Dr. Pukatzki earned his Ph.D. from Columbia University in New York City where he studied with Richard Kessin to determine how cells differentiate to take on new tasks. Using the social amoeba Dictyostelium discoideum as a model - this organism consists only of two basic cell types - he identified a protein degradation pathway as a crucial contributor of cellular differentiation. Class work with Howard Shuman and Aaron Mitchell inspired him to focus on bacterial pathogenesis and to help develop the Dictyostelium host model system. Since then he has used this model to study the pathogenesis of the bacterial pathogens Pseudomonas aeruginosa (pneumonia), Vibrio cholerae (diarrheal disease cholera), and Acinteobacter baumannii (hospital-acquired infections). While a research fellow in the laboratory of John Mekalanos at Harvard Medical School, he discovered that the type VI secretion pathway of Vibrio cholerae acts as a virulence trait for this enteric pathogen.
Dr. Pukatzki joined the faculty of the Department of Immunology and Microbiology at the University of Colorado School of Medicine in 2016 where he is expanding on his discovery by working on the molecular mechanisms that drive microbial pathogenesis.
Research Focus: Alarming numbers of drug-resistant variants of disease-causing bacteria are emerging in an ongoing challenge to human health, because the current arsenal of antibiotics are designed to kill – thereby applying selection pressure that leads to antibiotics resistance. To develop novel therapies with reduced selection pressure and resistance emergence by disarming pathogens instead of killing them, our research focuses on understanding how pathogenic bacteria interact with their human host.
Research Impact: The CDC estimates that every year >two million people experience antibiotic-resistant infections in the U.S. alone, and an increasing number of patients (currently 23,000 annually) die of previously treatable infections. These alarming statistics indicate that we are returning to the pre-antibiotic era. To discover much-needed, novel targets for antimicrobials, we pioneered use of the genetically tractable amoeba Dictyostelium discoideum that identified the type VI secretion system (T6SS) as a virulence trait in the cholera bacterium Vibrio cholerae. It turns out that the T6SS is operative in almost all major Gram-negative pathogens.
The T6SS assembles as a molecular syringe in the bacterial envelope, allowing the bacterium to inject toxins (so-called T6SS effectors) into target cells upon contact. T6SS effectors degrade the bacterial envelope of prey bacteria, unless the prey produces immunity proteins that bind and deactivate the incoming effectors. We recently discovered that V. cholerae strains utilize distinct effectors. Strains with different effector/immunity sets compete with each other, while strains with the same effector/immunity set are compatible and co-exist when making contact. As the T6SS restricts contact between bacterial cells, we are investigating whether compatible bacteria exchange genetic (virulence) information on contact to evolve through kin selection during infection.
We are also interested in how the T6SS contributes to pathogenicity, persistence, and transmission. We recently found that pandemic V. cholerae responds to host factors (mucin and bile salts) by activating the T6SS and killing strains of the same species as well as members of the human gut microbiota. This is an exciting finding, because it may explain how this pathogen establishes infections in the human small intestine. As immunity genes are not essential for growth until bacteria come in close contact with each other, we are exploiting the T6SS as a drug target to inhibit virulence without generating resistance.
Expertise: Our laboratory has an expertise in bacterial genetics, biochemistry, cell biology, and genomics to decipher the host-pathogen interface.
Vision for our research program: We aim to obtain a molecular understanding of the competitive fitness of pathogenic bacteria and its impact on virulence evolution during disease. This knowledge can be used to devise treatment strategies in which virulence is discouraged and resistant pathogens do not emerge. We view this as a chief endeavor in light of the growing multidrug resistance threat.
AHFMR Scholar (Alberta Heritage Foundation for Medical Research salary award) (2009–2016)
Postdoctoral Fellowship Award from the Cystic Fibrosis Foundation (2001–2003)
PhD Scholarship Award from the Federal Department of Research and Technology (1992–1994)
Fellowship Award from the German Academic Exchange Service (DAAD) (1989–1990)
Unterweger, D., Kostiuk, B., Pukatzki, S.: Adaptor proteins of type VI secretion system effectors. Trends in Microbiology 2016 Nov 14. pii: S0966-842X(16)30163-9. doi: 10.1016/j.tim.2016.10.003. [Epub ahead of print].
Bachmann, V., Kostiuk, B., Unterweger, D., Diaz-Satizabal, Ogg, S., Pukatzki, S.: Bile salts modulate the mucin-activated type VI secretion system of pandemic Vibrio cholerae. PLoS Neglected Tropical Diseases 9 (8): e0004031. doi:10.1371/journal.pntd.0004031. 2015.
Unterweger, D., Kostiuk, B., Oetjengerdes, R., Wilton, A., Diaz, L., and Pukatzki, S.: Chimeric adaptor proteins translocate diverse type VI secretion system effectors in Vibrio cholerae. EMBO Journal: 34(16): 2198-2210. 2015.
Unterweger, D., Miyata, S.T., Bachmann, V., Brooks, T., Provenzano, D., Pukatzki, S.: The Vibrio cholerae type VI secretion system employs diverse effector modules for intraspecific competition. Nature Communications, 5, Article number: 3549, doi:10.1038/ncomms4549. 2014.
Pukatzki, S. & Provenzano, D.: Vibrio cholerae as a predator: lessons from evolutionary principles. Frontiers in Microbiology. doi: 10.3389/fmicb.2013.00384. 2013.
Brooks, T., Kostiuk, B., Bachmann, V., Unterweger, D., Pukatzki, S.: Lytic activity of the Vibrio cholerae type VI secretion toxin VgrG-3 is inhibited by the antitoxin TsaB. Journal of Biological Chemistry 288: 7618-7625. 2013.
MacIntyre, D., Miyata, S. T., Kitaoka, M., Pukatzki, S.: The Vibrio cholerae type VI secretion system displays antimicrobial activity. Proceedings of the National Academy of Sciences 107: 19520-19524. 2010.
Pukatzki, S., Ma, A.T., Sturtevant, D., Krastins, B., Sarracino, D., Nelson, W.C., Heidelberg J.F., Mekalanos, J.J.: Identification of a conserved protein secretion system in Vibrio cholerae using the Dictyostelium host model system. Proceedings of the National Academy of Sciences 103: 1528-1533. 2006.
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