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Salmonella enterica serovar Typhi (S. Typhi) differs from most other salmonellae in that it causes a life-threatening systemic infection known as typhoid fever (1). The molecular bases for its unique clinical presentation are unknown (2). Here we find that the systemic administration of typhoid toxin, a unique virulence factor of S. Typhi, reproduces many of the acute symptoms of typhoid fever in an animal model. We identify specific carbohydrate moieties on specific surface glycoproteins that serve as receptors for typhoid toxin, which explains its broad cell target specificity. We present the atomic structure of typhoid toxin, which shows an unprecedented [A.sub.2][B.sub.5] organization with two covalently linked A subunits non-covalently associated to a pentameric B subunit. The structure provides insight into the toxin's receptor-binding specificity and delivery mechanisms and reveals how the activities of two powerful toxins have been co-opted into a single, unique toxin that can induce many of the symptoms characteristic of typhoid fever. These findings may lead to the development of potentially lifesaving therapeutics against typhoid fever., Salmonella enterica serovar Typhi (S. Typhi), the cause of typhoid fever, results in more than 200,000 annual deaths (1,3,4). Unlike other Salmonella serovars, which typically cause self-limiting gastroenteritis, S. Typhi [...]

The intracellular pathogen Legionella pneumophila modulates the activity of host GTPases to direct the transport and assembly of the membrane-bound compartment in which it resides (1-6). In vitro studies have indicated that the Legionella protein DrrA post-translationally modifies the GTPase Rab1 by a process called AMPylation (7). Here we used mass spectrometry to investigate post-translational modifications to Rab1 that occur during infection of host cells by Legionella. Consistent with in vitro studies, DrrA-mediated AMPylation of a conserved tyrosine residue in the switch II region of Rab1 was detected during infection. In addition, a modification to an adjacent serine residue in Rab1 was discovered, which was independent of DrrA. The Legionella effector protein AnkX was required for this modification. Biochemical studies determined that AnkX directly mediates the covalent attachment of a phosphocholine moiety to Rab1. This phosphocholine transferase activity used CDP-choline as a substrate and required a conserved histidine residue located in the FIC domain of the AnkX protein. During infection, AnkX modified both Rab1 and Rab35, which explains how this protein modulates membrane transport through both the endocytic and exocytic pathways of the host cell. Thus, phosphocholination of Rab GTPases represents a mechanism by which bacterial FIC-domain-containing proteins can alter host-cell functions., Legionella pneumophila is an intracellular pathogen that translocates proteins called effectors into the host-cell cytosol using a type IV secretion system called Dot/Icm (8). The Legionella protein DrrA (also known [...]

To link to full-text access for this article, visit this link: http://dx.doi.org/10.1016/j.cell.2009.01.056 Byline: Jayesh C. Patel (1), Karsten Hueffer (1), Tukiet T. Lam (2), Jorge E. Galan (1) Keywords: CELLBIO; HUMDISEASE; MICROBIO Abstract: Many bacterial pathogens and symbionts utilize type III secretion systems to deliver bacterial effector proteins into host cells. These effector proteins have the capacity to modulate a large variety of cellular functions in a highly regulated manner. Here, we report that the phosphoinositide phosphatase SopB, a Salmonella Typhimurium type III secreted effector protein, diversifies its function by localizing to different cellular compartments in a ubiquitin-dependent manner. We show that SopB utilizes the same enzymatic activity to modulate actin-mediated bacterial internalization and Akt activation at the plasma membrane and vesicular trafficking and intracellular bacterial replication at the phagosome. Thus, by exploiting the host cellular machinery, Salmonella Typhimurium has evolved the capacity to broaden the functional repertoire of a virulence factor to maximize its ability to modulate cellular functions. Author Affiliation: (1) Section of Microbial Pathogenesis, Yale University School of Medicine, 295 Congress Avenue, New Haven, CT 06536, USA (2) W.M. Keck Foundation Biotechnology Resource Laboratory, Yale University School of Medicine, 300 George Street, New Haven, CT 06511, USA Article History: Received 25 August 2008; Revised 1 December 2008; Accepted 29 January 2009 Article Note: (miscellaneous) Published: April 16, 2009

Author(s): Jorge E. Galán (corresponding author) [1]; Hans Wolf-Watz [2] Bacteria that have sustained long-standing close associations with eukaryotic hosts have evolved specific adaptations to survive and replicate in this [...]

Salmonella enterica, the cause of food poisoning and typhoid fever, has evolved sophisticated mechanisms to modulate Rho family guanosine triphosphatases (GTPases) to mediate specific cellular responses such as actin remodeling, macropinocytosis, and nuclear responses. These responses are largely the result of the activity of a set of bacterial proteins (SopE, SopE2, and SopB) that, upon delivery into host cells via a type III secretion system, activate specific Rho family GTPases either directly (SopE and SopE2) or indirectly (SopB) through the stimulation of an endogenous exchange factor. We show that different Rho family GTPases play a distinct role in Salmonella-induced cellular responses. In addition, we report that SopB stimulates cellular responses by activating SH3-containing guanine nucleotide exchange factor (SGEF), an exchange factor for RhoG, which we found plays a central role in the actin cytoskeleton remodeling stimulated by Salmonella. These results reveal a remarkable level of complexity in the manipulation of Rho family GTPases by a bacterial pathogen.

Bacterial vectors may offer many advantages over other antigen delivery systems for cancer vaccines. We engineered a Salmonella typhimurium vaccine strain to deliver the NY-ESO-1 tumor antigen (S. typhimurium-NY-ESO-1) through [...]

Salmonella is a facultative intracellular pathogen that causes diseases ranging from self-limiting enteritis to typhoid fever. This bacterium uses two type III secretion systems to deliver effector proteins directly into the host cell to promote infection and disease. Recent characterization of these virulence proteins and their host-cell targets is uncovering the molecular mechanisms of Salmonella pathogenesis and is revealing a picture of the atomic interface between this pathogen and its host. This level of analysis provides the possibility of designing novel therapeutics to disrupt infection and disease processes at the molecular level.