| 1. |
- Thorell, Kaisa, 1983, et al.
(författare)
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Identification of a Latin American-specific BabA adhesin variant through whole genome sequencing of Helicobacter pylori patient isolates from Nicaragua
- 2016
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Ingår i: BMC Evolutionary Biology. - : Springer Science and Business Media LLC. - 1471-2148. ; 16
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Tidskriftsartikel (refereegranskat)abstract
- Background: Helicobacter pylori (H. pylori) is one of the most common bacterial infections in humans and this infection can lead to gastric ulcers and gastric cancer. H. pylori is one of the most genetically variable human pathogens and the ability of the bacterium to bind to the host epithelium as well as the presence of different virulence factors and genetic variants within these genes have been associated with disease severity. Nicaragua has particularly high gastric cancer incidence and we therefore studied Nicaraguan clinical H. pylori isolates for factors that could contribute to cancer risk. Methods: The complete genomes of fifty-two Nicaraguan H. pylori isolates were sequenced and assembled de novo, and phylogenetic and virulence factor analyses were performed. Results: The Nicaraguan isolates showed phylogenetic relationship with West African isolates in whole-genome sequence comparisons and with Western and urban South-and Central American isolates using MLSA (Multi-locus sequence analysis). A majority, 77 % of the isolates carried the cancer-associated virulence gene cagA and also the s1/i1/m1 vacuolating cytotoxin, vacA allele combination, which is linked to increased severity of disease. Specifically, we also found that Nicaraguan isolates have a blood group-binding adhesin (BabA) variant highly similar to previously reported BabA sequences from Latin America, including from isolates belonging to other phylogenetic groups. These BabA sequences were found to be under positive selection at several amino acid positions that differed from the global collection of isolates. Conclusion: The discovery of a Latin American BabA variant, independent of overall phylogenetic background, suggests hitherto unknown host or environmental factors within the Latin American population giving H. pylori isolates carrying this adhesin variant a selective advantage, which could affect pathogenesis and risk for sequelae through specific adherence properties.
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| 2. |
- Karlsson, Roger, 1975, et al.
(författare)
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Comparative Analysis of Two Helicobacter pylori Strains using Genomics and Mass Spectrometry-Based Proteomics
- 2016
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Ingår i: Frontiers in Microbiology. - : Frontiers Media SA. - 1664-302X. ; 7
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Tidskriftsartikel (refereegranskat)abstract
- Helicobacter pylori, a gastroenteric pathogen believed to have co-evolved with humans over 100,000 years, shows significant genetic variability. This motivates the study of different H. pylon strains and the diseases they cause in order to identify determinants for disease evolution. In this study, we used proteomics tools to compare two H. pylori strains. Nic25_A was isolated in Nicaragua from a patient with intestinal metaplasia, and P12 was isolated in Europe from a patient with duodenal ulcers. Differences in the abundance of surface proteins between the two strains were determined with two mass spectrometry based methods, label free quantification (MaxQuant) or the use of tandem mass tags (TMT). Each approach used a lipid-based protein immobilization (LPITM) technique to enrich peptides of surface proteins. Using the MaxQuant software, we found 52 proteins that differed significantly in abundance between the two strains (up-or downregulated by a factor of 1.5); with TMT, we found 18 proteins that differed in abundance between the strains. Strain P12 had a higher abundance of proteins encoded by the cag pathogenicity island, while levels of the acid response regulator ArsR and its regulatory targets (KatA, AmiE, and proteins involved in urease production) were higher in strain Nic25_A. Our results show that differences in protein abundance between H. pylori strains can be detected with proteomic approaches; this could have important implications for the study of disease progression.
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| 3. |
- Thorell, Kaisa, 1983
(författare)
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Multi-level characterization of host and pathogen in Helicobacter pylori-associated gastric carcinogenesis
- 2014
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Today, more than half of the world’s population is infected with Helicobacter pylori, and two to three per cent of these will develop gastric cancer associated with this infection. Gastric cancer is today the third largest cause of cancer mortality worldwide, with more than 700 000 deaths annually, a number that is expected to increase. H. pylori is usually acquired in childhood, and establish a lifelong infection in the absence of treatment. However, most infected individuals remain asymptomatic; the causal relationship between H. pylori and gastric cancer is complex, affected both by bacterial and host factors, as well as environmental factors. To study this relationship we took a multi-level approach looking both at the host and bacteria in patients during the early stages of gastric cancer development. We studied patients from a low-risk, and a high-risk population for gastric cancer, Sweden and Nicaragua respectively. Altogether, we investigated the human gene expression, H. pylori genomic and transcriptomic, features, as well as microbiota composition, all in material from the same individuals. We also made a smaller study of the surface proteome of two H. pylori isolates. We found the Nicaraguan H. pylori isolates to carry and express in vivo, several of the established virulence factors associated with increased gastric cancer risk, such as CagA and the s1/m1 VacA genotype. We also identified the adhesin BabA to have a South American variant with a specific selection pressure on the BabA protein in this region. This could have effects on the adhesion properties and consequently, strain virulence in these strains. On the host level, we identified the kynurenine pathway of tryptophan degradation to be differentially expressed during the early stages of gastric carcinogenesis, a pathway that has been described to be involved both in immune modulation and in cancer development. We also identified the loss of acidic chitinase (CHIA) expression as a potential biomarker for pre-cancerous gastric lesions. This is the first study that in a large scale explores both the human and bacterial gene expression in the same tissue, an approach that presents new possibilities for the understanding of gastric cancer development.
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