The functional interface between Salmonella and its host cell: opportunities for therapeutic intervention.

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.

[1]  A. Hall,et al.  Rho GTPases in cell biology , 2002, Nature.

[2]  C. E. Stebbins,et al.  Re-structuring the host cell: up close with Salmonella's molecular machinery. , 2004, Microbes and infection.

[3]  D. Holden,et al.  Functions and effectors of the Salmonella pathogenicity island 2 type III secretion system , 2003, Cellular microbiology.

[4]  I. Vetter,et al.  The Guanine Nucleotide-Binding Switch in Three Dimensions , 2001, Science.

[5]  V. Gattone Emerging therapies for polycystic kidney disease. , 2005, Current opinion in pharmacology.

[6]  S. Grinstein,et al.  Elimination of host cell PtdIns(4,5)P2 by bacterial SigD promotes membrane fission during invasion by Salmonella , 2002, Nature Cell Biology.

[7]  S. Emr,et al.  Vacuole size control: regulation of PtdIns(3,5)P2 levels by the vacuole-associated Vac14-Fig4 complex, a PtdIns(3,5)P2-specific phosphatase. , 2003, Molecular biology of the cell.

[8]  J. Bamburg,et al.  Efficient Salmonella entry requires activity cycles of host ADF and cofilin , 2004, Cellular microbiology.

[9]  J. Galán,et al.  Temporal Regulation of Salmonella Virulence Effector Function by Proteasome-Dependent Protein Degradation , 2003, Cell.

[10]  B. Finlay,et al.  A synaptojanin‐homologous region of Salmonella typhimurium SigD is essential for inositol phosphatase activity and Akt activation , 2001, FEBS letters.

[11]  J. Galán,et al.  Role of tyrosine kinases and the tyrosine phosphatase SptP in the interaction of Salmonella with host cells , 2001, Cellular microbiology.

[12]  E. Egelman,et al.  Salmonella SipA Polymerizes Actin by Stapling Filaments with Nonglobular Protein Arms , 2003, Science.

[13]  E. McGhie,et al.  Collective efforts to modulate the host actin cytoskeleton by Salmonella type III-secreted effector proteins , 2001 .

[14]  L. Knodler,et al.  Modulation and Utilization of Host Cell Phosphoinositides by Salmonella spp , 2004, Infection and Immunity.

[15]  J. Galán,et al.  Manipulation of the host actin cytoskeleton by Salmonella--all in the name of entry. , 2005, Current opinion in microbiology.

[16]  M. Hensel,et al.  Salmonella pathogenicity islands encoding type III secretion systems. , 2001, Microbes and infection.

[17]  Jorge E. Galán,et al.  Structural mimicry in bacterial virulence , 2001, Nature.

[18]  J. Galán,et al.  Salmonella interactions with host cells: type III secretion at work. , 2001, Annual review of cell and developmental biology.

[19]  M. Hensel,et al.  SseF and SseG are translocated effectors of the type III secretion system of Salmonella pathogenicity island 2 that modulate aggregation of endosomal compartments , 2002, Cellular microbiology.

[20]  M. McNiven,et al.  Analysis of the mechanisms of Salmonella‐induced actin assembly during invasion of host cells and intracellular replication , 2004, Cellular microbiology.

[21]  A. Wittinghofer,et al.  Amino Acids of the Bacterial Toxin SopE Involved in G Nucleotide Exchange on Cdc42* , 2003, Journal of Biological Chemistry.

[22]  P. Majerus,et al.  SopB, a protein required for virulence of Salmonella dublin, is an inositol phosphate phosphatase. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[23]  L. Knodler,et al.  SopD2 is a Novel Type III Secreted Effector of Salmonella typhimurium That Targets Late Endocytic Compartments Upon Delivery Into Host Cells , 2003, Traffic.

[24]  K. Schuebel,et al.  S. typhimurium Encodes an Activator of Rho GTPases that Induces Membrane Ruffling and Nuclear Responses in Host Cells , 1998, Cell.

[25]  J. Galán,et al.  Role of the S. typhimurium actin-binding protein SipA in bacterial internalization. , 1999, Science.

[26]  M. Wenk,et al.  Salmonella Modulates Vesicular Traffic by Altering Phosphoinositide Metabolism , 2004, Science.

[27]  A. Alonso,et al.  Inhibition of Yersinia Tyrosine Phosphatase by Furanyl Salicylate Compounds* , 2005, Journal of Biological Chemistry.

[28]  R. Hayward,et al.  Control of actin turnover by a salmonella invasion protein. , 2004, Molecular cell.

[29]  B. Finlay,et al.  Salmonella type III effectors PipB and PipB2 are targeted to detergent‐resistant microdomains on internal host cell membranes , 2003, Molecular microbiology.

[30]  J. Galán,et al.  A Salmonella protein antagonizes Rac-1 and Cdc42 to mediate host-cell recovery after bacterial invasion , 1999, Nature.

[31]  A. Wittinghofer,et al.  Structural basis for the reversible activation of a Rho protein by the bacterial toxin SopE , 2002, The EMBO journal.

[32]  K. Aktories Bacterial toxins that target Rho proteins. , 1997, The Journal of clinical investigation.

[33]  Samuel I. Miller,et al.  Salmonella effectors translocated across the vacuolar membrane interact with the actin cytoskeleton , 2003, Molecular microbiology.

[34]  Xuejun C. Zhang,et al.  GTP hydrolysis mechanism of Ras-like GTPases. , 2004, Journal of molecular biology.

[35]  A. Alonso,et al.  Aurintricarboxylic Acid Blocks in Vitro and in Vivo Activity of YopH, an Essential Virulent Factor of Yersinia pestis, the Agent of Plague* , 2003, Journal of Biological Chemistry.

[36]  Crystal structure of the hexameric traffic ATPase of the Helicobacter pylori type IV secretion system. , 2000 .

[37]  M. Martínez-Lorenzo,et al.  Remodelling of the actin cytoskeleton is essential for replication of intravacuolar Salmonella , 2001, Cellular microbiology.

[38]  L. Hernandez,et al.  A Salmonella inositol polyphosphatase acts in conjunction with other bacterial effectors to promote host cell actin cytoskeleton rearrangements and bacterial internalization , 2001, Molecular microbiology.

[39]  C. Rosenberger,et al.  SifA permits survival and replication of Salmonella typhimurium in murine macrophages , 2001, Cellular microbiology.

[40]  R. Hayward,et al.  Direct nucleation and bundling of actin by the SipC protein of invasive Salmonella , 1999, The EMBO journal.

[41]  D. Holden,et al.  SseG, a virulence protein that targets Salmonella to the Golgi network , 2003, The EMBO journal.

[42]  V. Koronakis,et al.  Direct modulation of the host cell cytoskeleton by Salmonella actin-binding proteins. , 2002, Trends in cell biology.

[43]  Gabriel Waksman,et al.  Structures of two core subunits of the bacterial type IV secretion system, VirB8 from Brucella suis and ComB10 from Helicobacter pylori. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[44]  T. Marlovits,et al.  Structural Insights into the Assembly of the Type III Secretion Needle Complex , 2004, Science.

[45]  L. Knodler,et al.  Taking Possession: Biogenesis of the Salmonella‐Containing Vacuole , 2003, Traffic.

[46]  S. Miller,et al.  Salmonella: a model for bacterial pathogenesis. , 2001, Annual review of medicine.

[47]  Jue Chen,et al.  Delineation and characterization of the actin nucleation and effector translocation activities of Salmonella SipC , 2004, Molecular microbiology.

[48]  C. E. Stebbins,et al.  Modulation of host signaling by a bacterial mimic: structure of the Salmonella effector SptP bound to Rac1. , 2000, Molecular cell.

[49]  N. Marshall,et al.  Antisense approaches to immune modulation for transplant and autoimmune diseases. , 2005, Current opinion in pharmacology.

[50]  B. Finlay,et al.  Disruption of the Salmonella-Containing Vacuole Leads to Increased Replication of Salmonella enterica Serovar Typhimurium in the Cytosol of Epithelial Cells , 2002, Infection and Immunity.

[51]  Xin Hu,et al.  Computational analysis of tyrosine phosphatase inhibitor selectivity for the virulence factors YopH and SptP. , 2004, Journal of molecular graphics & modelling.

[52]  P. Mullan,et al.  A secreted effector protein of Salmonella dublin is translocated into eukaryotic cells and mediates inflammation and fluid secretion in infected ileal mucosa , 1997, Molecular microbiology.

[53]  B. Finlay,et al.  Characterization of Salmonella‐Induced Filaments (Sifs) Reveals a Delayed Interaction Between Salmonella‐Containing Vacuoles and Late Endocytic Compartments , 2001, Traffic.

[54]  B. Finlay,et al.  Salmonella induces the formation of filamentous structures containing lysosomal membrane glycoproteins in epithelial cells. , 1993, Proceedings of the National Academy of Sciences of the United States of America.

[55]  S. Savvides,et al.  Crystal structure of the hexameric traffic ATPase of the Helicobacter pylori type IV secretion system. , 2000, Molecular cell.

[56]  A. K. Criss,et al.  Coordinate Regulation of Salmonella enterica Serovar Typhimurium Invasion of Epithelial Cells by the Arp2/3 Complex and Rho GTPases , 2003, Infection and Immunity.

[57]  Edward H. Egelman,et al.  The bacterial protein SipA polymerizes G-actin and mimics muscle nebulin , 2002, Nature Structural Biology.

[58]  W. Hardt,et al.  Identification of SopE2 from Salmonella typhimurium, a conserved guanine nucleotide exchange factor for Cdc42 of the host cell , 2000, Molecular microbiology.

[59]  S. Méresse,et al.  Salmonella maintains the integrity of its intracellular vacuole through the action of SifA , 2000, The EMBO journal.

[60]  M. Hensel,et al.  Effector Proteins Encoded by Salmonella Pathogenicity Island 2 Interfere with the Microtubule Cytoskeleton after Translocation into Host Cells , 2004, Traffic.

[61]  Samuel I. Miller,et al.  The Salmonella enterica Serovar Typhimurium Translocated Effectors SseJ and SifB Are Targeted to the Salmonella-Containing Vacuole , 2003, Infection and Immunity.

[62]  Samuel I. Miller,et al.  Structural characterization of the molecular platform for type III secretion system assembly , 2005, Nature.

[63]  J. Borg,et al.  The Intracellular Fate of Salmonella Depends on the Recruitment of Kinesin , 2005, Science.

[64]  S. Emr,et al.  The role of phosphoinositides in membrane transport. , 2001, Current opinion in cell biology.

[65]  B. Finlay,et al.  Biogenesis of Salmonella typhimurium‐containing vacuoles in epithelial cells involves interactions with the early endocytic pathway , 1999, Cellular microbiology.

[66]  Javier Ruiz-Albert,et al.  Complementary activities of SseJ and SifA regulate dynamics of the Salmonella typhimurium vacuolar membrane , 2002, Molecular microbiology.

[67]  B. Finlay,et al.  The related effector proteins SopD and SopD2 from Salmonella enterica serovar Typhimurium contribute to virulence during systemic infection of mice , 2004, Molecular microbiology.

[68]  H. Wolf‐Watz,et al.  Small-Molecule Inhibitors Specifically Targeting Type III Secretion , 2005, Infection and Immunity.

[69]  B. Finlay,et al.  SifA, a Type III Secreted Effector of Salmonella typhimurium, Directs Salmonella‐Induced Filament (Sif) Formation Along Microtubules , 2002, Traffic.