Salmonella Pathogenesis and Processing of Secreted Effectors by Caspase-3

Department of Pediatric Gastroenterology and Nutrition, Harvard Medical School and Massachusetts General Hospital, Boston, MA 02129, USA.
Science (Impact Factor: 33.61). 10/2010; 330(6002):390-3. DOI: 10.1126/science.1194598
Source: PubMed


The enteric pathogen Salmonella enterica serovar Typhimurium causes food poisoning resulting in gastroenteritis. The S. Typhimurium effector Salmonella invasion protein A (SipA) promotes gastroenteritis by functional motifs that trigger either mechanisms of inflammation or bacterial entry. During infection of intestinal epithelial cells, SipA was found to be responsible for the early activation of caspase-3, an enzyme that is required for SipA cleavage at a specific recognition motif that divided the protein into its two functional domains and activated SipA in a manner necessary for pathogenicity. Other caspase-3 cleavage sites identified in S. Typhimurium appeared to be restricted to secreted effector proteins, which indicates that this may be a general strategy used by this pathogen for processing of its secreted effectors.

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    • "This mechanism of proteasomal recycling is employed by host cells to maintain caspase-3 at basal non-apoptotic levels at times when no danger is perceived (Tan et al., 2006). The presence of large numbers of ubiquitin ligase mimics in the bacterial effector repertoire means ubiqutination may be a means for bacterial pathogens to secure their intracellular niche for prolonged periods, and also could explain the mobilization of caspase-3 to the extremities of the cell seen during infection with S. Typhimurium and E. coli (Flynn and Buret, 2008; Srikanth et al., 2010). An alternative means of caspase-3 inhibition recently identified in long-term E. coli infection of immune cells, although not yet attributed to a specific effector or pathway, was S-nitrosylation (Dunne et al., 2013). "
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    ABSTRACT: Apoptosis is a critical process that intrinsically links organism survival to its ability to induce controlled death. Thus, functional apoptosis allows organisms to remove perceived threats to their survival by targeting those cells that it determines pose a direct risk. Central to this process are apoptotic caspases, enzymes that form a signaling cascade, converting danger signals via initiator caspases into activation of the executioner caspase, caspase-3. This enzyme begins disassembly of the cell by activating DNA degrading enzymes and degrading the cellular architecture. Interaction of pathogenic bacteria with caspases, and in particular caspase-3, can therefore impact both host cell and bacterial survival. With roles outside cell death such as cell differentiation, control of signaling pathways and immunomodulation also being described for caspase-3, bacterial interactions with caspase-3 may be of far more significance in infection than previously recognized. In this review, we highlight the ways in which bacterial pathogens have evolved to subvert caspase-3 both through effector proteins that directly interact with the enzyme or by modulating pathways that influence its activation and activity.
    Cellular Microbiology 09/2014; 16(12). DOI:10.1111/cmi.12368 · 4.92 Impact Factor
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    • "Activation of the effector protein SipA has been shown to be necessary for induction of HXA3 synthesis and the resulting PMN migration (Figure 2) (72). Remarkably, the mechanism for activating SipA was recently shown to require processing by the host enzyme caspase-3 at a particular cleavage site, resulting in two distinct effector domains (73). Furthermore, the two domains were shown to be functionally different. "
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    ABSTRACT: The human intestinal epithelium consists of a single layer of epithelial cells that forms a barrier against food antigens and the resident microbiota within the lumen. This delicately balanced organ functions in a highly sophisticated manner to uphold the fidelity of the intestinal epithelium and to eliminate pathogenic microorganisms. On the luminal side, this barrier is fortified by a thick mucus layer, and on the serosal side exists the lamina propria containing a resident population of immune cells. Pathogens that are able to breach this barrier disrupt the healthy epithelial lining by interfering with the regulatory mechanisms that govern the normal balance of intestinal architecture and function. This disruption results in a coordinated innate immune response deployed to eliminate the intruder that includes the release of antimicrobial peptides, activation of pattern-recognition receptors, and recruitment of a variety of immune cells. In the case of Salmonella enterica serovar typhimurium (S. typhimurium) infection, induction of an inflammatory response has been linked to its virulence mechanism, the type III secretion system (T3SS). The T3SS secretes protein effectors that exploit the host's cell biology to facilitate bacterial entry and intracellular survival, and to modulate the host immune response. As the role of the intestinal epithelium in initiating an immune response has been increasingly realized, this review will highlight recent research that details progress made in understanding mechanisms underlying the mucosal inflammatory response to Salmonella infection, and how such inflammatory responses impact pathogenic fitness of this organism.
    Frontiers in Immunology 07/2014; 5:311. DOI:10.3389/fimmu.2014.00311
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    • "The hypothesis that the S. Cerro population studied here shows unique host and/or tissue tropism characteristics is also supported by the finding that all 27 S. Cerro ST367 isolates sequenced here were found to carry a premature stop codon in sopA, causing a truncation of the gene from 782 aa (in S. Typhimurium LT2) to 433 aa. Previous studies have shown that SopA is involved in virulence during bovine gastrointestinal infections by S. Typhimurium and S. Dublin [34, 35], and that sopA mutations are implicated in reduced polymorphonuclear (PMN) cell migration [34, 36], and fluid secretion in ileal loops in calves [34]. Premature stop codons in sopA have been found in S. Typhi, S. Paratyphi A, and S. Gallinarum and it has been suggested that loss of a functional SopA has been an important factor in the virulence and adaptation of these serovars to a systemic niche in certain hosts [37, 38]. "
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    ABSTRACT: Background: Within the last decade, Salmonella enterica subsp. enterica serovar Cerro (S. Cerro) has become one of the most common serovars isolated from cattle and dairy farm environments in the northeastern US. The fact that this serovar is commonly isolated from subclinically infected cattle and is rarely associated with human disease, despite its frequent isolation from cattle, has led to the hypothesis that this emerging serovar may be characterized by reduced virulence. We applied comparative and population genomic approaches to (i) characterize the evolution of this recently emerged serovar and to (ii) gain a better understanding of genomic features that could explain some of the unique epidemiological features associated with this serovar. Results: In addition to generating a de novo draft genome for one Salmonella Cerro strain, we also generated whole genome sequence data for 26 additional S. Cerro isolates, including 16 from cattle operations in New York (NY) state, 2 from human clinical cases from NY in 2008, and 8 from diverse animal sources (7 from Washington state and 1 from Florida). All isolates sequenced in this study represent sequence type ST367. Population genomic analysis showed that isolates from the NY cattle operations form a well-supported clade within S. Cerro ST367 (designated here "NY bovine clade"), distinct from isolates from Washington state, Florida and the human clinical cases. A molecular clock analysis indicates that the most recent common ancestor of the NY bovine clade dates back to 1998, supporting the recent emergence of this clone.Comparative genomic analyses revealed several relevant genomic features of S. Cerro ST367, that may be responsible for reduced virulence of S. Cerro, including an insertion creating a premature stop codon in sopA. In addition, patterns of gene deletion in S. Cerro ST367 further support adaptation of this clone to a unique ecological or host related niche. Conclusions: Our results indicate that the increase in prevalence of S. Cerro ST367 is caused by a highly clonal subpopulation and that S. Cerro ST367 is characterized by unique genomic deletions that may indicate adaptation to specific ecological niches and possibly reduced virulence in some hosts.
    BMC Genomics 06/2014; 15(1):427. DOI:10.1186/1471-2164-15-427 · 3.99 Impact Factor
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