Pathogenesis of Helicobacter pylori Infection Daniela Basso, * Mario Plebani *,† and Johannes G. Kusters ‡ *Department of Laboratory Medicine, University-Hospital of Padova, Padova, Italy, † Leonardo Foundation, Abano Terme General Hospital, Abano Terme, Italy, ‡ Department of Medical Microbiology, University Medical Center Utrecht, Utrecht, The Netherlands While chronic Helicobacter pylori infection is usually without any symptoms, disease ranges from peptic ulcer, gastric adenocarcinoma to gastric MALT lymphoma. Although the clinical outcome of the infection is thought to be determined by host, bacterial and environmental factors, the focus of this review is on recent findings relevant to H. pylori adaptation and virulence factors. Helicobacter pylori Adaptation H. pylori has developed several strategies that allow it to perfectly adapt to the gastric mucosa of its human host, its only known natural niche. Bacterial mimicry and genetic diversification represent successful strategies employed by the bacterium to evade the immune response and to survive in the human stomach through- out the life of its host. Genetic diversification may help H. pylori to adapt to a new host after transmission, and to different micro-niches within a single host and to chang- ing conditions in the host over time. Genetic diversity arises from within-genome diversification and from inte- gration of DNA from other H. pylori strains. Central to this is the ability of H. pylori to take up exogenous DNA and incorporate it into its genome. The H. pylori machinery for exogenous dsDNA uptake is composed of the type-IV secretion system ComB, which transports dsDNA across the outer membrane at the cell poles, and by ComEC, which mediates the subsequent transport into the cyto- plasm through the inner membrane with higher specific- ity for DNA structure [1]. Adaptation to varying gastric conditions is enabled by several H. pylori genes that dis- play phase variation; these include genes encoding outer membrane proteins (OMPs), like BabA which is a Lewis b ligand, and genes involved in lipopolysaccharide (LPS) biosynthesis. In animal model systems of H. pylori infec- tion, Styer et al. [2] provided evidence that BabA expres- sion is lost during persistent infection by phase variation and nonreciprocal gene conversion of babA with a dupli- cate copy of babB, a paralog of babA with unknown func- tion. H. pylori not only binds to human Lewis antigens but also expresses Lewis antigens (H. pylori is a fucose expressing pathogen). The variable O-antigen chain part of the H. pylori LPS is uniquely composed of host-related Lewis antigens and this host-cell surface mimicry is thought to facilitate immune escape. Two studies [3,4] explored phenotype variation of H. pylori Lewis antigen expression. Both studies employed a mouse infection model to demonstrate that bacterial subpopulations expressing both Lewis x and Lewis y coexist and are stable during persistent infection. New subpopulations expressing Lewis b inevitably appear when Lewis b trans- genic mice are infected. This finding supports the hypoth- esis of an increased fitness of H. pylori variants that match the Lewis phenotype of their host [4]. Changes in Lewis phenotypes could be linked to phase variation of the metastable poly-C tracts of the galactosyltransferase gene encoding b-(1,3)galT and the fucosyltransferase-encod- ing genes futA, futB and futC that are all involved in Lewis antigen biosynthesis. Skoglund et al. [3] demonstrated that a neutral pH favors Lewis y expression, while a more acidic pH favors a switch from solely Lewis y to both Lewis x and Lewis y glycosylation. In agreement with the above findings, Lehours et al. [5] demonstrated an increased prevalence of Lewis x negative / Lewis y positive strains among the cagPAI negative isolates form patients with MALT lymphoma versus patients with gastritis, Keywords Outer membrane proteins, cagA, vacA, babA. Reprint requests to: Daniela Basso, Depart- ment of Laboratory Medicine, University- Hospital of Padova, Via Giustiniani 2, 35128 Padova, Italy. E-mail: daniela.basso@sanita.padova.it Abstract Helicobacter pylori infections are thought to eventually lead to symptoms as a result of the long-lasting interactions between the bacterium and its host. Mechanisms that allow this bacterium to cause a life-long infection involve modulation of both the immune response and host cellular processes. Last year many novel findings that improve our knowledge on how H. pylori vir- ulence factors interact with the host were reported, but because of space limitations we can only discuss a limited number of these studies. Among those are studies on the genetic variation of genes encoding outer mem- brane proteins and the mimicry of host antigens, factors that alter host-cell metabolism and factors that modulate the host’s immune response. Helicobacter ISSN 1523-5378 14 ª 2010 Blackwell Publishing Ltd, Helicobacter 15 (Suppl. 1): 14–20