Neal M. Alto, Ph.D.
Assistant Professor of Microbiology

Office: 214-633-1373
Fax: 214-648-5905
Email: Neal M. Alto, Ph.D.
Website:Laboratory of Neal M. Alto Ph.D

Our laboratory studies the molecular basis of microbial pathogenesis with a specific emphasis on elucidating the biochemical and cellular function of bacterial toxins and ‘effector’ proteins. Historically, bacteria have been the cause of some of the most deadly diseases and widespread epidemics of human civilization.  These pathogens continue to pose an enormous health risk due to the evolution of antibiotic-resistant strains and their potential to be used as agents of bioterrorism.  We are studying the virulence mechanisms of toxins and effector proteins with the goal of gaining significant molecular insights that will lead to improved vaccine development and new treatments for bacterial infectious disease.

Currently, our lab is focusing on an exciting field of microbial pathogenesis that has recently emerged from the discovery of bacterial Type III Secretion Systems (TTSS).  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 bioinformatics with RNAi based cellular genetics, structural analysis, and live-cell imaging techniques, 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.  Recently, we discovered a novel family of bacterial effector proteins that appear to 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 to studying the molecular aspects of pathogenesis, our lab uses bacterial infection paradigms to understand how eukaryotic signal transduction systems influence the cellular architecture of polarized epithelium.  Under physiological conditions, Enteropathogenic E. coli (EPEC) depolarizes epithelial cells via the delivery of ten to twelve Type III effector proteins.  Thus, EPEC infection serves as an excellent model to define new mechanisms of cellular polarization.  For example, we recently found that the EPEC effector EspF nucleates an actin/membrane remodeling machine by engaging two signaling molecules, Sorting Nexin 9 and N-WASP.  How EspF and other EPEC effectors translate these activities into a depolarization signal is currently being investigated.  Altogether, the studies in our lab have implications for several bacterial infectious diseases and more broadly, the role of signal transduction molecules in human defense systems.

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 2006 Jan 13; (124): 1-13.

Alto NM.  Shigella puts the brakes on the host cell cycle.  Cell Host and Microbe.  2007 (in press)

Alto NM, Weflen AW, Rardin MJ, YararD, Lazar CS, Tonikian R, Koller A, Taylor  SS, Boone C, Sidhu SS, Schmid SL, Hecht G, Dixon JE,  The Type III effector EspF coordinates membrane trafficking by the spatiotemporal activation of two eukaryotic signaling pathways. Journal of Cell Biology, Sept. 24; 2007.

Alto NM and Dixon JE.  Analysis of Rho-GTPase Mimicry by a Family of Bacterial Type III Effector Proteins. Method in Enzymology 2007 (in press).