Functional Plasticity in the Type IV Secretion System of Helicobacter pylori

Barrozo, Roberto M.; Cooke, Cara L.; Hansen, Lori M.; Lam, Anna M.; Gaddy, Jennifer A.; Johnson, Elizabeth; Cariaga, Taryn A.; Suárez, Giovanni; Peek, Richard M.; Cover, Timothy L.; Solnick, Jay V.

doi:10.1371/journal.ppat.1003189

Cited by 138 publications

(243 citation statements)

References 58 publications

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“…In addition, the apparent loss of cag PAI function by frameshift mutations in the cagX and cagY genes ( Supplementary Fig. 2 and Supplementary Tables 14-19), as well as by recombination in cagY in mice and in monkeys also happened in this time frame 30 , implying adaptation by mutation and recombination during early stages of the infection.…”

Section: Discussionmentioning

confidence: 95%

A mutation burst during the acute phase of Helicobacter pylori infection in humans and rhesus macaques

et al. 2014

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The evolution rate and genetic changes that occur during chronic infection with Helicobacter pylori have been analysed, but little is known about the genomic changes during the initial, acute bacterial infection phase. Here we analyse the rate and pattern of genome evolution in H. pylori from the genomes of two input strains isolated from human volunteers with asymptomatic infection, and the genomes of two output strains collected 20 and 44 days after re-infection. Similarly, we analyse genome evolution in bacteria from the genome sequences of input and output strains sequentially taken after experimental infection of a rhesus macaque. The estimated mutation rate reveals a mutation burst during the acute infection phase that is over 10 times faster than the mutation rate during chronic infection, and orders of magnitude faster than mutation rates in any other bacteria. The elevated frequency of mutations in outer membrane protein genes suggests that the mutation burst facilitates rapid host adaptation of the bacteria.

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Section: Discussionmentioning

confidence: 95%

A mutation burst during the acute phase of Helicobacter pylori infection in humans and rhesus macaques

et al. 2014

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“…WT H. pylori J166 was initially recovered from a human patient with a duodenal ulcer and has been shown to efficiently colonize rhesus macaques (36,(41)(42)(43). It expresses a T4SS encoded on the cagPAI and attaches to Leb blood group antigens by expression of BabA, though both functions are lost during passage in mice and rhesus monkeys (23,25,42). The complete genomes of WT H. pylori J166 and its rhesus-passaged variant were recently sequenced (27).…”

Section: Methodsmentioning

confidence: 99%

Dynamic Expression of the BabA Adhesin and Its BabB Paralog during Helicobacter pylori Infection in Rhesus Macaques

et al. 2017

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Most Helicobacter pylori strains express the BabA adhesin, which binds to ABO/Leb blood group antigens on gastric mucin and epithelial cells and is found more commonly in strains that cause peptic ulcers or gastric cancer, rather than asymptomatic infection. We and others have previously reported that in mice, gerbils, and rhesus macaques, expression of babA is lost, either by phase variation or by gene conversion, in which the babB paralog recombines into the babA locus. The functional significance of loss of babA expression is unknown. Here we report that in rhesus monkeys, there is independent selective pressure for loss of babA and for overexpression of BabB, which confers a fitness advantage. Surprisingly, loss of babA by phase variation or gene conversion is not dependent on the capacity of BabA protein to bind Leb, which suggests that it may have other, unrecognized functions. These findings have implications for the role of outer membrane protein diversity in persistent H. pylori infection.

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“…To determine whether STAT3 activation in DCs upon H. pylori infection was responsible for DC semimaturation, we blocked STAT3 activation by incubating cells with anti-IL-6 and anti-IL-10-neutralizing Abs and/or with the specific inhibitor of STAT3 activation and dimerization Stattic (25). Higher levels of CD86/ CD83 double-positive cells were only observed when DCs were incubated with anti-IL-10-neutralizing Ab (Fig.…”

Section: H Pylori Impairs DC Maturation and Function Through Stat3 Amentioning

confidence: 99%

Helicobacter pylori Cytotoxin-Associated Gene A Impairs Human Dendritic Cell Maturation and Function through IL-10–Mediated Activation of STAT3

Kaebisch

Mejías-Luque

Prinz

et al. 2014

The Journal of Immunology

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Helicobacter pylori infection induces chronic gastric inflammation that can progress to cancer. In this process, the virulence factor cytotoxin-associated gene A (CagA) plays a central role by directly altering epithelial cell signaling and inducing a strong Th1 immune response, which contributes to carcinogenesis. It is still barely understood how the bacterium evades clearance despite this solid immune response and persists lifelong. Dendritic cells (DCs) play a major role in determining the adaptive immune response toward H. pylori, and high levels of regulatory T cells have been detected infiltrating the gastric mucosa of H. pylori–infected patients, which contribute to bacterial persistence. Although murine studies indicate that H. pylori induces tolerization of DCs and impairs DC maturation, the virulence determinants involved are still controversial. Moreover, the signaling cascades engaged in human DC tolerization upon H. pylori infection remain unknown. In the current study, we analyzed the effect of H. pylori infection on human DC maturation and function, focusing on the virulence factors implicated and signaling pathways involved. Our results reveal that CagA is crucial for DC tolerization by modulating IL-10 secretion and, in turn, STAT3 phosphorylation, favoring a regulatory T cell immune response. Our findings help to unravel the paradox why CagA-positive strains, although eliciting a stronger inflammatory response, have overcome evolutionary pressure and persisted in their human host.

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Functional Plasticity in the Type IV Secretion System of Helicobacter pylori

Cited by 138 publications

References 58 publications

A mutation burst during the acute phase of Helicobacter pylori infection in humans and rhesus macaques

A mutation burst during the acute phase of Helicobacter pylori infection in humans and rhesus macaques

Dynamic Expression of the BabA Adhesin and Its BabB Paralog during Helicobacter pylori Infection in Rhesus Macaques

Helicobacter pylori Cytotoxin-Associated Gene A Impairs Human Dendritic Cell Maturation and Function through IL-10–Mediated Activation of STAT3

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