**1. Introduction**

*Helicobacter pylori (Hp)* was first isolated in culture media by Warren and Marshall in 1983. Since then much progress has been made regarding all the characteristics, the pathology and the resistance to antibiotics of this microorganism, However the history of this bacterium goes back a long time ago. In 1892 Bizzozzero described the presence of helical microorganisms in gastric mucosa of dogs and cats. In 1896 Salomon demonstrated the transmission to rats. In 1899 Iaworski & Krientis evidenced helicoidal microorganisms in human gastric biopsies. In 1967 Luck, in 1975 Steer, in 1979 Fung and in 1982 Gregory showed the bacterial ultrastructural morphology. In 1983 Marshall & Warren identified for the first time *Hp* [1]. In 1984 Langenberg hypothesized a relationship between stomach urease and spiral germs [2].

*Hp* is a Gram-negative, spiral-shaped bacterium, with positive findings for urease, oxidase and catalase. It colonizes the human gastric epithelium. The main pathologies related to *Hp* infection are the following: chronic active gastritis, peptic ulcer disease, gastric carcinoma and mucosa-associated lymphoid tissue (MALT) lymphoma. Further, epidemiological and eradication studies have demonstrated a casual relationship between *Hp* infections and endothelial dysfunction, leading to vascular diseases [3, 4]. Generally, the colonization occurs primarily during childhood especially in the developing areas, usually in the same family for a cohort effect [5]. This colonization is widely asymptomatic even if a long-lasting infection can be established in some subjects. After colonization all patients with *H. pylori* infection develop histological gastritis, which corresponds to classical chronic gastritis and is characterized by the infiltration of neutrophils and other inflammatory cells. However, most patients are asymptomatic for life, while few of them will develop a digestive disease. Infection is virtually lifelong in the absence of treatment, implying that evasion of the host response is efficient.

*Hp* infection is widespread with about 50% of world population infected. In developing countries, especially in lower socioeconomic classes, the prevalence is higher (about 80%), whereas in the developed areas such as the USA, Canada, Japan, and Western Europe, the prevalence is much lower (about 25–30%) [6–9].

The infection outcome mainly depends on three factors: strain virulence, host response and environmental factors. The strain pathogenicity depends on the virulence markers present in the bacterium. Host response shows the peculiarity that it is not protective, indeed in some cases may worsen the patients situation. Environmental factor, such as cigarette smoking is a major risk factor for duodenal ulceration among *Hp*-infected persons. Other important factors include stress, childhood living conditions, diet, alcohol and NSAIDs (non- steroidal anti-inflammatory drugs) use [10, 11].

Aim of this chapter was to study the virulence markers involved in the pathogenicity of *Hp* such as Vacuolating cytotoxin (VacA) and vacA gene (vacuolating cytotoxin gene A), intermediate region (i) of vacA, CagA protein and the cag pathogenicity island. The molecular diagnostic of the microorganism, the genotypic resistance related to the phenotypic one, the antibiotic resistance and the updated treatment strategies including also non-antibiotics therapy are similarly studied.

## **2. Pathogenicity and virulence markers**

#### **2.1 Pathogenicity**

The pathogenicity of *Helicobacter pylori* is shown in **Figure 1**.

Here it is reported the course of *Hp* infection in the patients beginning from the childhood to the advanced age considering what may happen at high level or at low level of acidity. The infection starts with the colonization of the microorganism in the normal gastric mucosa which can lead to an acute *Hp* infection at a low level of acid production. This in turn can result in a chronic *Hp* infection which may be asymptomatic for a lifetime or produce a non- atrophic pangastritis which can lead to MALT lymphoma. At high level of acidity the infection can result in an antral predominant gastritis with an evolution to duodenal ulcer. At a low level of acidity it can result in a corpus predominant atrophic gastritis which may evolve in gastric ulcer, intestinal metaplasia, dysplasia and gastric cancer in 2% of infected patients [12].

*Virulence Markers, Genotypic versus Phenotypic Resistance and New Treatment Strategies... DOI: http://dx.doi.org/10.5772/intechopen.97026*

#### **Figure 1.**

*Pathogenicity of* Helicobacter pylori. *From Suerbaum et al. [11].*

#### **2.2 Markers of virulence**

Gastric colonization is a prerequisite for *Hp*-associated disease and this is mediated by both flagella and urease: mutant strains lacking these features cannot establish infection. The most important determinants of virulence are the following: (a) Vacuolating cytotoxin (VacA) and vacA gene (vacuolating cytotoxin gene A), (b) Intermediate region (i) of vacA, (c) CagA protein and the cag pathogenicity island, (d) Hps60 superficial protein, (e) BabA adhesion, (f) Urease virulence determinant.

#### *2.2.1 Vacuolating cytotoxin (VacA) and vacA gene*

This is a protein found in culture supernatant that induces vacuolation in a variety of cultured epithelial cell lines, The expression of *Hp* vacA gene leads to the production of a vacuolating cytotoxic protein VacA, (present only in about 40% of isolates), which is responsible for inducing the formation of acidic vacuoles. This secreted protein toxin is responsible for the gastric epithelial erosion observed in infected hosts [13].

In **Figure 2** the schematic structure of Vac A is reported [10].

In this figure the mosaicism of VacA is underlined [13]. In fact the vacA gene contains two variables regions: the s- (signal) region encoding part of the signal peptide with the N-terminus of the mature protein (hydrophilic part) and the m- (middle) region encoding C-terminal portion of the final processed polypeptide (hydrophobic part). These regions are both cleaved upon secretion to yield a mature toxin monomer of 87–95 kilodaltons [14]. The combination between the *s* and *m* regions causes the strains virulence and is correlated with the kind of disease. In fact s1-type strains are associated with vacuolating activity, s2-type is non-vacuolating, m-region causes the specificty of cell vacuolating: m1 alleles are more toxigenic than strains with m2 alleles, vacA s1m1 is the most toxigenic combination and is associated with duodenal and gastric ulceration.

The subtype s1a m1 is the most virulent strain involved in patients with ulcer. A further region of the vacA gene (i- intermediate region) has been reported in literature to be associated with gastric cancer [15].
