Salmonella enterica Serovar Typhi Conceals the Invasion-Associated Type Three Secretion System from the Innate Immune System by Gene Regulation
TL;DR: It is shown that Salmonella enterica serovar Typhi, the causative agent of typhoid fever, tightly regulates expression of the invasion-associated type III secretion system (T3SS-1) and thus fails to activate these innate immune signaling pathways.
Abstract: Delivery of microbial products into the mammalian cell cytosol by bacterial secretion systems is a strong stimulus for triggering pro-inflammatory host responses. Here we show that Salmonella enterica serovar Typhi (S. Typhi), the causative agent of typhoid fever, tightly regulates expression of the invasion-associated type III secretion system (T3SS-1) and thus fails to activate these innate immune signaling pathways. The S. Typhi regulatory protein TviA rapidly repressed T3SS-1 expression, thereby preventing RAC1-dependent, RIP2-dependent activation of NF-κB in epithelial cells. Heterologous expression of TviA in S. enterica serovar Typhimurium (S. Typhimurium) suppressed T3SS-1-dependent inflammatory responses generated early after infection in animal models of gastroenteritis. These results suggest that S. Typhi reduces intestinal inflammation by limiting the induction of pathogen-induced processes through regulation of virulence gene expression.
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TL;DR: This Review compares and contrast the interactions of S. Typhi and NTS serovars with host innate immune receptors and discusses why the disease manifestations associated with S. typhi infection differ considerably from those associated with the closely related NTSSerovars.
Abstract: Salmonella enterica serovars are associated with an estimated 1 million deaths annually and are also useful model organisms for investigating the mechanisms of host-bacterium interactions. The insights gained from studies on non-typhoidal Salmonella (NTS) serovars have provided a fascinating overview of the mechanisms by which the innate immune system detects and responds to bacterial pathogens. However, specific virulence factors and changes in virulence gene regulation in S. enterica subsp. enterica serovar Typhi alter the innate immune responses to this pathogen. In this Review, we compare and contrast the interactions of S. Typhi and NTS serovars with host innate immune receptors and discuss why the disease manifestations associated with S. Typhi infection differ considerably from those associated with the closely related NTS serovars.
125 citations
TL;DR: The anaerobic food chain that characterizes resident gut-associated microbial communities is reviewed along with the winning metabolic strategy Salmonella serovars use to edge out competing microbes in the inflamed intestine.
Abstract: A metabolically diverse microbial community occupies all available nutrient-niches in the lumen of the mammalian intestine, making it difficult for pathogens to establish themselves in this highly competitive environment. Salmonella serovars sidestep the competition by using their virulence factors to coerce the host into creating a novel nutrient-niche. Inflammation-derived nutrients available in this new niche support a bloom of Salmonella serovars, thereby ensuring transmission of the pathogen to the next susceptible host by the fecal-oral route. Here we review the anaerobic food chain that characterizes resident gut-associated microbial communities along with the winning metabolic strategy Salmonella serovars use to edge out competing microbes in the inflamed intestine.
112 citations
TL;DR: It is shown that inflammation-derived electron acceptors induce a complete, oxidative TCA cycle in S. Typhimurium, allowing the bacteria to compete with the microbiota for colonization and to utilize a variety of carbon sources, including microbiota-derived succinate.
110 citations
TL;DR: The aim of this review is to describe the different stages required for Salmonella interaction with its hosts: attachment to host surfaces; entry processes; multiplication; suppression of host defense mechanisms; and to point out similarities and differences between animal and plant infections.
Abstract: Salmonella enterica species is a Gram negative bacterium, which is responsible for a wide range of food- and water-borne diseases in both humans and animals, thereby posing a major threat to public health. Recently, there has been an increasing number of reports, linking Salmonella contaminated raw vegetables and fruit with food poisoning. Many studies have shown that an essential feature of the pathogenicity of Salmonella is its capacity to cross a number of barriers requiring invasion of a large variety of cells and that the extent of internalization may be influenced by numerous factors. However, it is poorly understood how Salmonella successfully infects hosts as diversified as animals or plants. The aim of this review is to describe the different stages required for Salmonella interaction with its hosts: (i) attachment to host surfaces; (ii) entry processes; (iii), multiplication; (iv) suppression of host defence mechanisms ; and to point out similarities and differences between animal and plant infections.
90 citations
Cites background from "Salmonella enterica Serovar Typhi C..."
...The S. Typhi tviA regulator gene indirectly downregulates the expression of HilA, a master regulator of the T3SS1, preventing recognition of SopE and activation of NK-κB (Winter et al., 2014)....
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TL;DR: It is found that representative ST313 isolates invade non-phagocytic cells less efficiently and induce less Caspase-1-dependent macrophage death and IL-1β release than ST19 isolates, suggesting that both phenotypically and at the genomic level ST313 isolate are evolving signatures that facilitate a systemic lifestyle in humans.
Abstract: Salmonella is an enteric pathogen that causes a range of diseases in humans. Non-typhoidal Salmonella (NTS) serovars such as Salmonella enterica serovar Typhimurium generally cause a self-limiting gastroenteritis whereas typhoidal serovars cause a systemic disease, typhoid fever. However, S. Typhimurium isolates within the multi-locus sequence type ST313 have emerged in sub-Saharan Africa as a major cause of bacteremia in humans. The S. Typhimurium ST313 lineage is phylogenetically distinct from classical S. Typhimurium lineages, such as ST19, that cause zoonotic gastroenteritis worldwide. Previous studies have shown that the ST313 lineage has undergone genome degradation when compared to the ST19 lineage, similar to that observed for typhoidal serovars. Currently, little is known about phenotypic differences between ST313 isolates and other NTS isolates. We find that representative ST313 isolates invade non-phagocytic cells less efficiently than the classical ST19 isolates that are more commonly associated with gastroenteritis. In addition, ST313 isolates induce less Caspase-1-dependent macrophage death and IL-1β release than ST19 isolates. ST313 isolates also express relatively lower levels of mRNA of the genes encoding the SPI-1 effector sopE2 and the flagellin, fliC, providing possible explanations for the decrease in invasion and inflammasome activation. The ST313 isolates have invasion and inflammatory phenotypes that are intermediate; more invasive and inflammatory than Salmonella enterica serovar Typhi and less than ST19 isolates associated with gastroenteritis. This suggests that both phenotypically and at the genomic level ST313 isolates are evolving signatures that facilitate a systemic lifestyle in humans.
69 citations
Cites background from "Salmonella enterica Serovar Typhi C..."
...Interestingly the S. Typhi regulatory protein TviA downregulates the expression of SopE, which is 69% identical to SopE2 and is also a guanine nucleotide exchange factor (Friebel et al., 2001; Winter et al., 2014)....
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...It is perhaps counterintuitive that Salmonella isolates that cause more disseminated disease, such as S. Typhi and ST313 NTS, invade non-phagocytic cells at lower levels and have lower gene expression of key invasion effectors SopE and SopE2, respectively (Winter et al., 2014)....
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...…repressing flagella gene expression to reduce inflammation seems to be a common theme in Salmonella serovars that cause invasive disease and is potentially an important step for host adaptation (Winter et al., 2009, 2010, 2014; Freitas Neto et al., 2013; Kingsley et al., 2013; Yim et al., 2014)....
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...Typhi and ST313 NTS, invade non-phagocytic cells at lower levels and have lower gene expression of key invasion effectors SopE and SopE2, respectively (Winter et al., 2014)....
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References
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TL;DR: In this paper, a new vector strategy for the insertion of foreign genes into the genomes of gram negative bacteria not closely related to Escherichia coli was developed, which can utilize any gram negative bacterium as a recipient for conjugative DNA transfer.
Abstract: We have developed a new vector strategy for the insertion of foreign genes into the genomes of gram negative bacteria not closely related to Escherichia coli. The system consists of two components: special E. coli donor strains and derivatives of E. coli vector plasmids. The donor strains (called mobilizing strains) carry the transfer genes of the broad host range IncP–type plasmid RP4 integrated in their chromosomes. They can utilize any gram negative bacterium as a recipient for conjugative DNA transfer. The vector plasmids contain the P–type specific recognition site for mobilization (Mob site) and can be mobilized with high frequency from the donor strains. The mobilizable vectors are derived from the commonly used E. coli vectors pACYC184, pACYC177, and pBR325, and are unable to replicate in strains outside the enteric bacterial group. Therefore, they are widely applicable as transposon carrier replicons for random transposon insertion mutagenesis in any strain into which they can be mobilized but not stably maintained. The vectors are especially useful for site–directed transposon mutagenesis and for site–specific gene transfer in a wide variety of gram negative organisms.
7,278 citations
TL;DR: The use of a tetracycline-resistance transposon, Tn10 (refs 5, 6), inserted in gene aroA to produce non-reverting, aromatic-requiring derivatives of virulent S. typhimurium strains were virtually non-virulent; their use as live vaccines conferred excellent protection against challenge with a virulent strain.
Abstract: An auxotrophic mutant which requires a metabolite not available in vertebrate tissues should be unable to grow in such tissue and thus be non-virulent. Most mutations to auxotrophy do not affect virulence1–3, presumably because the required metabolites are available at sufficient concentration. However, Bacon et al.1,2 noted that a Salmonella typhi mutant requiring p-amino-benzoic acid (p AB) was less virulent (for mice) than its parent. Salmonella, unlike vertebrates, cannot assimilate exogenous folate and must synthesize it from p AB; the virtual absence of p AB from vertebrate tissues is shown by the efficacy of sulphonamide chemotherapy. Yancey et al.4 reported reduced virulence for a S. typhimurium mutant with a requirement for 2,3-dihydroxybenzoate (DHB), the precursor of the bacterial iron-acquisition compound, enterochelin. As DHB is not a known vertebrate metabolite, it would be expected to be absent from mouse tissues. Salmonella synthesize p AB and DHB from chorismate, the final product of the aromatic biosynthetic (aro) pathway. A complete block at any step of this pathway should make S. typhimurium auxotrophic for two compounds not available in vertebrate tissues, and thus non-virulent. We describe here the use of a tetracycline-resistance transposon, Tn10 (refs 5, 6), inserted in gene aroA to produce non-reverting, aromatic-requiring derivatives of virulent S. typhimurium strains. These derivatives were virtually non-virulent; their use as live vaccines conferred excellent protection against challenge with a virulent strain.
2,090 citations
TL;DR: The distribution of close homologues of S. typhimurium LT2 genes in eight related enterobacteria was determined using previously completed genomes of three related bacteria, sample sequencing of both S. enterica serovar Paratyphi A and Klebsiella pneumoniae as mentioned in this paper.
Abstract: Salmonella enterica subspecies I, serovar Typhimurium (S. typhimurium), is a leading cause of human gastroenteritis, and is used as a mouse model of human typhoid fever. The incidence of non-typhoid salmonellosis is increasing worldwide, causing millions of infections and many deaths in the human population each year. Here we sequenced the 4,857-kilobase (kb) chromosome and 94-kb virulence plasmid of S. typhimurium strain LT2. The distribution of close homologues of S. typhimurium LT2 genes in eight related enterobacteria was determined using previously completed genomes of three related bacteria, sample sequencing of both S. enterica serovar Paratyphi A (S. paratyphi A) and Klebsiella pneumoniae, and hybridization of three unsequenced genomes to a microarray of S. typhimurium LT2 genes. Lateral transfer of genes is frequent, with 11% of the S. typhimurium LT2 genes missing from S. enterica serovar Typhi (S. typhi), and 29% missing from Escherichia coli K12. The 352 gene homologues of S. typhimurium LT2 confined to subspecies I of S. enterica-containing most mammalian and bird pathogens-are useful for studies of epidemiology, host specificity and pathogenesis. Most of these homologues were previously unknown, and 50 may be exported to the periplasm or outer membrane, rendering them accessible as therapeutic or vaccine targets.
1,850 citations
"Salmonella enterica Serovar Typhi C..." refers background in this paper
...Chromosomal DNA sequences of both serovars are highly syntenic, with mostly minor inversions, deletions and insertions [35,36]....
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TL;DR: It is shown that in COS-7 cells, activated Ras effectively stimulates MAPK but poorly induces JNK activity, which strongly support a critical role for Rac1 and Cdc42 in controlling the JNK signaling pathway.
1,641 citations
TL;DR: The real-time RT-PCR technique is very accurate and sensitive, allows a high throughput, and can be performed on very small samples; therefore it is the method of choice for quantification of cytokine profiles in immune cells or inflamed tissues.
1,426 citations