Bacteriology; Genetics, Microbial; Microbiology
Our laboratory studies the pathogenesis of two intestinal pathogens, Salmonella enterica and Campylobacter jejuni. Combined, these two pathogens account for the majority of cases of infectious diarrhea world-wide leading to an estimated 2,000,000 deaths. We take a multidisciplinary approach in our studies involving bacterial genetics, biochemistry, cell biology, immunology as well as structural biology. As a result, we are beginning to define not only the molecular details of the host pathogen interactions but also the atomic interphase between these pathogens and the host.
Extensive Research Description
Microbial pathogens have evolved
unique ways to interact with their hosts. In many instances the terms of this interaction reflect the
co-evolutionary balance that the host and pathogen must reach in order to secure
their survival. It is therefore
not surprising that bacterial pathogens have evolved a large array of virulence
factors well suited to interfere with or stimulate a variety of host-cell
responses in order to invade, survive and replicate within their hosts. The identification and characterization
of these virulence factors is proving to be a fruitful area of research in more
ways than expected.
The understanding of how pathogens interact with their hosts is not only providing the basis for the development of novel therapeutic approaches but also a number of very sophisticated tools for probing basic aspects of cellular physiology and immunology. Our laboratory studies the pathogenesis of two intestinal pathogens, Salmonella enterica and Campylobacter jejuni. Combined, these two pathogens account for the vast majority of cases of infectious diarrhea world-wide leading to an estimated 2,000,000 deads. We are interested in characterizing the bacterial determinants involved in these interactions as well as the cell biology and immunobiology of this process.
We take a multidisciplinary approach in our studies involving bacterial genetics, biochemistry, cell biology, immunology as well as structural biology. As a result, we are beginning to define not only the molecular details of the host pathogen interactions but also the atomic interphase between these pathogens and the host. Our laboratory has also an interest in vaccine development that stems from our discovery of a specialized organelle in Salmonella enterica (the “type III secretion system”) that mediates the transfer of bacterial proteins into host cells. We have harnessed this system for the delivery of heterologous proteins as a means to delivery antigens to the Class I and Class II antigen presenting pathways by avirulent strains of Salmonella.
Specific areas of interest include:
- The study of type III secretion, a specialized bacterial organelle whose function is to delivery bacterial proteins into eukaryotic host cells. We are interested in understanding the mechanism of action of this multi-protein machine, as well as to understand the activities of the proteins delivered by this machine. We carried out these studies in Salmonella enterica but it is expected that knowledge gained from these studies may help understand the pathogenesis of many other bacteria since this system is conserved and widespread among several important pathogens.
- The harnessing of the protein-delivery capability of the type III secretion machine for the development of therapeutic approaches, including vaccines.
- The development of strategies that target the activities of type III secretion systems with the ultimate goal of developing new therapeutics to combat diseases caused by pathogens that encode these protein-delivery machines.
- The study the mechanism of pathogenesis of Salmonella typhi, which can only infect humans causing typhoid fever, a life-threatening disease that causes more than 500,000 deaths world-wide. We focus our efforts on the study of "typhoid toxin", a toxin exclusively produced by Salmonella typhi that we recently identified.
- The study of the mechanisms by which Campylobacter jejuni enters and survives within host cells. In particular, we are interested in understanding how this bacterium harnesses host-cell machinery to gain access to the cell, deviating from standard endocytic pathways and thus avoiding delivery to lysosomes.
- The investigation of the in vivo metabolism of C. jejuni. We are specifically interested in identifying its carbon sources and respiration substrates during infection.
- Akeda Y, Galan JE. (2005). Chaperone release and unfolding of substrates in type III secretion. Nature 437: 911-915.
- Marlovitz, T.C., Kubori, T., Lara-Tejero, M., Thomas, D.R., Unger, V.M., and Galán, J.E. (2006). Assembly of the inner rod determines needle length in the type III secretion injectisome. Nature 441(7093):637-40.
- Hofreuter, D., Novik, V., and J. E. Galán. 2008. Metabolic diversity in Campylobacter jejuni enhances specific tissue colonization. Cell Host & Microbe 4(5):425-33
- Patel, J. C., Hueffer, K., Lam, T. T. , J. E. Galán. 2009. Diversification of a Salmonella virulence effector protein function by ubiquitin-dependent differential localization. Cell 137(2):283-94.
- Lara-Tejero, M., J. Kato, S. Wagner, X. Liu, and J. E. Galán. 2011. A Sorting Platform Determines the Order of Protein Secretion in Bacterial Type III Systems. Science 331: 1188-1191.
- Spano, S. and J. E. Galán. 2012. A Rab32-depdent pathway controls Salmonella Typhi host restriction. Science 338:960-963.
- Song, J., X. Gao, and J. E. Galán. 2013. Conferring virulence: structure and function of the chimeric A2B5 typhoid toxin. Nature 499, 350–354.