Outer membrane proteins (OMPs) and lipoproteins (IPs) of Gram-negative bacteria are of enormous importance as virulence factors, stabilizers of outer membrane integrity, and protective immune targets (vaccines). To date, little has been known regarding the OMPs of Francisella tularensis (Type A) strains that are pathogenic for humans (e.g., F. tularensis SCHU S4). However, selected OMPs could prove invaluable as subunit vaccines for tularemia. In this regard, we have achieved two important milestones that warrant further investigation of the OMPs as acellular vaccines for tularemia. First, we developed a sucrose density gradient method for the physical separation of the outer and cytoplasmic membranes of F. tularensis (J.F. Huntley et al., 2007, J. Bacteriol. 189:561). This method has allowed, for the first time, direct examination of the OMP components of this important Category A select agent. Second, we have demonstrated that OMP-immunized mice are protected against intranasal challenge with SCHU S4. We now wish to extend these studies by completing the identification of the entire spectrum of OMPs in F. tularensis SCHU S4 (Aim 1). We also will test native and recombinant OMPs of SCHU S4 for their vaccinogenic potentials using mouse models of tularemia (Aim 2). Various routes for mouse immunizations (intraperitoneal, intranasal) and pulmonary challenges (intranasal, aerosol) will be employed. As part of this initiative, we also will examine newer adjuvants (e.g., cationic lipid-DNA liposomes, ISCOMs, CpG, and AdDP) to potentially enhance immunoprotection.
In Aim 3, we shall investigate the humoral aspect of protective immunity induced by OMP vaccines by performing passive transfer experiments in mice, and by assessing antibody classes and isotypes elicited. Included in these studies will be assessments of key correlates of protective immunity (Th1 and Th2 cytokines, regulators, etc.); humanized mice may be particularly useful for these studies. As an off-shoot of this project, we also shall evaluate the roles of selected OMPs and LPs as virulence factors for F. tularensis by examining OMP-deficient mutants in both in vitro (infection/growth in human monocytes) and in vivo (mouse infection) systems. The combined studies will provide important new knowledge for understanding F. tularensis pathogenesis and for devising new acellular vaccines for tularemia.

Public Health Relevance

Bacterial surface proteins, also known as outer membrane proteins (OMPs) in certain bacteria, are of enormous importance to many bacterial pathogens. To date, little has been known regarding the OMPs of Francisella tularensis strains that are dangerous to humans, but such OMPs could prove invaluable as new vaccines for tularemia. In this project, we seek to identify and characterize previously unknown OMPs of F. tularensis and potentially develop them as new vaccines for tularemia.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Specialized Center--Cooperative Agreements (U54)
Project #
5U54AI057156-10
Application #
8440802
Study Section
Special Emphasis Panel (ZAI1-DDS-M)
Project Start
Project End
2015-02-28
Budget Start
2013-03-01
Budget End
2015-02-28
Support Year
10
Fiscal Year
2013
Total Cost
$439,333
Indirect Cost
$64,931
Name
University of Texas Medical Br Galveston
Department
Type
DUNS #
800771149
City
Galveston
State
TX
Country
United States
Zip Code
77555
Navarro, Juan-Carlos; Giambalvo, Dileyvic; Hernandez, Rosa et al. (2016) Isolation of Madre de Dios Virus (Orthobunyavirus; Bunyaviridae), an Oropouche Virus Species Reassortant, from a Monkey in Venezuela. Am J Trop Med Hyg 95:328-38
Park, Arnold; Yun, Tatyana; Hill, Terence E et al. (2016) Optimized P2A for reporter gene insertion into Nipah virus results in efficient ribosomal skipping and wild-type lethality. J Gen Virol 97:839-43
Aghazadeh, Amirali; Lin, Adam Y; Sheikh, Mona A et al. (2016) Universal microbial diagnostics using random DNA probes. Sci Adv 2:e1600025
Inglis, Fiona M; Lee, Kim M; Chiu, Kevin B et al. (2016) Neuropathogenesis of Chikungunya infection: astrogliosis and innate immune activation. J Neurovirol 22:140-8
Hatcher, Christopher L; Mott, Tiffany M; Muruato, Laura A et al. (2016) Burkholderia mallei CLH001 Attenuated Vaccine Strain Is Immunogenic and Protects against Acute Respiratory Glanders. Infect Immun 84:2345-54
Chen, Hui; Hagström, Anna E V; Kim, Jinsu et al. (2016) Flotation Immunoassay: Masking the Signal from Free Reporters in Sandwich Immunoassays. Sci Rep 6:24297
Crannell, Zachary Austin; Cabada, Miguel Mauricio; Castellanos-Gonzalez, Alejandro et al. (2015) Recombinase polymerase amplification-based assay to diagnose Giardia in stool samples. Am J Trop Med Hyg 92:583-7
Walker, David H; Dumler, J Stephen (2015) The role of CD8 T lymphocytes in rickettsial infections. Semin Immunopathol 37:289-99
Mott, Tiffany M; Vijayakumar, Sudhamathi; Sbrana, Elena et al. (2015) Characterization of the Burkholderia mallei tonB Mutant and Its Potential as a Backbone Strain for Vaccine Development. PLoS Negl Trop Dis 9:e0003863
Gregory, Anthony E; Judy, Barbara M; Qazi, Omar et al. (2015) A gold nanoparticle-linked glycoconjugate vaccine against Burkholderia mallei. Nanomedicine 11:447-56

Showing the most recent 10 out of 362 publications