Genetic variants of Helicobacter pylori type IV secretion system components CagL and CagI and their association with clinical outcomes

Abstract

Background Helicobacter pylori infection is associated with risk for chronic gastritis (CG), gastric ulcer (GU), duodenal ulcer (DU), and gastric cancer (GC). The H. pylori Cag type IV secretion system (TFSS) translocates the virulence factor cytotoxin-associated gene A protein into host cells and plays an important role in initiating gastric carcinogenesis. The CagL and CagI proteins are components of the TFSS. The Arg-Gly-Asp (RGD) motif of CagL, and the six most distal C-terminal amino acids (Ser-Lys-Ile-Ile-Val-Lys, and Ser-Lys-Val-Ile-Val-Lys) of CagL and CagI are essential for TFSS adhesion to host cells. Additionally, the CagL variant Tyr58Glu59 was previously shown to be associated with GC patients.ResultsWe isolated 43 H. pylori isolates from 17 CG, 8 GU, 8 DU, and 10 GC patients in Southeast Asia. Total DNAs were extracted and sequenced with MiSeq. H. pylori strain ATCC 26695, which was isolated from CG patients, was used as a reference. We examined the full sequences of H. pylori cagL and cagI using whole-genome sequencing (WGS), and analyzed whether single nucleotide variants and amino acid changes (AACs) correlated with adverse clinical outcomes. Three isolates were excluded from the analysis due to cagPAI rearrangements. CagL RGD motifs were conserved in 39 isolates (97.5%). CagL-Glu59 and Ile234 in the C-terminal motif were more common in 10 H. pylori isolates from GC patients (p < 0.001 and p < 0.05, respectively). When 5 Vietnamese isolates from GC patients were excluded, CagL-Glu59 still remains significant (p < 0.05), but not Ile234. CagL-Tyr58 was seen in only one isolate. The CagI C-terminal motif was completely conserved across all 40 isolates, and there were no significant AACs in CagI.ConclusionsUsing WGS, we analyzed genetic variants in clinical H. pylori isolates and identified putative novel and candidate variants in uncharacterized CagL and CagI sequences that are related to gastric carcinogenesis. In particular, CagL-Glu59 has the possible association with GC.Electronic supplementary materialThe online version of this article (doi:10.1186/s13099-017-0165-1) contains supplementary material, which is available to authorized users.

Characterization and genetic diversity of Helicobacter pylori type IV secretion system components, CagI and CagN and its association with clinical outcomes among Iranian patients

“…In the meantime, the most variable region in CagN amino acid sequence was found at residues 53 to 63, which includes many missense mutations and it is postulated to contain GDEEITEEEKK in the P12 reference strain. Our ndings revealed that there was no signi cant correlation between clinical outcomes and cagI and cagN variants at both nucleotide and amino acid levels (P > 0.05), which is in consistent with previous study reported by Ogawa et al [26]. Pham et al, stated that C-terminal motif (SKVIVK) in CagI is essential for T4SS function, and thus is completely conserved among H. pylori strains.…”

“…In agreement with above mentioned study, our ndings also con rmed that the CagI C-terminal motif was completely conserved among all H. pylori isolates. Ogawa et al discovered complete RGD motifs in CagL sequences were observed from all isolates, which possibly imply the importance of the RGD motif for CagL function [26]. A recent investigation on this topic was performed by Yadegar et al in Iran, in which almost 97% of H. pylori clinical strains contained cagL gene [29].…”

“…To understand the precise role of CagI and CagN in CagA translocation and pathogenesis need to be further investigated. The oncogenic potential of H. pylori strains is associated with their virulence capacity, genetic diversity and speci c sequence polymorphisms within the key genes involving in translocation and phosphorylation of T4SS effectors [24][25][26][27]. Therefore, the present study aimed to determine the prevalence of cagI and cagN genes and their amino acid sequence polymorphisms in Iranian H. pylori-infected patients with various gastroduodenal diseases.…”

Variations in cag pathogenicity island genes of Helicobacter pylori from Latin American groups may influence neoplastic progression to gastric cancer

“…Previous publications reported an association of GC with the presence of variants in position 58 and 59 of cagL protein; in two studies 35,36 the concurrent presence of tyrosine (Y) in amino acid position 58 and glutamic acid (E) in position 59 (Y58E59) compared with the combination aspartic acid (D58) and Lysine (K59), induced more efficiently a shift of gastric integrin a5b1 in the corpus, which has been related with gastric carcinogenesis. In our previous publication we did not observe the Y amino acid in position 58 in any sample, although we did find that carriers of D at this position are at lower risk of GC in comparison with the asparagine (N) carriers 28 .…”

“…In particular the cagL S10F variant (located at codon 10) changes from serine (polar) to phenylalanine (non-polar). Interestingly, among the 43 Asian strains recently sequenced, no single S10F variant was found, suggesting that this is a Western-strain specific variant 35 . Thus, overall, the differences observed in these studies are likely to be driven by geographical origins of HP.…”