James E. Bina, PhD

Associate Professor


Dr. Jim Bina

Contact

412-648-8958
Fax: 412-624-1401

407 Bridgeside Point II

450 Technology Drive

Pittsburgh, PA 15219

Education

PhD in Microbiology & Immunology, University of British Columbia (Canada)

Research Summary

Our research is centered on defining the molecular mechanisms used by bacteria to resist antibiotics and cause disease in humans. Our work currently focuses on two important gram negative human pathogens: Vibrio cholerae and Francisella tularensis.

Vibrio cholerae 

V. cholerae is a highly motile gram-negative, facultative human pathogen that causes the potentially lethal diarrheal disease cholera. V. cholerae is a significant health threat in the developing world where this organism is responsible for an estimated 3-5 million cholera cases each year with a mortality rate of ~1.5%. Cholera is acquired by ingestion of food or water contaminated with V. cholerae. Upon ingestion, V. cholerae colonizes the small intestine where the organism produces a variety of virulence factors that lead to disease.

Virulence factor production in V. cholerae is induced in vivo in response to unknown stimuli. A key question in cholera research is to determine how these unknown stimuli effect gene expression in vivo. We recently showed that cFP, a cyclic dipeptide that is produced by V. cholerae, functioned as an inhibitor of virulence factor production. Since cFP is produced in a growth-dependent manner, and functions independently of the quorum sensing systems, we hypothesize that cFP functions as a novel cell density-dependent signaling molecule that regulates gene expression during pathogenesis. We are currently working to define the genes involved in cFP biosynthesis and to define the signal transduction pathway by which cFP inhibits virulence factor production.  We are also exploring the possible use of cFP-like chemicals as novel anti-virulence therapeutics for cholera treatment.

In addition to the production of virulence factors, to cause disease V. cholerae must also protect itself from the antibacterial effects of toxic molecules that are present in the host gastrointestinal tract. V. cholerae does this by the expression of active efflux systems belonging to the RND family. The RND family efflux systems are ubiquitous transporters found among gram negative bacteria. The RND systems function to remove toxic molecules from within the cell and thus contribute to the evolution of antibiotic resistance. We have shown that the RND systems are also required for the production of virulence factors in V. cholerae. This suggested that there is a relationship between RND efflux activity and virulence gene expression and provided the first evidence that the RND efflux systems influence pathogenesis by a mechanism other than antimicrobial resistance. We are currently studying the genetic linkage between efflux and virulence factor production.

Francisella tularensis  

F. tularensis is a gram negative bacterium that causes the zoonotic disease tularemia.  F. tularensis is one of the most infectious pathogens known with an LD50 of fewer than 10 bacteria. F. tularensis is most frequently transmitted to humans by insect vectors or the handling of contaminated material, but can also be transmitted by inhalation.  Untreated, inhalation tularemia is associated with a 30-60% mortality rate. The high infectivity, high virulence, and easy of dissemination by aerosols have led to the development of F. tularensis as a b ioweapon by several nations. These properties have also let to growing concerns about the potential use of F. tularensis in bioterrorism.

 

Very little is known about F. tularensis pathogenesis. During infection of mammalian hosts F. tularensis is believed to grow intracellularly in macrophages. Subsequently, F. tularensis inhibits both phagosome and lysosome fusion by an unknown mechanism. Recent findings suggest that F. tularensis, like Listeria monocytogenes, rapidly escapes the phagosome and resides and replicates within the cytoplasm of host cells. Following an initial growth lag, intracellular F. tularensis enters logarithmic growth by 12 hours post-infection and eventually induces apoptosis and cell death.

My laboratory is working on the development and application of Francisella-specific genetic tools to define potential virulence factors and vaccine targets in this organism. We employ  multiple disciplinary approaches including genetics, genomics, biochemistry and immunology and are collaborating with investigators at Emory University and the University of Tennessee Health Science Center to characterize the function of F. tularensis genes in virulence  and immune evasion.

Research Lab Affiliation

Publications

Bina X. R; Taylor D. L; Vikram A; Ante V; and Bina J. E. (2013) Vibrio cholerae ToxR downregulates virulence factor production in response to cyclo(Phe-Pro). mBio. 4: e00366-13. |  View Abstract

Taylor D. L; Bina X. R; and Bina J. E. (2012) Vibrio cholerae VexH encodes a multiple drug efflux pump that contributes to the production of cholera toxin and the toxin co-regulated pilus. PLoS One. 7: e38208. |  View Abstract

Bina, X. R; Provenzano, D; Nguyen, N; and Bina, J. E. (2008) Vibrio cholerae RND family efflux systems are required for antimicrobial resistance, optimal virulence factor production, and colonization of the infant mouse small intestine. Infect Immun. 76: 3595-3605. |  View Abstract

Bina J.E; Zhu J; Dziejman M; Faruque S; Calderwood S; and Mekalanos J. (2003) ToxR regulon of Vibrio cholerae and its expression in vibrios shed by cholera patients. PNAS. 100: 2801-2806. |  View Abstract

Reynoso C. M; Miller M. A; Bina J. E; Gallivan J. P; and Weiss D. S. (2012) Riboswitches for intracellular study of genes involved in Francisella pathogenesis. MBio. 3: e00253-12. |  View Abstract

Napier B. A; Meyer L; Bina J. E; Miller M. A; Sjostedt A; and Weiss D. S. (2012) Link between intraphagosomal biotin and rapid phagosomal escape in Francisella. Proc Natl Acad Sci USA. [Epub ahead of print 10/17/12] |  View Abstract

Miller, M. A; Stabenow, J. M; Parvathareddy, J; Wodowski, A. J; Fabrizio, T. P; Bina, X. R; Zalduondo, L; and Bina, J. E. (2012) Visualization of Murine Intranasal Dosing Efficiency Using Luminescent Francisella tularensis: Effect of Instillation Volume and Form of Anesthesia. PLoS ONE. 7: e31359. |  View Abstract