Pathogenic adaptation of intracellular bacteria by rewiring a
            <i>cis</i>
            -regulatory input function

Osborne, Suzanne E.; Walthers, Don; Tomljenovic, Ana M.; Mulder, David T.; Silphaduang, Umaporn; Duong, Nancy; Lowden, Michael J.; Wickham, Mark; Waller, Ross F.; Kenney, Linda J.; Coombes, Brian K.

doi:10.1073/pnas.0811669106

Cited by 58 publications

(76 citation statements)

References 46 publications

(47 reference statements)

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“…Results of the lethality experiments correlate with five-to eightfold less tissue invasion and a comparable decrease in the cell and ECM attachment in vitro by Ty2Δt2544. In addition, the CI of the mutant bacteria was significantly less than that of the WT (P < 0.001) (29,30). Considering the genomic location of t2544, to the best of our knowledge, this is the first report of functional characterization of PAI-VI and experimental evidence in favor of its role in Salmonella pathogenesis.…”

Section: Discussionmentioning

confidence: 74%

An adhesion protein of Salmonella enterica serovar Typhi is required for pathogenesis and potential target for vaccine development

Ghosh

Chakraborty²,

Theeya³

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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More than half of all Salmonella enterica serovar Typhi genes still remain unannotated. Although pathogenesis of S. Typhi is incompletely understood, treatment of typhoid fever is complicated by the emergence of drug resistance. Effectiveness of the currently available vaccines is also limited. In search of novel virulence proteins, we have identified several putative adhesins of S. Typhi through computational approaches. Our experiment shows that a 27-kDa outer membrane protein (T2544) plays a major role in bacterial adhesion to the host through high-affinity binding to laminin.

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Section: Discussionmentioning

confidence: 74%

An adhesion protein of Salmonella enterica serovar Typhi is required for pathogenesis and potential target for vaccine development

Ghosh

Chakraborty²,

Theeya³

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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“…Collectively, these observations suggest that abundant outer membrane and periplasmic proteins belong to this group. This group was also notable for the presence of PagC, PagD, PagK, and SrfN, of which PagC, PagD, and SrfN have been reported to be required for virulence (7,23,(46)(47). We determined that these proteins are secreted to host cells in outer membrane vesicles (OMV) (Yoon et al, submitted).…”

Section: Vol 79 2011mentioning

confidence: 95%

Discovery of Novel Secreted Virulence Factors from Salmonella enterica Serovar Typhimurium by Proteomic Analysis of Culture Supernatants

et al. 2011

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Salmonella enterica serovar Typhimurium is a leading cause of acute gastroenteritis throughout the world. This pathogen has two type III secretion systems (TTSS) encoded in Salmonella pathogenicity islands 1 and 2 (SPI-1 and SPI-2) that deliver virulence factors (effectors) to the host cell cytoplasm and are required for virulence. While many effectors have been identified and at least partially characterized, the full repertoire of effectors has not been catalogued. In this proteomic study, we identified effector proteins secreted into defined minimal medium designed to induce expression of the SPI-2 TTSS and its effectors. We compared the secretomes of the parent strain to those of strains missing essential (ssaK::cat) or regulatory (⌬ssaL) components of the SPI-2 TTSS. We identified 20 known SPI-2 effectors. Excluding the translocon components SseBCD, all SPI-2 effectors were biased for identification in the ⌬ssaL mutant, substantiating the regulatory role of SsaL in TTS. To identify novel effector proteins, we coupled our secretome data with a machine learning algorithm (SIEVE, SVM-based identification and evaluation of virulence effectors) and selected 12 candidate proteins for further characterization. Using CyaA reporter fusions, we identified six novel type III effectors and two additional proteins that were secreted into J774 macrophages independently of a TTSS. To assess their roles in virulence, we constructed nonpolar deletions and performed a competitive index analysis from intraperitoneally infected 129/SvJ mice. Six mutants were significantly attenuated for spleen colonization. Our results also suggest that non-type III secretion mechanisms are required for full Salmonella virulence.Salmonella enterica serovars are intracellular pathogens that can cause gastroenteritis and typhoid fever. In the developing world, they are a leading cause of morbidity and mortality resulting from dehydration and untreated sepsis (21)(22)43). Salmonella actively secretes effector proteins into the host cell cytoplasm to create a replicative niche and inhibit the immune system. Many of these effectors are delivered by one of two type III secretion systems (TTSS), which are encoded on Salmonella pathogenicity islands 1 and 2 (SPI-1 and SPI-2, respectively) (24). The SPI-1 TTSS facilitates host cell entry and inflammation, whereas SPI-2 mediates intracellular survival (19,51). Both SPI-1 and SPI-2 are required in a mouse model of persistent infection (35). While over 30 TTSS effectors have been identified to date (5,25, 42,(58)(59), the list is thought to be an underestimate of the true effector repertoire because several virulence phenotypes are dependent on TTS but are not linked to any known effectors (34,57).A proteomic study of Escherichia coli O157:H7 identified over 31 new type III effectors. This analysis took advantage of a sepL mutant that secreted effector proteins into culture medium in vitro (60). E. coli SepL interacts with Tir (63), a type III effector that inserts into the host plasma membrane and functi...

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“…Techniques used to determine genetic relatedness, such as MLST and single nucleotide polymorphism (SNP) analysis (43,55,95), are usually based on the sequences of conserved genes, which are under mutational constraints. In contrast, noncoding, intergenic regions have not been used extensively for phylogenetic analysis, yet it is becoming clear that changes in promoter regions are key drivers of evolutionary adaptations (67,98). In this study, we analyzed three E. coli intergenic regions from 284 diverse isolates to determine if there were molecular signatures associated with different host sources.…”

mentioning

confidence: 99%

Intergenic Sequence Comparison of Escherichia coli Isolates Reveals Lifestyle Adaptations but Not Host Specificity

White

Sibley

et al. 2011

Appl Environ Microbiol

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Establishing the risk of human infection is one of the goals of public health. For bacterial pathogens, the virulence and zoonotic potential can often be related to their host source. Escherichia coli bacteria are common contaminants of water associated with human recreation and consumption, and many strains are pathogenic. In this study, we analyzed three promoter-containing intergenic regions from 284 diverse E. coli isolates in an attempt to identify molecular signatures associated with specific host types. Promoter sequences controlling production of curli fimbriae, flagella, and nutrient import yielded a phylogenetic tree with isolates clustered by established phylogenetic grouping (A, B1, B2, and D) but not by host source. Virulence genes were more prevalent in groups B2 and D isolates and in human isolates. Group B1 isolates, primarily from nonhuman sources, were the most genetically similar, indicating that they lacked molecular adaptations to specific host environments and were likely host generalists. Conversely, B2 isolates, primarily from human sources, displayed greater genetic distances and were more likely to be host adapted. In agreement with these hypotheses, prevalence of S activity and the rdar morphotype, phenotypes associated with environmental survival, were significantly higher in B1 isolates than in B2 isolates. Based on our findings, we speculate that E. coli host specificity is not defined by genome-wide sequence changes but, rather, by the presence or absence of specific genes and associated promoter elements. Furthermore, the requirements for colonization of the human gastrointestinal tract may lead to E. coli lifestyle changes along with selection for increased virulence.Pathogenic strains of Escherichia coli cause millions of cases of human infection each year (52) as well as severe problems in the livestock industry (78). Yet in other situations, many E. coli strains coexist peacefully as commensals in the intestinal tract of their warm-blooded hosts. A significant amount of research has sought to understand the relationship between pathogenic and commensal E. coli strains and determine if they can be distinguished from each other (18,55,72,95). E. coli is also a common contaminant of water and various food sources (63). From a public health standpoint, it is important to establish the zoonotic and virulence potential of strains, which may be related to their natural lifestyle and host source.E. coli has been proposed to have two principal habitats, the primary being the intestinal tract of mammals and birds and the secondary being water, sediment, and soil (58, 81). Survival and adaptation in both habitats are necessary for continued evolutionary success. For isolates that have evolved toward commensalism, signs of adaptation should be apparent, be it through altered regulatory sequences, gene expression, or metabolism (29). E. coli strains can be differentiated into four main phylogenetic groups (A, B1, B2, and D) along with two minor groups (C and E) (41). In general, these grou...

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Pathogenic adaptation of intracellular bacteria by rewiring a cis -regulatory input function

Cited by 58 publications

References 46 publications

An adhesion protein of Salmonella enterica serovar Typhi is required for pathogenesis and potential target for vaccine development

An adhesion protein of Salmonella enterica serovar Typhi is required for pathogenesis and potential target for vaccine development

Discovery of Novel Secreted Virulence Factors from Salmonella enterica Serovar Typhimurium by Proteomic Analysis of Culture Supernatants

Intergenic Sequence Comparison of Escherichia coli Isolates Reveals Lifestyle Adaptations but Not Host Specificity

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