Microbial infectious disease has been the cause of the most wide spread and deadly epidemics in human civilization. The success of these organisms is attributed, in part, to the evolution of virulence factors that usurp host cellular communication networks and signal transduction systems. Because microbial pathogens have performed life and death ?experiments? on their hosts with great success, our study of infectious disease mechanisms has revealed remarkable new insights into eukaryotic cellular biology.
We are focusing on an exciting field of microbial pathogenesis that has recently emerged from the discovery of bacterial Type III/IV Secretion Systems. These molecular machines coordinate the translocation of 10-20 ?effector? proteins from the bacterium directly into human cells. Each effector protein is uniquely designed to hijack the host immune system and allow bacterial pathogens to establish a replication niche within a hostile cellular environment. We estimate that over 150 uncharacterized effector genes contribute to the virulence traits of pathogens including Shigella, Salmonella, Yersinia, E. coli, Legionella, and Bartonella species. By combining classic biochemistry techniques with high throughput genetics, structural biology, and live-cell imaging we hope to achieve the following goals: 1) define the biochemical mechanisms of novel toxins and effectors proteins, 2) determine the physiological role of these virulent molecules to facilitate bacterial dissemination, innate immune evasion, and human disease progression, and 3) use this information to design therapeutic strategies aimed at effectively combating human infectious disease.
There are several ongoing projects in the lab. We are particularly interested in the ability of toxins and effector proteins to chemically modify human small G-proteins or directly mimic the activities of key regulatory molecules. Recently, we discovered a novel family of bacterial effector proteins that mimic the activities of the Ras small G-protein superfamily. These findings define an entirely new mechanism of bacterial pathogenesis and further illustrate the remarkable ability of bacterial effector proteins to mimic the atomic structure or enzymatic properties of human signaling proteins. We are now engaged in characterizing the host signaling specificity of these effectors and identifying the role of GTPase mimicry to promote bacterial pathogenesis. In addition, we have discovered several new Type III effector proteins that usurp small G-protein signaling pathways through unknown biochemical means. These new avenues will reveal how pathogenic bacteria integrate spatially and temporally restricted information into a proper host cellular response.
RESEARCH INTERESTS
Microbioal Pathogenesis
Human Signal Transduction
Mechanisms of Toxins and Effectors
Ras Super-family GTPases
RECENT PUBLICATIONS
Hodges K, Alto NM, Ramaswamy K, Dudeja P, Hecht G, "The enteropathogenic E. coli effector protein EspF decreases sodium hydrogen exchanger 3 activity." Cellular Microbiology, EPUB May 2008
Alto NM and Dixon JE, "Analysis of Rho-GTPase Mimicry by a Family of Bacterial Type III Effector Proteins." Methods in Enzymology, 439:131-43, Summer 2008
Alto NM, "Mimicking Small G-proteins: An emerging theme from the bacterial virulence arsenal." Cellular Microbiology, 10 (3):566-75, March 2008
Alto NM et al., "The Type III effector EspF coordinates membrane trafficking by the spatiotemporal activation of two eukaryotic signaling pathways." The Journal of Cell Biology, 24;178(7):1265-78, September 2007
Alto NM, "Shigella puts the brakes on the host cell cycle." Cell Host and Microbe, 2(3):141-2, September 2007
SIGNIFICANT PUBLICATIONS
Alto NM, Shao F, Lazar CS, Brost RL, Chua G, Mattoo S, McMahon SA, Ghosh P, Hughes TR, Boone C, Dixon JE, "Identification of a Bacterial Type III Effector Family with G Protein Mimicry Functions" Cell, 124:1-13, January 2006
Westphal RS, Tavalin SJ, Lin JW, Alto NM, Fraser ID, Langeberg LK, Sheng M, Scott JD, "Regulation of NMDA receptors by an associated phosphatase-kinase signaling complex" Science, 285(5424):93-6, July 1999
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