Microbiology, Immunology and Biochemistry Faculty Directory
Jim Bina, Ph.D.
858 Madison Ave.
701 Molecular Science Building
Memphis, TN 38163
My research focuses on the molecular mechanisms of bacterial pathogenesis and antibiotic resistance. To do this we use genetic, genomic and biochemical approaches to understand how bacteria cause disease in humans. Our work currently focuses on two important human pathogenic bacteria.
My laboratory is studying the role for antibiotic efflux systems in V. cholerae pathogenesis and antimicrobial resistance to bile salts, antibiotics and antimicrobial peptides. We are using genetic and genomic techniques to define the role of efflux systems in V. cholerae colonization of the small intestine and virulence factor production.
V. cholerae is a highly motile gram-negative, facultative human pathogen that causes the potentially lethal diarrheal disease cholera. Cholera is acquired by ingestion of food or watercontaminated with V. cholerae. Upon ingestion, V. cholerae survives passage through the gastric acid barrier of the stomach and colonizes the mucosa of the small intestine. In response to undefined stimuli during colonization, two membrane-associated transcriptional activator complexes, ToxRS and TcpPH, initiate transcription of the toxT gene. The ToxT protein is a transcriptional activator of the AraC family that directly activates the transcription of the genes responsible for the production of cholera toxin (CT) and the toxin-coregulated pilus (TCP). The TCP is a type IV bundle-forming pilus that is essential for colonization of the intestinal tract. CT is an A-B type enterotoxin that is responsible for the profuse diarrhea that is characteristic of cholera. Collectively, this regulatory system has been called the ToxR regulon.
The signals encountered in vivo by V. cholerae leading to the activation of the ToxR regulon remain unknown. However, several stimuli have been shown to affect induction of the ToxR regulon in vitro. One such stimulus has been bile acids. Bile acids are steroid carboxylic acids derived from cholesterol. Bile acids are produced in the liver and stored in the gall bladder. Upon ingestion of food, bile is released from the gall bladder into the duodenum where the detergent properties of bile salts contribute to the digestion of lipids. In addition to functioning in digestion, bile acids represent an important antimicrobial barrier to colonization of the small intestine by potential pathogens. The concentration of bile acids in the upper duodenum can reach molar concentrations that are toxic for many non-enteric bacteria.
Bile acids are believed to be an in vivo cue to which V. cholerae modulates the expression of many factors that are important for virulence. Bile extracts have been reported to function as a chemotactic signal, induce hypermotility, induce changes in outer membrane porin proteins and modulated the production of virulence factors in both ToxT-dependent and ToxT-independent manners. All of these bile-associated phenotypes are associated with V. cholerae virulence which suggests that bile may represent an important in vivo cue sensed by V. cholerae. Efflux systems play an important role in bile resistance by regulating the amount of bile that accumulates within the cell. By regulating the concentration of bile within the cell, efflux systems can effect the expression of genes that are important for virulence.
The long term goal of this research project is to develop an effective vaccine for tularemia the disease caused by the gram negative bacterium F. tularensis. The development of an effective vaccine is dependent upon the identification of vaccine candidate genes. My laboratory is focusing on the development of new genetic techniques to identify F. tularensis genes that are required for virulence. We are using both in vitro and in vivo screens to identify genes that are important for virulence. The identification of genes that play a role in infection provides further understanding of the basic biology of F. tularensis, and paves the way for the development virulence-targeted therapeutics.
F. tularensis is a gram negative bacterium that causes the zoonotic disease tularemia. F. tularensis is a highly infectious bacterium requiring as few as 10 bacteria to cause disease. F. tularensis has an extremely wide host range and can persist in the environment for weeks in contaminated animal carcasses, soil, water, and vegetation. F. tularensis is most frequently transmitted to humans by insect vectors including flies, ticks and mosquitoes. Additional modes of transmission include ingestion, inhalation or handling of F. tularensis contaminated material. Because F. tularensis is highly infective and easy to disseminate by aerosol, it is a prime candidate for use in biological warfare and bioterrorism. Indeed several countries including the U.S., Japan, and the Soviet Union developed F. tularensis for use as a biological weapon. These facts plus elevated worldwide terrorist activities have resulted in growing concerns about the potential use of F. tularensis as a bioterrorist weapon.
Infection with F. tularensis can cause several different disease syndromes depending on the route of entry. Infection of F. tularensis through the skin or mucous membranes results in ulceroglandular tularemia which represents the most common form of the disease (~90% of cases). On rare occasions, F. tularensis can also be directly transmitted to the eye to produce ocularglandular tularemia or ingested to produce oropharyngeal tularemia. These forms of the disease require medical treatment but are rarely fatal (mortality rate <1%). In contrast, typhoidal tularemia is the term used to describe the form of the disease which is contracted via inhalation of F. tularensis and results in septicemia. Typhoidal tularemia carries a 30-60% mortality rate.
Very little is known about F. tularensis pathogenesis. During infection of mammalian hosts F. tularensis is believed to grow intracellularly in macrophages. F. tularensis entry into macrophages occurs without triggering a respiratory burst. Inhibition of the respiratory burst, which is not required for intracellular growth, is mediated by a bacterial acid phosphatase (AcpA). 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.
- Postdoc with John Mekalanos, Harvard Medical School, 1999-2004
- Ph.D. with R.E.W Hancock, University of British Columbia, Department of Microbiology, 1994-1998
- M.Sc. with Louis Sequeira & Caitilyn Allen, University of Wisconsin, Department of Bacteriology, 1992-1994
- B.Sc., University of Wisconsin, Department of Bacteriology, 1992