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U.S. Department of Health and Human Services

Vaccines, Blood & Biologics

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Bacterial Vaccine Safety: Biomarkers of Virulence and Attenuation in Bordetella Pertussis (Whooping Cough) and Anthrax Bacteria

Principal Investigator: E. Scott Stibitz, PhD
Office / Division / Lab: OVRR / DBPAP / LESTD


General Overview

Our laboratory is studying disease-causing bacteria for which new vaccines or improvements on existing vaccines are now being developed.

We are developing new ways to study respiratory infections caused by the bacterium Bordetella pertussis (whooping cough) and the mechanisms by which it causes severe disease. Although a vaccine for this organism exists, the number of whooping cough cases in the US continues to rise, making this research vital to ultimate control.

Our studies of Bacillus anthracis are in part aimed at creating tools and methods to facilitate development of an improved anthrax vaccine that can be stored in a national stockpile for long periods of time without losing its potency. Such improvements are critical if the US is to have usable vaccine stockpiles for use in an emergency.

We also support the development and evaluation of vaccines against Staphylococcus aureus, which causes many infections in the US each year, some of which are extremely serious (e.g., "flesh-eating" bacteria that can cause death in a matter of hours). S. aureus also causes infections of implanted devices such as pacemakers and joint replacements that can be very difficult to treat without removing the device. Currently no vaccine for this disease exists and development of new vaccines against this organism is especially critical due to problems with antibiotic resistance typified by MRSA (methicillin-resistant Staphylococcus aureus), and the new strains of community-acquired MRSA (CA-MRSA).

Our laboratory is also studying the use of live biotherapeutic products (i.e., probiotics--live microorganisms that provide health benefits to an individual when consumed in appropriate quantities) to help treat and prevent bacterial infections and other conditions. The investigation of the full potential of these promising products is currently being hindered by difficulties in evaluation of the manufacturing process, purity, safety and quality of these products. We seek to solve this problem by developing better tests for the purity and safety of probiotics, thereby allowing their further testing and development in the clinic.


Scientific Overview

Our laboratory takes a genetic approach to studies of bacterial pathogenesis and vaccine development.

In our studies of Bordetella pertussis we introduce specific mutations that affect the expression and regulation of virulence factors, such as toxins and adhesins. We then test the effects of these mutations in a mouse model of respiratory infection that uses bioluminescent B. pertussis to track infection without harming the test animal. This approach has several advantages over older methods that involve sacrificing a group of test animals at each time point, and reduces dramatically the number of animals that must be used.

Our approach to studying Bacillus anthracis pathogenesis has also been largely genetic. We developed and have recently improved, new genetic tools to introduce specific mutations into this organism. These tools, which are now used widely around the world, are significantly easier and more powerful than previous such techniques. They also allow the consecutive deletion or mutation of a unlimited number of genes. This approach has been critical to our studies of anthrax vaccine stability. For example, it has enabled us to create improved strains of the organism used to produce protective antigen (part of the anthrax toxin). These strains lack a number of secreted proteases (currently up to 16 separate deletions). This characteristic increases the production of protective antigen and leads to a purified product that has increased stability.

Our new program in Staphylococcus aureus will follow a similar path, synergizing our genetic capabilities with other OVRR researchers to evaluate new vaccine candidates and identify new candidates for virulence factors and vaccine antigens.

Finally, we are using bacteriophages to develop improved tests for detecting pathogens in probiotic products. We plan to exploit the exquisite specificity of these bacterial viruses to specifically kill product organisms, thereby increasing the sensitivity of detection of extraneous and potentially harmful bacterial pathogens, such as Salmonella and Shigella. Such tests are necessary to ensure the safety of these preparations, a factor that is especially important when tested in clinical trials in very sick or otherwise compromised patients.


Publications

Infect Immun 2013 Apr;81(4):1306-15
An Epicutaneous Model of Community-Acquired Staphylococcus aureus Skin Infections.
Prabhakara R, Foreman O, De Pascalis R, Lee GM, Plaut RD, Kim SY, Stibitz S, Elkins KL, Merkel TJ

PLoS One 2013;8(3):e59232
Stably Luminescent Staphylococcus aureus Clinical Strains for Use in Bioluminescent Imaging.
Plaut RD, Mocca CP, Prabhakara R, Merkel TJ, Stibitz S

Infect Immun 2013 Jan;81(1):278-84
Use of site-directed mutagenesis to model the effects of spontaneous deamidation on the immunogenicity of Bacillus anthracis protective antigen.
Verma A, McNichol B, Domínguez-Castillo RI, Amador-Molina JC, Arciniega JL, Reiter K, Meade BD, Ngundi MM, Stibitz S, Burns DL

Virol J 2012 Oct 26;9:246
Whole genome sequencing of phage resistant Bacillus anthracis mutants reveals an essential role for cell surface anchoring protein CsaB in phage AP50c adsorption.
Bishop-Lilly KA, Plaut RD, Chen PE, Akmal A, Willner KM, Butani A, Dorsey S, Mokashi V, Mateczun AJ, Chapman C, George M, Luu T, Read TD, Calendar R, Stibitz S, Sozhamannan S

Infect Immun 2012 Sep;80(9):3189-93
A dissemination bottleneck in murine inhalational anthrax.
Plaut RD, Kelly VK, Lee GM, Stibitz S, Merkel TJ

Cell Microbiol 2012 Aug;14(8):1219-1230
Bacillus anthracis protease InhA regulates BslA-mediated adhesion in human endothelial cells.
Tonry JH, McNichol BA, Ramarao N, Chertow DS, Kim KS, Stibitz S, Schneewind O, Kashanchi F, Bailey CL, Popov S, Chung MC

Microbiology 2012 Jul;158(Pt 7):1665-76
The Bordetella pertussis model of exquisite gene control by the global transcription factor BvgA.
Decker KB,James TD, Stibitz S, Hinton DM

Infect Immun 2012 Mar;80(3):1025-36
Phenotypic Modulation of the Virulent Bvg Phase Is Not Required for Pathogenesis and Transmission of Bordetella bronchiseptica in Swine.
Nicholson TL, Brockmeier SL, Loving CL, Register KB, Kehrli ME Jr, Stibitz SE, Shore SM

Proc Natl Acad Sci U S A 2011 Oct 11;108(41):17159-64
Identification of the bacterial protein FtsX as a unique target of chemokine-mediated antimicrobial activity against Bacillus anthracis.
Crawford MA, Lowe DE, Fisher DJ, Stibitz S, Plaut RD, Beaber JW, Zemansky J, Mehrad B, Glomski IJ, Strieter RM, Hughes MA

J Mol Biol 2011 Jun 24;409(5):692-709
Different Requirements for sigma Region 4 in BvgA Activation of the Bordetella pertussis Promoters P(fim3) and P(fhaB).
Decker KB, Chen Q, Hsieh ML, Boucher P, Stibitz S, Hinton DM

Mol Microbiol 2010 Sep;77(5):1326-40
Novel architectural features of Bordetella pertussis fimbrial subunit promoters and their activation by the global virulence regulator BvgA.
Chen Q, Decker KB, Boucher PE, Hinton D, Stibitz S

Infect Immun 2010 Jul;78(7):2901-9
Pertactin is required for Bordetella to resist neutrophil-mediated clearance.
Inatsuka CS, Xu Q, Vujkovic-Cvijin I, Wong S, Stibitz S, Miller JF, Cotter PA

Infect Immun 2009 Jan;77(1):255-65
Role of anthrax toxins in dissemination, disease progression, and induction of protective adaptive immunity in the mouse aerosol challenge model.
Loving CL, Khurana T, Osorio M, Lee GM, Kelly VK, Stibitz S, Merkel TJ

Infect Immun 2009 Jan;77(1):274-85
Four superoxide dismutases contribute to Bacillus anthracis virulence and provide spores with redundant protection from oxidative stress.
Cybulski RJ Jr, Sanz P, Alem F, Stibitz S, Bull RL, O'Brien AD

Clin Vaccine Immunol 2008 Nov;15(11):1737-41
Role of the N-terminal amino acid of Bacillus anthracis lethal factor in lethal toxin cytotoxicity and its effect on the lethal toxin neutralization assay.
Verma A, Wagner L, Stibitz S, Nguyen N, Guerengomba F, Burns DL

Infect Immun 2008 Apr;76(4):1774-80
O antigen Protects Bordetella parapertussis from Complement.
Goebel EM, Wolfe DN, Elder K, Stibitz S, Harvill ET

Infect Immun 2007 Nov;75(11):5233-9
Bacillus anthracis Exosporium Protein BclA Affects Spore Germination, Interaction with Extracellular Matrix Proteins, and Hydrophobicity.
Brahmbhatt TN, Janes BK, Stibitz ES, Darnell SC, Sanz P, Rasmussen SB, O'brien AD

Curr Opin Microbiol 2007 Feb;10(1):17-23
c-di-GMP-mediated regulation of virulence and biofilm formation.
Cotter PA, Stibitz S

Infect Immun 2006 Mar;74(3):1949-53
Routine markerless gene replacement in Bacillus anthracis.
Janes BK, Stibitz S

Mol Microbiol 2005 Nov;58(3):700-13
Role of BvgA phosphorylation and DNA binding affinity in control of Bvg-mediated phenotypic phase transition in Bordetella pertussis.
Jones AM, Boucher PE, Williams CL, Stibitz S, Cotter PA

Mol Microbiol 2005 Apr;56(1):175-88
BvgA functions as both an activator and a repressor to control Bvg phase expression of bipA in Bordetella pertussis.
Williams CL, Boucher PE, Stibitz S, Cotter PA

Mol Microbiol 2005 Feb;55(3):788-98
Demonstration of differential virulence gene promoter activation in vivo in Bordetella pertussis using RIVET.
Veal-Carr WL, Stibitz S

     
 

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