Summary Infections frequently contain multiple strains (genotypes) of the same pathogen, yet they are still usually treated as uniform entities. In this Review, we discuss problems with inconsistent definition of the term "strain" and review the prevalence and implications of multiple-strain infections. Up to now, multiple-strain infections have been shown unambiguously in 51 human pathogens (and 21 non-human ones) and are likely to arise in most pathogen species. In human pathogens, multiple-strain infections usually reach considerable frequencies (median 11·3%, mean 21·7% of infections), which are certainly underestimated in many cases because of technical limitations of detection. For many diseases, the importance of multiple-strain infections is still unclear, but theoretical work and experimental results from animal models suggest a broad range of clinically relevant effects. Multiple-strain infections can affect host immune responses and our ability to prevent and treat infection efficiently. Competition and mutualism between strains change pathogen and disease dynamics and promote pathogen evolution. Co-infection enables gene transfer among strains. Taking multiple-strain infections into account will improve our understanding of host-pathogen interactions and disease dynamics, and will provide a basis for novel control approaches.

https://www.thelancet.com/pdfs/journals/laninf/PIIS1473-3099(11)70241-9.pdf

Prevalence and implications of multiple-strain infections

Pathophysiology of Gastroesophageal Reflux Disease

Helicobacter pylori causes peptic ulceration and gastric adenocarcinoma; the latter is common in Iran but not in Iraq. We hypothesized that more virulent H. pylori strains may be found in Iran than in Iraq and so compared established and newly described virulence factors in strains from these countries. We studied 59 unselected dyspeptic patients from Iran and 49 from Iraq. cagA was found in similar proportions of strains from both countries (76% in Iran versus 71% in Iraq) and was significantly associated with peptic ulcer disease in Iraq (P <or= 0.01) but not in Iran. cagA alleles encoding four or more tyrosine phosphorylation motifs were found in 12% of the Iranian strains but none of the Iraqi strains (P = 0.02). There were no significant differences in the vacA signal-, middle-, or intermediate-region types between Iranian and Iraqi strains. Among the strains from Iran, vacA genotypes showed no specific peptic ulcer associations, but among the strains from Iraq, vacA i1 strains were associated with gastric ulcer (P <or= 0.02), mimicking their previously demonstrated association with gastric cancer in Iran. dupA was found in similar proportions of Iranian and Iraqi strains (38% and 32%, respectively) and was associated with peptic ulceration in Iraqi patients (P <or= 0.01) but not Iranian patients. H. pylori strains from Iraq and Iran possess virulence factors similar to those in Western countries. The presence of cagA with more phosphorylation motifs in Iranian strains may contribute to the higher incidence of gastric cancer. However, the association between strain virulence markers and disease in Iraq but not Iran suggests that other host and environmental factors may be more important in the disease-prone Iranian population.

Differences in Virulence Markers between Helicobacter pylori Strains from Iraq and Those from Iran: Potential Importance of Regional Differences in H. pylori-Associated Disease

Helicobacter pylori has been associated with the development of two malignant diseases: gastric adenocarcinoma and gastric mucosa-associated lymphoid tissue (MALT) lymphoma. Although the cag pathogenicity island, especially the cagA gene, has been linked with adenocarcinoma, few data concerning H. pylori pathogenic factors involved in low-grade gastric MALT lymphoma are available. The goal of this study was to analyze the prevalence of and correlation between genes coding for seven H. pylori virulence factors (cagA, cagE, vacA, iceA, babA, hopQ, and oipA) and two novel adhesins (sabA and hopZ) by comparing a collection of 43 H. pylori strains isolated from patients with low-grade gastric MALT lymphoma to 39 strains isolated from age-matched patients with gastritis only. Our results show that taken individually, none of the nine genes tested can be considered associated with MALT strains and allow us to conclude that MALT pathogenesis is not linked with more proinflammatory H. pylori strains. We demonstrated that in patients infected with strains harboring the iceA1 allele, sabA functional status, and hopZ “off” status, the odds of developing a MALT lymphoma were 10 times higher. However, the low prevalence of such strains (10 of 43 MALT strains) renders this triple association a low-sensitivity marker for MALT strains. Our data confirmed that H. pylori virulence factors are correlated with one another. If the involvement of H. pylori in MALT lymphoma is well established, the pathomechanism by which gastric lymphoma occurs remains to be identified.

Evaluation of the Association of Nine Helicobacter pylori Virulence Factors with Strains Involved in Low-Grade Gastric Mucosa-Associated Lymphoid Tissue Lymphoma

Aim To clarify the association between Helicobacter pylori (H. pylori) infection and the risk of esophageal carcinoma through a meta-analysis of published data. Methods Studies which reported the association between H. pylori infection and esophageal cancer published up to June 2013 were included. The odds ratios (ORs) and corresponding 95%CIs of H. pylori infection on esophageal cancer with respect to health control groups were evaluated. Data were extracted independently by two investigators and discrepancies were resolved by discussion with a third investigator. The statistical software, STATA (version 12.0), was applied to investigate heterogeneity among individual studies and to summarize the studies. A meta-analysis was performed using a fixed-effect or random-effect method, depending on the absence or presence of significant heterogeneity. Results No significant association between H. pylori infection and esophageal squamous cell carcinoma (ESCC) risk was found in the pooled overall population (OR = 0.97, 95%CI: 0.76-1.24). However, significant associations between H. pylori infection and ESCC risk were found in Eastern subjects (OR = 0.66, 95%CI: 0.43-0.89). Similarly, cytotoxin-associated gene-A (CagA) positive strains of infection may decrease the risk of ESCC in Eastern subjects (OR = 0.77, 95%CI: 0.65-0.92), however, these associations were not statistically significant in Western subjects (OR = 1.26, 95%CI: 0.97-1.63). For esophageal adenocarcinoma (EAC) the summary OR for H. pylori infection and CagA positive strains of infection were 0.59 (95%CI: 0.51-0.68) and 0.56 (95%CI: 0.45-0.70), respectively. Conclusion H. pylori infection is associated with a decreased risk of ESCC in Eastern populations and a decreased risk of EAC in the overall population.

Kornelis R van Slochteren

Papers

The importance of vacA, cagA, and iceA genotypes of Helicobacter pylori infection in peptic ulcer disease and gastroesophageal reflux disease