Genome and Methylome Variation in Helicobacter pylori With a cag Pathogenicity Island During Early Stages of Human Infection

Helicobacter pylori cagA-positive strains are critically involved in the development of gastric cancer. Upon delivery into gastric epithelial cells via type IV secretion, the cagA-encoded CagA interacts with and thereby perturbs the pro-oncogenic phosphatase SHP2 and the polarity-regulating kinase PAR1b via the tyrosine-phosphorylated EPIYA-C/D segment and the CM sequence, respectively. Importantly, sequences spanning these binding regions exhibit variations among CagA proteins, which influence the pathobiological/oncogenic potential of individual CagA. Here we isolated an H. pylori strain (Hp_TH2099) naturally infecting the stomach of a housed macaque, indicating a zoonotic feature of H. pylori infection. Whole genome sequence analysis revealed that Hp_TH2099 belongs to the hpAsia2 cluster and possesses ABC-type Western CagA, which contains hitherto unreported variations in both EPIYA-C and CM sequences. The CM variations almost totally abolished PAR1b binding. Whereas pTyr + 5 variation in the EPIYA-C segment potentiated SHP2-binding affinity, pTyr-2 variation dampened CagA tyrosine phosphorylation and thus impeded CagA-SHP2 complex formation. As opposed to the H. pylori standard strain, infection of mouse ES cell-derived gastric organoids with Hp_TH2099 failed to elicit CagA-dependent epithelial destruction. Thus, the macaque-isolated H. pylori showed low virulence due to attenuated CagA activity through multiple substitutions in the sequences involved in binding with SHP2 and PAR1b.

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“…pylori infection, which facilitates adaptation of H . pylori to the new host 48 , 49 . In contrast, H .…”

Section: Discussionmentioning

confidence: 99%

Evaluating the origin and virulence of a Helicobacter pylori cagA-positive strain isolated from a non-human primate

Hashi

Imai

Yahara

et al. 2018

Sci Rep

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“…The population of bacteria causing any given infection is most often heterogeneous, and in part this heterogeneity is a consequence of phenotypic variants being selected for during infection ( 14 , 23 , 32 , 36 , 50 – 52 ). Such phenotypic variants can have enhanced abilities to circumvent the host immune response ( 14 ), altered adherence properties ( 53 ), altered metabolism/growth profiles ( 54 ), altered tissue tropism ( 55 ), altered antibiotic resistance profiles ( 56 ), etc.…”

Section: Discussionmentioning

confidence: 99%

Phenotypic Variation in the Group A Streptococcus Due to Natural Mutation of the Accessory Protein-Encoding Gene rocA

Sarkar

Danger

Jain

et al. 2018

mSphere

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This study investigates the regulatory and phenotypic consequences of a naturally occurring mutation in a strain of the bacterial pathogen the group A Streptococcus (Streptococcus pyogenes). We show that this mutation, which occurs in a regulator-encoding gene, rocA, leads to altered virulence factor expression and reduces the ability of this isolate to survive in human blood. Critically, the blood survival phenotype and the assortment of genes regulated by RocA differ compared to previous studies into RocA activity. The data are consistent with there being strain- or serotype-specific variability in RocA function. Given that phenotypic variants can lead to treatment failures and escape from preventative regimes, our data provide information with regard to a mechanism of phenotypic variation in a prevalent Gram-positive pathogen.

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“…45 A second queried genetic changes during challenge after vaccination with a trivalent vaccine containing VacA, CagA, and NapA or placebo. 46 Both studies found enrichment of nonsynonymous changes in cagPAI genes and OMPs. Interestingly, nonsense mutations in vaccine target genes were observed in a subset of the vaccination group, which correlated with higher IgG responses although not statistically significant.…”

Section: Genomic Diversification As a Mechanism For Phenotypic Varimentioning

confidence: 97%

“…One study examined genetic changes that accumulated during gerbil infection with and without high salt diet or iron limitation . A second queried genetic changes during challenge after vaccination with a trivalent vaccine containing VacA, CagA, and NapA or placebo . Both studies found enrichment of nonsynonymous changes in cag PAI genes and OMPs.…”

Section: Regulation Of Virulencementioning

confidence: 99%

Pathogenesis of Helicobacter pylori infection

2018

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In this review, we highlight progress in the last year in characterizing known virulence factors like flagella and the Cag type IV secretion system with sophisticated structural and biochemical approaches to yield new insight on the assembly and functions of these critical virulence determinants. Several aspects of Helicobacter pylori physiology were newly explored this year and evaluated for their functions during stomach colonization, including a fascinating role for the essential protease HtrA in allowing access of H. pylori to the basolateral side of the gastric epithelium through cleavage of the tight junction protein E-cadherin to facilitate CagA delivery. Molecular biology tools standard in model bacteria, including regulated gene expression during animal infection and fluorescent reporter gene fusions, were newly applied to H. pylori to explore functions for urease beyond initial colonization and establish high salt consumption as a mediator of gene expression changes. New sequencing technologies enabled validation of long postulated roles for DNA methylation in regulating H. pylori gene expression. On the cell biology side, elegant work using lineage tracing in the murine model and organoid primary cell culture systems has provided new insights into how H. pylori manipulates gastric tissue functions, locally and at a distance, to promote its survival in the stomach and induce pathologic changes. Finally, new work has bolstered the case for genomic variation as an important mechanism to generate phenotypic diversity during changing environmental conditions in the context of diet manipulation in animal infection models and during human experimental infection after vaccination.

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Genome and Methylome Variation in Helicobacter pylori With a cag Pathogenicity Island During Early Stages of Human Infection

Cited by 47 publications

References 74 publications

Evaluating the origin and virulence of a Helicobacter pylori cagA-positive strain isolated from a non-human primate

Evaluating the origin and virulence of a Helicobacter pylori cagA-positive strain isolated from a non-human primate

Phenotypic Variation in the Group A Streptococcus Due to Natural Mutation of the Accessory Protein-Encoding Gene rocA

Pathogenesis of Helicobacter pylori infection

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