David B Schauer

Massachusetts Institute of Technology, Cambridge, MA, United States

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Publications (157)

  • Emily M Mallick · Megan E McBee · Vijay K Vanguri · [...] · David B Schauer
    [Show abstract] [Hide abstract] ABSTRACT: Enterohemorrhagic E. coli (EHEC) is an important subset of Shiga toxin-producing (Stx-producing) E. coli (STEC), pathogens that have been implicated in outbreaks of food-borne illness and can cause intestinal and systemic disease, including severe renal damage. Upon attachment to intestinal epithelium, EHEC generates "attaching and effacing" (AE) lesions characterized by intimate attachment and actin rearrangement upon host cell binding. Stx produced in the gut transverses the intestinal epithelium, causing vascular damage that leads to systemic disease. Models of EHEC infection in conventional mice do not manifest key features of disease, such as AE lesions, intestinal damage, and systemic illness. In order to develop an infection model that better reflects the pathogenesis of this subset of STEC, we constructed an Stx-producing strain of Citrobacter rodentium, a murine AE pathogen that otherwise lacks Stx. Mice infected with Stx-producing C. rodentium developed AE lesions on the intestinal epithelium and Stx-dependent intestinal inflammatory damage. Further, the mice experienced lethal infection characterized by histopathological and functional kidney damage. The development of a murine model that encompasses AE lesion formation and Stx-mediated tissue damage will provide a new platform upon which to identify EHEC alterations of host epithelium that contribute to systemic disease.
    Article · Oct 2012 · The Journal of clinical investigation
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    [Show abstract] [Hide abstract] ABSTRACT: Pediatric inflammatory bowel disease (IBD) is challenging to diagnose because of the non-specificity of symptoms; an unequivocal diagnosis can only be made using colonoscopy, which clinicians are reluctant to recommend for children. Diagnosis of pediatric IBD is therefore frequently delayed, leading to inappropriate treatment plans and poor outcomes. We investigated the use of 16S rRNA sequencing of fecal samples and new analytical methods to assess differences in the microbiota of children with IBD and other gastrointestinal disorders. We applied synthetic learning in microbial ecology (SLiME) analysis to 16S sequencing data obtained from i) published surveys of microbiota diversity in IBD and ii) fecal samples from 91 children and young adults who were treated in the gastroenterology program of Children's Hospital (Boston, USA). The developed method accurately distinguished control samples from those of patients with IBD; the area under the receiver-operating-characteristic curve (AUC) value was 0.83 (corresponding to 80.3% sensitivity and 69.7% specificity at a set threshold). The accuracy was maintained among data sets collected by different sampling and sequencing methods. The method identified taxa associated with disease states and distinguished patients with Crohn's disease from those with ulcerative colitis with reasonable accuracy. The findings were validated using samples from an additional group of 68 patients; the validation test identified patients with IBD with an AUC value of 0.84 (e.g. 92% sensitivity, 58.5% specificity). Microbiome-based diagnostics can distinguish pediatric patients with IBD from patients with similar symptoms. Although this test can not replace endoscopy and histological examination as diagnostic tools, classification based on microbial diversity is an effective complementary technique for IBD detection in pediatric patients.
    Full-text available · Article · Jun 2012 · PLoS ONE
  • [Show abstract] [Hide abstract] ABSTRACT: Systemic cytokine and chemokine changes induced by C. rodentium infection in C57BL/6 mice. Serum cytokines and chemokines were measured by quantitative multiplex analysis using Luminex technology. (One-way ANOVA with Tukey's multiple comparison test: * P<0.05, ** P<0.01, *** P<0.001). Lines indicate group means (n = 5 to 6 animals per timepoint). (TIF)
    File available · Data · Mar 2012
  • [Show abstract] [Hide abstract] ABSTRACT: Infection kinetics and body weight changes in C57BL/6 mice infected with C. rodentium. C. rodentium bacterial burden (A) was detectable by 3DPI and maximal around 7 DPI with clearance beginning by 10 DPI. Monitoring of body weights (B) demonstrated no statistically significant weight loss over the course of infection. (TIF)
    File available · Data · Mar 2012
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    [Show abstract] [Hide abstract] ABSTRACT: Acute and chronic forms of inflammation are known to affect liver responses and susceptibility to disease and injury. Furthermore, intestinal microbiota has been shown critical in mediating inflammatory host responses in various animal models. Using C. rodentium, a known enteric bacterial pathogen, we examined liver responses to gastrointestinal infection at various stages of disease pathogenesis. For the first time, to our knowledge, we show distinct liver pathology associated with enteric infection with C. rodentium in C57BL/6 mice, characterized by increased inflammation and hepatitis index scores as well as prominent periportal hepatocellular coagulative necrosis indicative of thrombotic ischemic injury in a subset of animals during the early course of C. rodentium pathogenesis. Histologic changes in the liver correlated with serum elevation of liver transaminases, systemic and liver resident cytokines, as well as signal transduction changes prior to peak bacterial colonization and colonic disease. C. rodentium infection in C57BL/6 mice provides a potentially useful model to study acute liver injury and inflammatory stress under conditions of gastrointestinal infection analogous to enteropathogenic E. coli infection in humans.
    Full-text available · Article · Mar 2012 · PLoS ONE
  • [Show abstract] [Hide abstract] ABSTRACT: Serum chemistry changes in C57BL/6 mice inoculated with C. rodentium. Systemic parameters assessing liver function (ALT, AST, ALP, total bilirubin), kidney function (creatinine, BUN, CPK) and electrolytes (Ca2+, Cl−, Na+, K+) were measured at 0, 3, 7, and 14 DPI. (One-way ANOVA with Tukey's multiple comparison test: * P<0.05, ** P<0.01, *** P<0.001). Lines indicate group means. (TIF)
    File available · Data · Mar 2012
  • [Show abstract] [Hide abstract] ABSTRACT: PLS-DA analysis of 3 and 7 DPI animals. Animals were assigned one of three classes; 3DPI (no necrosis), 3 DPI (necrosis), and 7 DPI. (A) Animal separation based on the first two principal components. (B) Target covariation using all serum target, liver targets, and histological scores. (TIF)
    File available · Data · Mar 2012
  • [Show abstract] [Hide abstract] ABSTRACT: Liver cytokine and chemokine changes induced by C. rodentium infection in C57BL/6 mice. Liver cytokines and chemokines were measured by quantitative multiplex analysis using Luminex technology. Statistically significant changes as a group were only found for IL-1β (L), MCP-1 (L), MIP-1α (L), and RANTES (L) (One-way ANOVA with Dunnett's multiple comparison test comparing all columns to controls: * P<0.05, ** P<0.01, *** P<0.001). Lines indicate group means (n = 6 livers per timepoint). (TIF)
    File available · Data · Mar 2012
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    Emily M Mallick · Michael John Brady · Steven A Luperchio · [...] · David B Schauer
    [Show abstract] [Hide abstract] ABSTRACT: Upon binding to intestinal epithelial cells, enterohemorrhagic E. coli (EHEC), enteropathogenic E. coli (EPEC), and Citrobacter rodentium trigger formation of actin pedestals beneath bound bacteria. Pedestal formation has been associated with enhanced colonization, and requires intimin, an adhesin that binds to the bacterial effector Tir, which is translocated to the host cell membrane and promotes bacterial adherence and pedestal formation. Intimin has been suggested to also promote cell adhesion by binding one or more host receptors, and allelic differences in intimin have been associated with differences in tissue and host specificity. We assessed the function of EHEC, EPEC, or C. rodentium intimin, or a set of intimin derivatives with varying Tir-binding abilities in animal models of infection. We found that EPEC and EHEC intimin were functionally indistinguishable during infection of gnotobiotic piglets by EHEC, and that EPEC, EHEC, and C. rodentium intimin were functionally indistinguishable during infection of C57BL/6 mice by C. rodentium. A derivative of EHEC intimin that bound Tir but did not promote robust pedestal formation on cultured cells was unable to promote C. rodentium colonization of conventional mice, indicating that the ability to trigger actin assembly, not simply to bind Tir, is required for intimin-mediated intestinal colonization. Interestingly, streptomycin pre-treatment of mice eliminated the requirement for Tir but not intimin during colonization, and intimin derivatives that were defective in Tir-binding still promoted colonization of these mice. These results indicate that EPEC, EHEC, and C. rodentium are functionally interchangeable during infection of gnotobiotic piglets or conventional C57BL/6 mice, and that whereas the ability to trigger Tir-mediated pedestal formation is essential for colonization of conventional mice, intimin provides a Tir-independent activity during colonization of streptomycin pre-treated mice.
    Full-text available · Article · Jan 2012 · Frontiers in Microbiology
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    Nisanart Charoenlap · Zeli Shen · Megan E McBee · [...] · David B Schauer
    [Show abstract] [Hide abstract] ABSTRACT: Helicobacter cinaedi, a common human intestinal bacterium, has been implicated in various enteric and systemic diseases in normal and immunocompromised patients. Protection against oxidative stress is a crucial component of bacterium-host interactions. Alkyl hydroperoxide reductase C (AhpC) is an enzyme responsible for detoxification of peroxides and is important in protection from peroxide-induced stress. H. cinaedi possesses a single ahpC, which was investigated with respect to its role in bacterial survival during oxidative stress. The H. cinaedi ahpC mutant had diminished resistance to organic hydroperoxide toxicity but increased hydrogen peroxide resistance compared with the wild-type (WT) strain. The mutant also exhibited an oxygen-sensitive phenotype and was more susceptible to killing by macrophages than the WT strain. In vivo experiments in BALB/c and BALB/c interleukin-10 (IL-10)−/− mice revealed that the cecal colonizing ability of the ahpC mutant was significantly reduced. The mutant also had diminished ability to induce bacterium-specific immune responses in vivo, as shown by immunoglobulin (IgG2a and IgG1) serum levels. Collectively, these data suggest that H. cinaedi ahpC not only contributes to protecting the organism against oxidative stress but also alters its pathogenic properties in vivo.
    Full-text available · Article · Dec 2011 · Infection and immunity
  • E.M. Mallick · M. McBee · V. Vanguri · [...] · D. Schauer
    File available · Data · Jun 2011
  • E.M. Mallick · M. McBee · V. Vanguri · [...] · D. Schauer
    File available · Data · Jun 2011
  • [Show abstract] [Hide abstract] ABSTRACT: Vertebrates are constantly threatened by the invasion of microorganisms and have evolved systems of immunity to eliminate infectious pathogens in the body. Initial sensing of microbial agents is mediated by the recognition of pathogens by means of molecular structures expressed uniquely by microbes of a given type. So-called 'Toll-like receptors' are expressed on host epithelial barrier cells play an essential role in the host defense against microbial pathogens by inducing cell responses (e.g., proliferation, death, cytokine secretion) via activation of intracellular signaling networks. As these networks, comprising multiple interconnecting dynamic pathways, represent highly complex multi-variate "information processing" systems, the signaling activities particularly critical for governing the host cell responses are poorly understood and not easily ascertained by a priori theoretical notions. We have developed over the past half-decade a "data-driven" computational modeling approach, on a 'cue-signal-response' combined experiment/computation paradigm, to elucidate key multi-variate signaling relationships governing the cell responses. In an example presented here, we study how a canonical set of six kinase pathways combine to effect microbial agent-induced apoptotic death of a macrophage cell line. One modeling technique, partial least-squares regression, yielded the following key insights: {a} signal combinations most strongly correlated to apoptotic death are orthogonal to those most strongly correlated with release of inflammatory cytokines; {b} the ratio of two key pathway activities is the most powerful predictor of microbe-induced macrophage apoptotic death; {c} the most influential time-window of this signaling activity ratio is surprisingly fast: less than one hour after microbe stimulation.
    Article · May 2011 · Proceedings of SPIE - The International Society for Optical Engineering
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    [Show abstract] [Hide abstract] ABSTRACT: Enterohemorrhagic Escherichia coli (EHEC) O157:H7 causes hemorrhagic colitis and may result in potentially fatal hemolytic uremia syndrome in humans. EHEC colonize the intestinal mucosa and promote the formation of actin-rich pedestals via translocated type III effectors. Two EHEC type III secreted effectors, Tir and EspFu/TccP, are key players for pedestal formation. We discovered that an EHEC effector protein called Non-LEE-encoded Ligase (NleL) is an E3 ubiquitin ligase. In vitro, we showed that the NleL C753 residue is critical for its E3 ligase activity. Functionally, we demonstrated that NleL E3 ubiquitin ligase activity is involved in modulating Tir-mediated pedestal formation. Surprisingly, EHEC mutant strain deficient in the E3 ligase activity induced more pedestals than the wild-type strain. The canonical EPEC strain E2348/69 normally lacks the nleL gene, and the ectopic expression of the wild-type EHEC nleL, but not the catalytically-deficient nleL(C753A) mutant, in this strain resulted in fewer actin-rich pedestals. Furthermore, we showed that the C. rodentium NleL homolog is a E3 ubiquitin ligase and is required for efficient infection of murine colonic epithelial cells in vivo. In summary, our study demonstrated that EHEC utilizes NleL E3 ubiquitin ligase activity to modulate Tir-mediated pedestal formation.
    Full-text available · Article · Apr 2011 · PLoS ONE
  • Megan E. McBee · Yu Zeng · Nicola Parry · [...] · David B. Schauer
    [Show abstract] [Hide abstract] ABSTRACT: Peak infection with C. rodentium precedes onset of weight loss and disease development. (a) Fecal burden of C. rodentium in uninfected (closed square) and infected (open square) mice from Day 0 to Day 14. (b) Percent change in body weight normalized to day 0 to day 14 in uninfected (closed square) and C. rodentium-infected (open square) mice. Data are presented as mean ± SEM. *** P<0.001 by two-way ANOVA with Bonferroni post-tests. (1.25 MB TIF)
    File available · Data · Oct 2010
  • Megan E. McBee · Yu Zeng · Nicola Parry · [...] · David B. Schauer
    [Show abstract] [Hide abstract] ABSTRACT: Cytokine measurements in C57BL/6J mice with acute infectious colitis. Colon tissue (a) and serum (b) cytokine concentrations in uninfected (Cr-; n = 9 serum, n = 10 tissue) and C. rodentium infected (Cr+; n = 10) mice at 14 DPI. Colon concentrations were normalized to total protein in sample. Bar equals mean value. * P < 0.05, ** P < 0.01, *** P < 0.001 by unpaired Student's T test. (9.5 MB TIF)
    File available · Data · Oct 2010
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    Megan E McBee · Yu Zeng · Nicola Maria Anne Parry · [...] · David B Schauer
    [Show abstract] [Hide abstract] ABSTRACT: Background: Diagnosis of chronic intestinal inflammation, which characterizes inflammatory bowel disease (IBD), along with prediction of disease state is hindered by the availability of predictive serum biomarker. Serum biomarkers predictive of disease state will improve trials for therapeutic intervention, and disease monitoring, particularly in genetically susceptible individuals. Chronic inflammation during IBD is considered distinct from infectious intestinal inflammation thereby requiring biomarkers to provide differential diagnosis. To address whether differential serum biomarkers could be identified in murine models of colitis, immunological profiles from both chronic spontaneous and acute infectious colitis were compared and predictive serum biomarkers identified via multivariate modeling. Methodology/principal findings: Discriminatory multivariate modeling of 23 cytokines plus chlorotyrosine and nitrotyrosine (protein adducts from reactive nitrogen species and hypochlorite) in serum and tissue from two murine models of colitis was performed to identify disease-associated biomarkers. Acute C. rodentium-induced colitis in C57BL/6J mice and chronic spontaneous Helicobacter-dependent colitis in TLR4(-/-) x IL-10(-/-) mice were utilized for evaluation. Colon profiles of both colitis models were nearly identical with chemokines, neutrophil- and Th17-related factors highly associated with intestinal disease. In acute colitis, discriminatory disease-associated serum factors were not those identified in the colon. In contrast, the discriminatory predictive serum factors for chronic colitis were neutrophil- and Th17-related factors (KC, IL-12/23p40, IL-17, G-CSF, and chlorotyrosine) that were also elevated in colon tissue. Chronic colitis serum biomarkers were specific to chronic colitis as they were not discriminatory for acute colitis. Conclusions/significance: Immunological profiling revealed strikingly similar colon profiles, yet distinctly different serum profiles for acute and chronic colitis. Neutrophil- and Th17-related factors were identified as predictive serum biomarkers of chronic colitis, but not acute colitis, despite their presence in colitic tissue of both diseases thereby demonstrating the utility of mathematical modeling for identifying disease-associated serum biomarkers.
    Full-text available · Article · Oct 2010 · PLoS ONE
  • Megan E. McBee · Yu Zeng · Nicola Parry · [...] · David B. Schauer
    [Show abstract] [Hide abstract] ABSTRACT: Cytokine measurements in TLR4-/- x IL10-/- (DKO) mice with chronic spontaneous Helicobacter-dependent colitis. Colon tissue (a) and serum (b) cytokine concentrations in Helicobacter spp.-negative (Hsp-; n = 6) and Helicobacter spp.-positive (Hsp+; n = 8 tissue, n = 10 serum) DKO mice. Colon concentrations were normalized to total protein in sample. Bar equals mean value. * P < 0.05, ** P < 0.01, *** P < 0.001 by unpaired Student's T test. (9.5 MB TIF)
    File available · Data · Oct 2010
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    Alexander Sheh · Chung Wei Lee · Kenichi Masumura · [...] · David B Schauer
    [Show abstract] [Hide abstract] ABSTRACT: Helicobacter pylori is a human carcinogen, but the mechanisms evoked in carcinogenesis during this chronic inflammatory disease remain incompletely characterized. We determined whether chronic H. pylori infection induced mutations in the gastric mucosa of male and female gpt delta C57BL/6 mice infected for 6 or 12 mo. Point mutations were increased in females infected for 12 mo. The mutation frequency in this group was 1.6-fold higher than in uninfected mice of both sexes (P < 0.05). A:T-to-G:C transitions and G:C-to-T:A transversions were 3.8 and 2.0 times, respectively, more frequent in this group than in controls. Both mutations are consistent with DNA damage induced by oxidative stress. No increase in the frequency of deletions was observed. Females had more severe gastric lesions than males at 6 mo postinfection (MPI; P < 0.05), but this difference was absent at 12 MPI. In all mice, infection significantly increased expression of IFNgamma, IL-17, TNFalpha, and iNOS at 6 and 12 mo, as well as H. pylori-specific IgG1 levels at 12 MPI (P < 0.05) and IgG2c levels at 6 and 12 MPI (P < 0.01 and P < 0.001). At 12 MPI, IgG2c levels in infected females were higher than at 6 MPI (P < 0.05) and also than those in infected males at 12 MPI (P < 0.05). Intensity of responses was mediated by sex and duration of infection. Lower H. pylori colonization indicated a more robust host response in females than in males. Earlier onset of severe gastric lesions and proinflammatory, Th1-biased responses in female C57BL/6 mice may have promoted mutagenesis by exposing the stomach to prolonged oxidative stress.
    Full-text available · Article · Aug 2010 · Proceedings of the National Academy of Sciences
  • Alexander Sheh · Chung-Wei Lee · Kenichi Masumura · [...] · David Schauer
    Article · May 2010 · Gastroenterology

Publication Stats

5k Citations

Institutions

  • 2001-2002
    • Massachusetts Institute of Technology
      • • Department of Civil and Environmental Engineering
      • • Division of Comparative Medicine
      Cambridge, MA, United States