H. pylori induced chronic gastritis is a definitive risk factor for the development of gastric cancer. However, it was found that the statuses of some of the chief virulence factors (CagA and VacA) do not always correlate with particular outcomes of infection, as also discussed previosuly [
22]. In view of this, it appears that virulence of
H. pylori is a complex phenotype that need to be seen as a function of bacterial strategies aimed at survival and adaptation. However, it is not clear how the bacterium maintains its niches for almost an entire life span of its host without being cleared. Perhaps, there operate highly orchestrated, biological interactions between the host and the pathogen; the nature of such interactions is not clearly understood. Of late, roles of new virulence determinants are becoming plausible.
H. pylori harbors up to 45% strain specific genes [
23], mostly gained through horizontal gene transfer events [
24]. Recently, some of the members of the plasticity region cluster were proposed to be likely involved in promoting proinflammatory capacity of some of the strains [
22,
25] thus imparting a survival advantage. Our experiments with one such protein, from the plasticity region cluster suggest that some of the members of this cluster encode proinflammatory and/or proapoptotic roles (Alvi
et al., unpublished data). Most persistent microbes seemingly evolve strategies to avenge innate responses to gain niche and to maintain growth fitness. For example,
H. pylori traditionally harness its chief virulence factors, CagA and VacA to cause pathology
via a two pronged approach: 1) downregulate T-cell responses (through the VacA mediated cell cycle arrest) and 2) upregulate mucosal proinflammatory pathways (by CagA). Surprisingly, in our studies, one of the plasticity region cluster protein appeared to be able to perform both the immune stimulatory (macrophage proliferation, secretion of IL8 and TNF-alpha) and immune evasion (apoptosis of activated macrophages) tasks single handedly (unpublished observations). Thus we believe that some of the bacterial proinflammatory proteins [such as JHP0940 [
22] and others] are capable of taking up the functions of Vac A/Cag A, especially in the case of the deficiency of the latter and probably function as 'persistence factors' (Alvi
et al., unpublished data); this however awaits validation using appropriate animal models.
In a recent study [
25], 42 isolates of
H. pylori were profiled to find that 1,319 genes were present in all isolates, while 341 (20.5%) genes were variably present among different isolates. Of the variable genes, 127 (37%) were interspersed within the plasticity region cluster. They observed disease association of such genes and found thirty genes to be significantly associated with nonatrophic gastritis, duodenal ulcer, or gastric cancer, 14 (46.6%) of such putative disease-linked genes were operational from within the plasticity region and the cag PAI (many of the constituent genes of the cag PAI form part of the plasticity region cluster of
H. pylori). In the observation of Romo-Gonzalez [
25], two genes (HP0674 and JHP0940) were absent in all gastric cancer isolates. In our own studies (Tenguria and Ahmed, unpublished), strains representing intestinal metaplasia cases failed to amplify JHP0940 gene (data not shown). It is therefore possible that some of the genes are deleted by the pathogen as the disease progresses through intestinal metaplasia to gastric cancer. However, such observations need functional validation and mechanistic explanation. Nevertheless, the disease-linked genes as discussed above, may be pursued as (putative) biomarkers of the risk for progression of
H. pylori induced inflammation towards more serious gastroduodenal illnesses such as atrophic gastritis, intestinal metaplasia and gastric adenocarcinoma.