Helicobacter pylori cagL amino acid polymorphisms and its association with gastroduodenal diseases

Shukla, Sanket K.; Prasad, Kashi Nath; Tripathi, Archana; Jaiswal, Virendra; Khatoon, Jahanarah; Ghsohal, Uday Chand; Krishnani, Narendra; Husain, Nuzhat

doi:10.1007/s10120-012-0189-7

Cited by 18 publications

(39 citation statements)

References 11 publications

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“…This finding is contrary to the study performed by Ogawa et al from Japan where A41 was only detected among CagL variants in GC isolates (2/10, 20%), although in a not significant relationship vs non‐GC isolates. In addition, the majority of our strains had Asparagine (N) at position 122, which is in line with the data obtained by Shukla et al from India where all of the strains were found to have N122 variant. In contrast, K122 was predominantly observed among Japanese and Taiwanese isolates .…”

Section: Discussionsupporting

confidence: 93%

Genetic diversity and amino acid sequence polymorphism in Helicobacter pylori CagL hypervariable motif and its association with virulence markers and gastroduodenal diseases

Yadegar

2019

Cancer Medicine

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Genetic variability in cagL gene especially within the Helicobacter pylori CagL hypervariable motif (CagLHM) may affect the development of gastric cancer. Therefore, this study was conducted to investigate the association of CagL diversity with clinical outcomes and with H pylori virulence markers. A total of 126 patients with different gastric diseases including non‐ulcer dyspepsia (NUD), peptic ulcer disease (PUD), gastric erosion (GE), and gastric cancer (GC) were enrolled. H pylori was cultured from gastric biopsies, and the isolates were screened for the presence of cagL, cagA, vacA, babA2, sabA, and cagPAI integrity by PCR. The amino acid polymorphisms of cagL were analyzed using DNA sequencing. We isolated 61 (48.4%) H pylori strains from 36 NUD, eight PUD, 12 GE, and five GC patients. Almost all isolates were cagL positive (97%), and their RGD, RHS, and SKIIVK motifs were highly conserved. Among 10 CagLHM variants identified, NEIGQ and NKIGQ were detected as the most prevalent sequences. Interestingly, a significant association was found between the presence of NKMGK and PUD (P = 0.002). Notably, the NEIGQ isolates with multiple C‐type EPIYA repeat that carried intact cagPAI correlated with disease risk for PUD, GE, and GC (P = 0.021). In conclusion, we identified novel variants of H pylori CagLHM sequences in Iranian population such as NKMGK, which was associated with disease risk for PUD. Further studies using a large number of strains are required to better clarify the function of certain CagLHM motifs in gastric carcinogenesis and disease outcome.

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Section: Discussionsupporting

confidence: 93%

Genetic diversity and amino acid sequence polymorphism in Helicobacter pylori CagL hypervariable motif and its association with virulence markers and gastroduodenal diseases

Yadegar

2019

Cancer Medicine

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“…pylori -mediated proinflammatory responses. The amino acid polymorphism combinations examined in this study were: D58K59 and Y58E59 which have both been linked with increased gastric cancer risk [ 7 , 8 ]; and N58E59, N58K59 and D58E59 which have not shown a specific link to H . pylori disease progression [ 7 – 9 ].…”

Section: Resultsmentioning

confidence: 99%

“…According to Rizzato et al [ 9 ], the cagL gene shows 74 nucleotide polymorphisms, including 31 non-synonymous polymorphisms. To date, only a subset of these 31 amino acid polymorphisms have been examined for cancer association: Yeh et al examined residues 58, 59, 122, 201, 210, 216, 221 and 234 [ 7 ]; Shukla et al examined residues 35, 58, 59, 60, 62 and 122 [ 8 ]; and Rizzato et al examined residues 35, 55, 58, 60 and 176 [ 9 ]. Of these, only polymorphisms at amino acid residues 55 [ 9 ], 58 [ 7 – 9 ] and 59 [ 7 , 8 ] have been shown to correlate with host gastric cancer risk.…”

Section: Discussionmentioning

confidence: 99%

“…pylori clinical isolates bearing the CagL amino acid polymorphism Y58E59 were significantly over-represented in Taiwanese gastric cancer patients compared to non-cancer patients [ 7 ]. In contrast, increased gastric cancer risk has subsequently been reported to associate with the CagL polymorphisms D58K59 in Indian patients [ 8 ] and N58 in a Mexican patient cohort [ 9 ]. Despite such geographical disparity, understanding the molecular basis for the association of CagL polymorphisms with gastric cancer risk is of great medical interest as it could provide crucial insights into the molecular mechanisms of H .…”

Section: Introductionmentioning

confidence: 99%

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Preservation of Helicobacter pylori CagA Translocation and Host Cell Proinflammatory Responses in the Face of CagL Hypervariability at Amino Acid Residues 58/59

et al. 2015

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Carriage of the CagA oncoprotein by the human gastric cancer-associated pathogen Helicobacter pylori is significantly associated with this typically benign chronic infection advancing to a potentially fatal outcome. However it remains to be elucidated why only a small subset of individuals infected with H. pylori CagA-positive strains develops gastric cancer. H. pylori translocates CagA into host cells using a type IV secretion apparatus that interacts with host integrin receptors via a three-amino-acid-residue RGD motif on the H. pylori protein CagL. The RGD motif of CagL also plays a major role in the induction of proinflammatory responses. Upstream of this motif is a conserved glycine flanked by four hypervariable amino acid residues (residues 58, 59, 61 and 62). Certain amino acid polymorphisms at 58 and 59 are significantly prevalent in strains from gastric cancer patients in particular geographic regions; Y58E59 is seen in Taiwan and D58K59 in India. In light of the seemingly contradictory findings of recent CagL mutagenesis studies, we have examined the contribution of sequence promiscuity specifically at CagL residues 58 and 59 to CagA translocation and H. pylori-mediated proinflammatory responses of gastric epithelial cells. Using isogenic mutants of H. pylori strains P12 and 26695 with amino acid substitutions at CagL residues 58 and 59, we determined that carriage of the polymorphisms Y58E59, D58K59, D58E59, N58E59 or N58K59 did not significantly alter the capacity of H. pylori to translocate CagA into, or induce IL-8 secretion in, host cells. Our findings, together with other recently published data, suggest that the variation at CagL residues 58 and 59 does not influence type IV secretion system function in isolation, but rather may work in concert with particular polymorphisms elsewhere in CagL to modulate disease progression.

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“…We have also found that two novel strain-variable CagL loop motifs, TSPSA5343536 in loop 1, and TASLI (aa 170 to 175 in loop 4), are involved in determining the strength of integrin interaction (TSPSA and TASLI), or modulate CagL cell binding (TASLI). The first of these latter CagL segments has been previously highlighted: several research groups have determined an association between amino acid polymorphisms in this segment adjacent to TSPSA (in particular in amino acids 58 and 59) and the cancer risk of infected patients343643. There is conflicting evidence on the role of these amino acids, and the pathological association of polymorphisms has not been causally confirmed yet.…”

Section: Discussionmentioning

confidence: 99%

Systematic site-directed mutagenesis of the Helicobacter pylori CagL protein of the Cag type IV secretion system identifies novel functional domains

Bönig

Olbermann

Bats

et al. 2016

Sci Rep

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The Cag Type IV secretion system, which contributes to inflammation and cancerogenesis during chronic infection, is one of the major virulence factors of the bacterial gastric pathogen Helicobacter pylori. We have generated and characterized a series of non-marked site-directed chromosomal mutants in H. pylori to define domains of unknown function of the essential tip protein CagL of the Cag secretion system. Characterizing the CagL mutants, we determined that their function to activate cells and transport the effector CagA was reduced to different extents. We identified three novel regions of the CagL protein, involved in its structural integrity, its possible interaction with the CagPAI T4SS pilus protein CagI, and in its binding to integrins and other host cell ligands. In particular two novel variable CagL motifs were involved in integrin binding, TSPSA, and TASLI, which is located opposite of its integrin binding motif RGD. We thereby defined functionally important subdomains within the CagL structure, which can be used to clarify CagL contributions in the context of other CagPAI proteins or for inhibition of the CagT4SS. This structure-function correlation of CagL domains can also be instructive for the functional characterization of other potential VirB5 orthologs whose structure is not yet known.

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Helicobacter pylori cagL amino acid polymorphisms and its association with gastroduodenal diseases

Cited by 18 publications

References 11 publications

Genetic diversity and amino acid sequence polymorphism in Helicobacter pylori CagL hypervariable motif and its association with virulence markers and gastroduodenal diseases

Genetic diversity and amino acid sequence polymorphism in Helicobacter pylori CagL hypervariable motif and its association with virulence markers and gastroduodenal diseases

Preservation of Helicobacter pylori CagA Translocation and Host Cell Proinflammatory Responses in the Face of CagL Hypervariability at Amino Acid Residues 58/59

Systematic site-directed mutagenesis of the Helicobacter pylori CagL protein of the Cag type IV secretion system identifies novel functional domains

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