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Frederick, MD, United States

Asensi G.F.,Federal University of Rio de Janeiro | de Sales N.F.F.,Federal University of Rio de Janeiro | Dutra F.F.,Federal University of Rio de Janeiro | Feijo D.F.,Federal University of Rio de Janeiro | And 9 more authors.
Microbial Cell Factories | Year: 2013

Background: Staphylococcus aureus is unrestrictedly found in humans and in animal species that maintain thermal homeostasis. Inadequate cleaning of processing equipment or inappropriate handling can contaminate processed food and cause severe food poisoning. Staphylococcal enterotoxin B (SEB), a potent superantigenic exotoxin, is produced by 50% of clinical isolates of S. aureus and is associated with massive food poisoning and with the induction of toxic shock syndrome.Results: A gene sequence encoding a recombinant SEB (rSEB), devoid of superantigenic activity, was successfully cloned and expressed in a cytoplasmic or a secreted form in the food-grade lactic acid bacterium Lactococcus lactis. The recombinant protein detected in the cytoplasm or in the culture medium exhibited the expected molecular mass and was recognized by a SEB-polyclonal antibody. Oral immunization with the recombinant L. lactis strains induced a protective immune response in a murine model of S. aureus infection. Immunized mice survived intraperitoneal challenge with an S. aureus SEB-producer strain. Counts of S. aureus in the spleen of rSEB-immunized mice were significantly reduced. The rSEB-immunized mice showed significant titers of anti-SEB IgA and IgG in stools and serum, respectively. Both recombinant L. lactis strains were able to elicit cellular or systemic immune responses in mice, with no significant difference if rSEB was produced in its cytoplasmic or secreted form. However, recombinant L. lactis expressing the cytoplasmic rSEB increased the survival rate of the challenged mice by 43%.Conclusions: These findings show the vaccine efficacy of L. lactis carrying an attenuated SEB, in a murine model, following lethal S. aureus challenge. © 2013 Asensi et al.; licensee BioMed Central Ltd. Source


VanderKraats N.D.,Center for Pharmacogenomics | Hiken J.F.,Center for Pharmacogenomics | Edwards J.R.,Center for Pharmacogenomics | Zhang H.,U.S. Department of Agriculture | Zhao K.,Laboratory of Molecular Immunology
Epigenetics : official journal of the DNA Methylation Society | Year: 2013

Marek's disease (MD) is characterized as a T cell lymphoma induced by a cell-associated α-herpesvirus, Marek's disease virus type 1 (MDV1). As with many viral infectious diseases, DNA methylation variations were observed in the progression of MD; these variations are thought to play an important role in host-virus interactions. We observed that DNA methyltransferase 3a (DNMT3a) and 3b (DNMT3b) were differentially expressed in chicken MD-resistant line 6 3 and MD-susceptible line 7 2 at 21 d after MDV infection. To better understand the role of methylation variation induced by MDV infection in both chicken lines, we mapped the genome-wide DNA methylation profiles in each line using Methyl-MAPS (methylation mapping analysis by paired-end sequencing). Collectively, the data sets collected in this study provide a more comprehensive picture of the chicken methylome. Overall, methylation levels were reduced in chickens from the resistant line 6 3 after MDV infection. We identified 11,512 infection-induced differential methylation regions (iDMRs). The number of iDMRs was larger in line 7 2 than in line 6 3, and most of iDMRs found in line 6 3 were overlapped with the iDMRs found in line 7 2. We further showed that in vitro methylation levels were associated with MDV replication, and found that MDV propagation in the infected cells was restricted by pharmacological inhibition of DNA methylation. Our results suggest that DNA methylation in the host may be associated with disease resistance or susceptibility. The methylation variations induced by viral infection may consequentially change the host transcriptome and result in diverse disease outcomes. Source


Lu Z.,U.S. National Institutes of Health | Bourdi M.,Laboratory of Molecular Immunology | Li J.H.,U.S. National Institutes of Health | Aponte A.M.,U.S. National Institutes of Health | And 5 more authors.
EMBO Reports | Year: 2011

Acetaminophen/paracetamol-induced liver failure-which is induced by the binding of reactive metabolites to mitochondrial proteins and their disruption-is exacerbated by fasting. As fasting promotes SIRT3-mediated mitochondrial-protein deacetylation and acetaminophen metabolites bind to lysine residues, we investigated whether deacetylation predisposes mice to toxic metabolite-mediated disruption of mitochondrial proteins. We show that mitochondrial deacetylase SIRT3 -/- mice are protected from acetaminophen hepatotoxicity, that mitochondrial aldehyde dehydrogenase 2 is a direct SIRT3 substrate, and that its deacetylation increases acetaminophen toxic-metabolite binding and enzyme inactivation. Thus, protein deacetylation enhances xenobiotic liver injury by modulating the binding of a toxic metabolite to mitochondrial proteins. © 2011 European Molecular Biology Organization. Source


Stumpfe D.,Chemical Biology and Medicinal Chemistry | Bill A.,C o Kekule Institute of Organic Chemistry and Biochemistry | Novak N.,Laboratory of Molecular Immunology | Loch G.,University of Bonn | And 8 more authors.
ACS Chemical Biology | Year: 2010

Virtual screening (VS) of chemical libraries formatted in silico provides an alternative to experimental high-throughput screening (HTS) for the identification of small molecule modulators of protein function. We have tailored a VS approach combining fingerprint similarity searching and support vector machine modeling toward the identification of small molecular probes for the study of cytohesins, a family of cytoplasmic regulator proteins with multiple cellular functions. A total of 40 new structurally diverse inhibitors were identified, and 26 of these compounds were more active than the primary VS template, a single known inhibitory chemotype, in at least one of three different assays (guanine nucleotide exchange, Drosophila insulin signaling, and human leukocyte cell adhesion). Moreover, these inhibitors displayed differential inhibitory profiles. Our findings demonstrate that, at least for the cytohesins, computational extrapolation from known active compounds was capable of identifying small molecular probes with highly diversified functional profiles. © 2010 American Chemical Society. Source


Lim J.K.,Laboratory of Molecular Immunology | McDermott D.H.,Laboratory of Molecular Immunology | Lisco A.,U.S. National Institutes of Health | Foster G.A.,Red Cross | And 4 more authors.
Journal of Infectious Diseases | Year: 2010

Background. West Nile virus (WNV) is a neurotropic flavivirus transmitted to humans by mosquito vectors. Homozygosity for CCR5Δ32, a complete loss-of-function mutation in CC chemokine receptor 5 (CCR5), has been previously associated with severe symptomatic WNV infection in patients who present with clinical disease; however, whether it acts at the level of initial infection or in promoting clinical progression is unknown. Methods. Here, we address this gap in knowledge by comparing CCR5Δ32 distribution among US blood donors identified through a comprehensive blood supply screening program (34,766,863 donations from 2003 through 2008) as either WNV true positive (634 WNV-positive cases) or false positive (422 WNV-negative control participants). All subjects self-reported symptoms occurring during the 2 weeks following blood donation using a standardized questionnaire. Results. No difference was observed in CCR5Δ32 homozygous frequency between the WNV-positive cases and WNV-negative control participants. However, CCR5Δ32 homozygosity was associated in cases but not controls with clinical symptoms consistent with WNV infection (P = .002). Conclusions. CCR5 deficiency is not a risk factor for WNV infection per se, but it is a risk factor for both early and late clinical manifestations after infection. Thus, CCR5 may function normally to limit disease due to WNV infection in humans. © 2010 by the Infectious Diseases Society of America. All rights reserved. Source

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