also presented.


The New England Journal of Medicine | 1989

Severe group A streptococcal infections associated with a toxic shock-like syndrome and scarlet fever toxin A.

Dennis L. Stevens; Martha H. Tanner; Jay Winship; Raymond Swarts; Kristen M. Ries; Patrick M. Schlievert; Edward H. Kaplan

Abstract There is concern that group A streptococci, which have caused less serious infections in developed countries in recent decades, may be acquiring greater virulence. We describe 20 patients from the Rocky Mountain region who had group A streptococcal infections from 1986 to 1988 that were remarkable for the severity of local tissue destruction and life-threatening systemic toxicity. Among the 20 patients (median age, 36), necrotizing fasciitis with or without myositis was the most common soft-tissue infection (55 percent). Nineteen patients (95 percent) had shock, 16 (80 percent) had renal impairment, and 11 (55 percent) had acute respiratory distress syndrome. The mortality rate was 30 percent. All patients but 1 had positive tissue cultures for Streptococcus pyogenes; 12 had positive blood cultures. Most of the patients had no underlying disease; 2 used intravenous drugs. Strains of group A beta-hemolytic streptococci isolated from 10 patients were not of a single M or T type; however, 8 of the 1...


Nature | 2009

Glycerol monolaurate prevents mucosal SIV transmission

Qingsheng Li; Jacob D. Estes; Patrick M. Schlievert; Lijie Duan; Amanda J. Brosnahan; Peter J. Southern; Cavan Reilly; Marnie L. Peterson; Nancy Schultz-Darken; Kevin Brunner; Karla R. Nephew; Stefan E. Pambuccian; Jeffrey D. Lifson; John V. Carlis; Ashley T. Haase

Although there has been great progress in treating human immunodeficiency virus 1 (HIV-1) infection, preventing transmission has thus far proven an elusive goal. Indeed, recent trials of a candidate vaccine and microbicide have been disappointing, both for want of efficacy and concerns about increased rates of transmission. Nonetheless, studies of vaginal transmission in the simian immunodeficiency virus (SIV)–rhesus macaque (Macacca mulatta) model point to opportunities at the earliest stages of infection in which a vaccine or microbicide might be protective, by limiting the expansion of infected founder populations at the portal of entry. Here we show in this SIV–macaque model, that an outside-in endocervical mucosal signalling system, involving MIP-3α (also known as CCL20), plasmacytoid dendritic cells and CCR5+ cell-attracting chemokines produced by these cells, in combination with the innate immune and inflammatory responses to infection in both cervix and vagina, recruits CD4+ T cells to fuel this obligate expansion. We then show that glycerol monolaurate—a widely used antimicrobial compound with inhibitory activity against the production of MIP-3α and other proinflammatory cytokines—can inhibit mucosal signalling and the innate and inflammatory response to HIV-1 and SIV in vitro, and in vivo it can protect rhesus macaques from acute infection despite repeated intra-vaginal exposure to high doses of SIV. This new approach, plausibly linked to interfering with innate host responses that recruit the target cells necessary to establish systemic infection, opens a promising new avenue for the development of effective interventions to block HIV-1 mucosal transmission.


Proceedings of the National Academy of Sciences of the United States of America | 2002

Genome sequence of a serotype M3 strain of group A Streptococcus: Phage-encoded toxins, the high-virulence phenotype, and clone emergence

Stephen B. Beres; Gail L. Sylva; Kent D. Barbian; Benfang Lei; Jessica S. Hoff; Nicole D. Mammarella; Meng Yao Liu; James C. Smoot; Stephen F. Porcella; Larye D. Parkins; David Campbell; Todd M. Smith; John K. McCormick; Donald Y.M. Leung; Patrick M. Schlievert; James M. Musser

Genome sequences are available for many bacterial strains, but there has been little progress in using these data to understand the molecular basis of pathogen emergence and differences in strain virulence. Serotype M3 strains of group A Streptococcus (GAS) are a common cause of severe invasive infections with unusually high rates of morbidity and mortality. To gain insight into the molecular basis of this high-virulence phenotype, we sequenced the genome of strain MGAS315, an organism isolated from a patient with streptococcal toxic shock syndrome. The genome is composed of 1,900,521 bp, and it shares ≈1.7 Mb of related genetic material with genomes of serotype M1 and M18 strains. Phage-like elements account for the great majority of variation in gene content relative to the sequenced M1 and M18 strains. Recombination produces chimeric phages and strains with previously uncharacterized arrays of virulence factor genes. Strain MGAS315 has phage genes that encode proteins likely to contribute to pathogenesis, such as streptococcal pyrogenic exotoxin A (SpeA) and SpeK, streptococcal superantigen (SSA), and a previously uncharacterized phospholipase A2 (designated Sla). Infected humans had anti-SpeK, -SSA, and -Sla antibodies, indicating that these GAS proteins are made in vivo. SpeK and SSA were pyrogenic and toxic for rabbits. Serotype M3 strains with the phage-encoded speK and sla genes increased dramatically in frequency late in the 20th century, commensurate with the rise in invasive disease caused by M3 organisms. Taken together, the results show that phage-mediated recombination has played a critical role in the emergence of a new, unusually virulent clone of serotype M3 GAS.


Molecular Genetics and Genomics | 1986

Regulation of exoprotein gene expression in Staphylococcus aureus by agr

P. Recsei; Barry N. Kreiswirth; M. O'Reilly; Patrick M. Schlievert; A. Gruss; RichardP. Novick

SummaryInsertion of the erythromycin-resistance transposon Tn551 into the Staphylococcus aureus chromosome at a site which maps between the purB and ilv loci has a pleiotrophic effect on the production of a number of extracellular proteins. Production of alpha, beta and delta hemolysin, toxic shock syndrome toxin (TSST-1) and staphylokinase was depressed about fifty-fold while protein A production was elevated twenty-fold. Hybridization analysis showed that the defect in expression of TSST-1 and alpha hemolysin was at the transcriptional level. Inability of the mutant strain to express either a cloned TSST-1 gene or the chromosomal gene indicates that the transposon has inactivated a trans-active positive control element. This element has been designated agr for accessory gene regulator.


Critical Reviews in Microbiology | 1990

Staphylococcal and Streptococcal Pyrogenic Toxins Involved in Toxic Shock Syndrome and Related Illnesses

Gregory A. Bohach; David J. Fast; Robert D. Nelson; Patrick M. Schlievert

Toxic-shock syndrome (TSS) is an acute onset, multiorgan illness which resembles severe scarlet fever. The illness is caused by Staphylococcus aureus strains that express TSS toxin-1 (TSST-1), enterotoxin B, or enterotoxin C. TSST-1 is associated with menstrual TSS and approximately one-half of nonmenstrual cases; the other two toxins cause nonmenstrual cases, 47% and 3%, respectively. The three toxins are expressed in culture media under similar environmental conditions. These conditions may explain the association of certain tampons with menstrual TSS. Biochemically, the toxins are all relatively low molecular weight and fairly heat and protease stable. Enterotoxins B and C, share nearly 50% sequence homology with streptococcal scarlet fever toxin A; they share no homology with TSST-1 despite sharing numerous biological properties. Numerous animal models for development of TSS have suggested mechanisms of toxin action, though the exact molecular action is not known. The toxins are all potent pyrogens, induce T lymphocyte proliferation, requiring interleukin 1 release from macrophages, suppress immunoglobulin production, enhance endotoxin shock, and enhance hypersensitivity skin reactions. The genetic control of the toxins has been studied and suggests the exotoxins are variable traits. Some additional properties of TSS S. aureus which facilitate disease causation have been clarified.


Clinical Infectious Diseases | 2003

Hospital Transmission of Community-Acquired Methicillin-Resistant Staphylococcus aureus among Postpartum Women

Lisa Saiman; Mary O Keefe; Philip L. Graham; Fann Wu; Battouli Saïd Salim; Barry N. Kreiswirth; Anita Lasala; Patrick M. Schlievert; Phyllis Della Latta

Infections caused by community-acquired methicillin-resistant Staphylococcus aureus (CA-MRSA) are being increasingly observed in patients who lack traditional risk factors. We described 8 postpartum women who developed skin and soft-tissue infections caused by MRSA at a mean time of 23 days (range, 4-73 days) after delivery. Infections included 4 cases of mastitis (3 of which progressed to breast abscess), a postoperative wound infection, cellulitis, and pustulosis. The outbreak strains were compared with the prototype CA-MRSA strain MW2 and found to be indistinguishable by pulsed-field gel electrophoresis. All were spa type 131, all contained the staphylococcal chromosomal cassette mec type IV, and all expressed Panton-Valentine leukocidin and staphylococcal enterotoxins C and H. The route of transmission was not discovered: the results of surveillance cultures of samples obtained from employees of the hospital, the hospital environment, and newborns were negative for the outbreak strain. We report that MW2, which was previously limited to the midwestern United States, has spread to the northeastern United States and has become a health care-associated pathogen.


Proceedings of the National Academy of Sciences of the United States of America | 1991

STREPTOCOCCUS PYOGENES CAUSING TOXIC-SHOCK-LIKE SYNDROME AND OTHER INVASIVE DISEASES : CLONAL DIVERSITY AND PYROGENIC EXOTOXIN EXPRESSION

James M. Musser; Alan R. Hauser; Michael H. Kim; Patrick M. Schlievert; Kimberlyn Nelson; R K Selander

Genetic diversity and relationships among 108 isolates of the bacterium Streptococcus pyogenes recently recovered from patients in the United States with toxic-shock-like syndrome or other invasive diseases were estimated by multilocus enzyme electrophoresis. Thirty-three electrophoretic types (ETs), representing distinctive multilocus clonal genotypes, were identified, but nearly half the disease episodes, including more than two-thirds of the cases of toxic-shock-like syndrome, were caused by strains of two related clones (ET 1 and ET 2). These two clones were also represented by recent pathogenic European isolates. A previous report of a relatively high frequency of expression of exotoxin A among isolates recovered from toxic-shock-like syndrome patients in the United States was confirmed; and the demonstration of this association both within clones and among distantly related clones supports the hypothesis that exotoxin A is a causal factor in pathogenesis of this disease. Near identity of the nucleotide sequences of the exotoxin A structural gene of six isolates of five ETs in diverse phylogenetic lineages was interpreted as evidence that the gene has been horizontally distributed among clones, presumably by bacteriophage-mediated transfer.


Antimicrobial Agents and Chemotherapy | 2003

Comparative Molecular Analysis of Community- or Hospital-Acquired Methicillin-Resistant Staphylococcus aureus

P. D. Fey; B. Saïd-Salim; M. E. Rupp; S. H. Hinrichs; D. J. Boxrud; Catherine C. Davis; Barry N. Kreiswirth; Patrick M. Schlievert

ABSTRACT Community-acquired methicillin-resistant Staphylococcus aureus (CA-MRSA) is a growing public health concern that has been associated with pediatric fatalities. It is hypothesized that the evolution of CA-MRSA is a recent event due to the acquisition of mec DNA by previously methicillin-susceptible strains that circulated in the community. This study investigated the genetic relatedness between CA-MRSA, hospital-associated MRSA (HA-MRSA), and nonmenstrual toxic shock syndrome (nmTSS) isolates. Thirty-one of 32 CA-MRSA isolates were highly related as determined by pulsed-field gel electrophoresis and spa typing yet were distinguishable from 32 HA-MRSA strains. The 31 related CA-MRSA isolates produced either staphylococcal enterotoxin B (n = 5) or C (n = 26), and none made TSS toxin 1. All CA-MRSA isolates tested contained a type IV staphylococcal cassette chromosome mec (SCCmec) element. In comparison, none of the HA-MRSA isolates (n = 32) expressed the three superantigens. Antibiotic susceptibility patterns were different between the CA-MRSA and HA-MRSA isolates; CA-MRSA was typically resistant only to β-lactam antibiotics. Six of twenty-one nmTSS isolates were indistinguishable or highly related to the CA-MRSA isolates. MnCop, an nmTSS isolate obtained in Alabama in 1986, was highly related to the CA-MRSA isolates except that it did not contain an SCCmec element. These data suggest that CA-MRSA strains may represent a new acquisition of SCCmec DNA in a previously susceptible genetic background that was capable of causing nmTSS. CA-MRSA poses a serious health risk not only because it is resistant to the antibiotics of choice for community-acquired staphylococcal infections but also because of its ability to cause nmTSS via superantigen production.


The Lancet | 1993

Toxic shock syndrome toxin-secreting Staphylococcus aureus in Kawasaki syndrome

Donald Y.M. Leung; B.L Kotzin; H.C Meissner; R.D Fulton; Debra L. Murray; Patrick M. Schlievert

Kawasaki syndrome (KS), the main cause of acquired heart disease in children, is associated with the selective expansion of V beta 2+ T cells in peripheral blood. Our study suggests that KS may be caused by a superantigen--a staphylococcal or streptococcal toxin. Bacteria were cultured without knowledge of their origin, from the throat, rectum, axilla, and groin of 16 patients with untreated acute KS and 15 controls. Bacteria producing toxins were isolated from 13 of 16 KS patients but from only 1 of 15 controls (p < 0.0001). Toxic shock syndrome toxin (TSST) secreting Staphylococcus aureus was isolated from 11 of the 13 toxin-positive cultures, and streptococcal pyogenic exotoxin (SPE) B and C were found in the other 2. These toxins are known to stimulate V beta 2+ T cells. All TSST-producing KS isolates were tryptophan auxotrophs indicating they were clonally related. S aureus isolates from acute KS patients were unusual because they produced less lipase, haemolysin, and protease compared to other isolates (p < 0.01). S aureus colonies from KS patients were white, and could be easily mistaken for coagulase-negative staphylococci, whereas colonies of non-KS isolates were gold. These observations suggest that the expansion of V beta 2+ T cells in most patients with KS may be caused by a new clone of TSST-producing S aureus, and, in a minority of patients, SPEB-producing or SPEC-producing streptococci.

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Donald Y.M. Leung

University of Colorado Denver

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Joseph A. Merriman

Roy J. and Lucille A. Carver College of Medicine

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Wilmara Salgado-Pabón

Roy J. and Lucille A. Carver College of Medicine

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