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The extraordinary bacterial Type VI secretion machine

Wednesday, December 10, 2014


John Mekalanos, Ph.D.
Chair, Department of Microbiology and Immunobiology
Harvard Medical School

Dr. Mekalanos’s research interests include the genetic basis for microbial pathogenesis, virulence regulation, functional genomics, and vaccine development. Although he has worked on half a dozen different bacterial species, Vibrio cholerae has remained his passion and pleasure. This organism has served up an unexpected number of major discoveries in the field that include the coordinate control of virulence factors, the role of phages, chromosomal islands, and virulence regulation in the emergence of human pathogens, and several novel cell biological phenomenon that have broad importance. Over the last three decades, Mekalanos’s laboratory has contributed numerous tools for discovery and has directly or indirectly contributed to vaccine development efforts for cholera, typhoid, pertussis, toxigenic strains of E. coli, and anthrax. Several of his genetically engineered live attenuated vaccine candidates have reached clinical phase I and II trials in human subjects.


Bacterial pathogenesis typically involves multiple factors that influence the infection process. Type VI Secretion Systems (T6SS) are nanomachines that deliver proteins called effectors into target cells. The machines are evolutionarily related to the contractile tails of bacteriophages but are located within the cell cytosol. Through dynamic conformational changes in the tail sheath-like structure, these machines deliver payloads of toxic effector proteins into target cells in less than five milliseconds. By defining biochemical activity of effectors, one can reveal how many of these proteins might kill other bacterial cells as well as mammalian host cells during pathogenesis. Furthermore, emerging evidence suggests that T6SS effectors are antibacterial both in vitro and in vivo (during infection) suggesting that these may influence in-host colonization processes by eliminating competing members of the commensal microbiota. The Mekalanos lab has also investigated the transcriptional changes that occur in prey cells that are undergoing attack by the T6SS and its effectors. Remarkably, lethal attacks from competing T6SS+ bacterial species results in the production of reactive oxygen species (ROS) in prey cells when measured using several different types of reporters. ROS was induced in E. coli when exposed to not only T6SS effectors, but also P1 phage and the antibiotic polymyxin B. His lab concludes that the generation of ROS is a general outcome of contact-dependent interactions of aggressive competing bacterial species and may contribute to the lethality of such attacks.

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