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The Salmonella Protein SpvB and Actin

Salmonella spp. cause billions of human and agricultural infections each year, leading to over three million human deaths due to typhoid fever alone. The spread of multidrug resistant strains of Salmonella and biosecurity concerns have recently focused more attention on this widespread pathogen. Salmonella species utilize two virulence associated type III protein secretions systems (contained in the pathogenicity islands SPI-1 and SPI-2) to inject virulence factors into host cells. SPI-1 functions in the early stages of infection, inducing bacterial uptake into non-phagocytic cells of the intestine. SPI-2 is involved subsequently in systemic infection, allowing the bacteria to form a replicative niche (the Salmonella containing vacuole, or SCV) inside host cells and to colonize tissues beyond the intestine.

Intracellular replication of several strains of Salmonella in human and animal cell lines, as well as systemic infection in animal models, requires the spv virulence locus (plasmid or chromosomally located), and, in particular, the SpvB gene. Although controversy exists regarding whether SpvB is delivered via a SPI-2 dependent translocation process, this virulence factor exerts its function subsequent to the actin reorganizing effects of both SPI-1 invasion associated effectors and as well as those of the SPI-2 SCV-related effectors. Expressed alone in mammalian cells or delivered by pathogenic bacteria, SpvB disrupts the host cell cytoskeleton culminating in a cell death with many features of apoptosis. It has been hypothesized that this apoptotic death may facilitate pathogen spread to fresh cells through autophagy. Its important role in virulence makes SpvB an attractive target for antibacterial development.

We have determined the crystal structure of the catalytic domain of SpvB, and have shown by mass spectrometric analysis that SpvB modifies actin at Arg 177, inhibiting its ATPase activity. We have also described two crystal structures of SpvB-modified, polymerization-deficient actin. These structures reveal that ADP-ribosylation does not lead to dramatic conformational changes in actin, suggesting a model in which this large family of toxins inhibits actin polymerization primarily through steric disruption of intra-filament contacts.


S. Mariana Margarit, Walter Davidson, Lee Frego, and C.E Stebbins (2006). "A Steric Antagonism of Actin Polymerization by a Salmonella Virulence Protein." Structure, Aug;14(8):1219-29.
[Abstract]  [pdf] [pdb SpvB] [pdb SpvB NADH] [pdb Actin Orthorhombic] [pdb Actin Hexagonal]


Dr. Mariana Margarit was the lead scientist on the SpvB project.