Barriers overcome by
1. Introduction
For most of the 20th century, the human stomach has been considered an environment that is inhospitable for the growth of any bacteria. But the first isolation of a curved, microaerophilic, gram-negative bacterium,
Progression of gastric inflammation by long term association of
On the other hand, the host immune response is characterized by the cardinal signs of inflammation. Both innate and adaptive immune systems are activated by inhabiting
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It is known from several studies that MMP, a family of zinc-dependent endopeptidases that selectively degrade or remodel most of ECM components and other structural molecules are intimately associated to different diseases including gastric ulcer and cancer. At present, both
2. Gastric inflammation: An overview
Persistent association of microaerophilic, gram-negative enteric bacteria results in chronic gastric inflammation which in turn leads to gastric cancer. Accumulating evidences suggest that
Gastric inflammation is accompanied by induction of oxidative stress by reactive oxygen species (ROS), inducible nitric oxide synthase (iNOS) and subsequent secretion of proinflammatory cytokines like interleukin (IL)-1β, IL-6 and tumor necrosis factor (TNF)-α (Yamaoka et al., 1996). Gastric epithelial cells also secrete IL-8 (Jung et al., 1997) which attracts the polymorphonuclear (PMN) cells. Local inflammation is also associated to reduced prostaglandin synthesis and increased infiltration of mast cells, neutrophils, macrophages and
Over-secretion of pro-inflammatory cytokines and growth factors promote neovascularisation, which cause invasion and metastasis. Vascular endothelial growth factor (VEGF), the main mediator of angiogenesis is reported to be over-expressed in 54% of severe gastric cancer patients with lymph node and liver metastasis (Saukkonen et al., 2003). Along with VEGF, other pro-angiogenic factors like IL-6, IL-8 and iNOS are also upregulated in tumor cells. IL-8 promotes angiogenesis in gastric tumor by interacting with its receptors CXCR1 and CXCR2, present on surface of endothelial cells. Over expression of iNOS has been observed in both primary tumors as well as lymph node metastases compared to normal mucosa (Wang et al., 2005). Excess nitric oxide increases the activity of VEGF thereby promoting blood flow, vascular permeability and endothelial cell proliferation and migration (Wang et al., 2005). Other than stimulating angiogenesis, iNOS promotes gastric carcinoma through various ways including inhibiting DNA repair enzymes, inducing oxidative DNA damage, oncogene expression and apoptosis deregulation (Ohshima et al., 2003). The niche of
In cancer tissues, there is very less information available regarding the association between a specific factor and methylation of a gene. Aberrant DNA methylation is frequently associated with different human cancers. DNA methylation is involved with change in gene expression pattern, which can be confirmed by measuring the mRNA levels of the corresponding genes. Nakajima
From evolutionary view point, the successful adaptability of
3. Genetics of H. pylori and gastropathy
The clinical outcome of
cagA was the first reported gene that varies in
The extent of biological activity of CagA is directly associated with the number of phosphorylation sites or the number of EPIYA motifs present at the C-terminal region of CagA (Higashi et al., 2002b, Azuma, 2004, Azuma et al., 2004). Thus, molecular weight of the CagA protein varies from 128 kDa -148 kDa and the
Soon after
Approximately 4% of the
Recent studies have proposed the possibility of using genetic markers in the plasticity zone as indicators of pathogenicity for
Recently, a novel duodenal ulcer promoting gene (
4. Immunobiology of host and H. pylori interaction in both in vivo and in vitro
Through evolution,
After entering the gastric milieu, most of the bacteria remain in the gastric mucosa and only about 10%
The genetic study in relation to the virulence factor has been extensively studied in relation to
The other virulence factor in
5. Role of T cells in H. pylori infection
Very limited information is available on how the host immune system; particularly the adaptive immune system is modulated by
Bacterial chemotaxis is their inherent property by which it can migrate from a harsh environment towards more favorable environment. Genetically modified
The mechanism underlying differentiation of T cell has been intensively investigated: Stat1 and Stat4 signaling drive TH1 response; Stat6 signaling promotes TH2 whereas Stat3 signaling drives TH17 responses. IL-2 drives TH1 responses and results in (interferon) IFNγ production; that may have carcinogenic effect. However, role of TH2 and TH17 are not well known (Dunn et al., 2006) until recent reports suggest that TH17 may play a pivotal role in
The role of Tregs in modulating host immune response during
It has been hypothesized that better hygiene in Europe and America has inversely proportional with the rise of asthma, due to lack of early exposure to microbial antigens. Arnold
6. Tracking the matrix metalloproteinases during infection
Proteinase are a class of enzymes capable of hydrolysing peptide bonds. These biocatalysts are largely classified into two major groups: exopeptidases and endopeptidases, depending on the site of cleaving a peptide bond either proximal or distal to the amino or carboxy termini of the substrate respectively. They are further subdivided into serine proteases, threonine proteases, cysteine proteases, aspartate proteases, metalloproteases, glutamic acid proteases based on their catalytic properties (Hartley, 1960). Source of proteases are mainly restricted to stomach, pancreas and small intestine; where they are utilized for digestion of protein. Matrix metalloproteinases (MMPs) are Zn-requiring endopeptidases, the essential player for ECM remodeling of tissues. The function of MMPs are tightly regulated at several levels by via different mechanisms including synthesis in zymogen, localization in cellular compartments like granules or lysosomes, inhibition by protease inhibitors and inactivation in response to change in pH and/or temperature. However, virulent bacteria colonizing the gut sometime secrete proteases that can directly activate host MMPs, thereby increasing their biochemical efficiency to degrade host’s ECM (Löwer et al., 2008). Therefore, disbalance of proteases and/or protease inhibitors play decisive role in chronic inflammation and cancer (Wex et al., 2004). In this chapter we will limit our discussion to MMPs as their role in gastric inflammation as well as in gastric cancer is just relevant (Knapinska and Fields). MMPs comprise more than 29 different proteases that differ in the expression profile, substrate specificity, subcellular localisation and functional implications (Birkedal-Hansen et al., 1993). Among them, gelatinases, (MMP-2 and MMP-9) and stromelysin-1 (MMP-3) collectively cleave gelatins (types I and V), collagens (type IV, V, VII, IX and X), elastin, fibronectin, laminin and proteoglycan core proteins. The activities of MMPs are regulated by the endogenous tissue inhibitors of metalloproteinases (TIMPs), while cytokines, growth factors, tumour promoters and transcription factors including nuclear factor NF-κB and activator protein AP-1 modulate their gene expressions. The balance between MMPs and TIMPs is a critical factor for diverse cellular functions including cellular proliferation, migration, adhesion and apoptosis (Somerville et al., 2003). Based on the important role of certain members of MMPs in cancer, including gastric cancer, they have been studied to a large extent in chronic gastritis and premalignant lesions in the stomach (Pender and MacDonald, 2004, Schuppan and Hahn, 2000).
To explore the role of host proteinases during
Another way of exploring host-pathogen interaction is to co-culture the parasite and the host cell that it infects. In this regard AGS cell lines co-cultured with
7. Th-17 governs matrix metalloproteases: A pertinent query in clinical therapy
Upon
Studies using
Activated CD4+ T cells secrete IL-21, which regulates the growth and functional properties of T cells, B cells, NK cells and DC (Leonard and Spolski, 2005). Of late, it is reported that IL-21 secretes from TH17 in Stat-3 dependent manner and in turn IL-21 can induce IL-17 production the maintaining TH17 cell population in an autocrine manner(Wei et al., 2007). In contrast, IL-21 is also reported as a TH2 secreted cytokine which prevents the differentiation of naive CD4+ T cells into TH1 cells (Wurster et al., 2002). Therefore the role of IL-21 though appears complex, yet it’s a crucial cytokine which promotes gelatinase activities during
8. Management of H. pylori infection and future avenues
As, much greater percentage of the world’s population are infected with
The study on tribal populations in India reported that biopsy samples contain strains having
Antibiotics along with proton pump inhibitors (PPIs) known as ‘Triple therapy’ have been used for
Although, ‘Triple therapy’ is successful in individual cases, yet the recurrence of bacterial infection especially in highly endemic countries makes vaccination as an alternative approach to standard therapy. However, till date vaccination against
Though large-scale research is going around the world in relation to
Abbreviations
MMP: matrix metalloproteinase
ECM: extracellular matrix
ROS: reactive oxygen species
TSSIV: type IV Secretion System
IL: interleukin
IFNγ: interferon gamma
DC: dendritic cell
NK cell: natural killer cell
APC: antigen presenting cell
TIMP: tissue inhibitor of metalloproteinase
EGFR: epidermal growth factor receptor
Erk: extracellular signal-regulated kinase
iNOS: inducible nitric oxide species.
NF-κB: nuclear factor kappa B
AP-1: activator protein 1
Treg: regulatory T cell
TH: T helper cell
TGF-β: transforming growth factor beta
miRNA: micro-RNA
SabA: sialic acid-binding protein
VacA: vacuolating associated cytotoxin gene
CagA: cytotoxin-associated gene A
Cag-PAI: cytotoxin-associated gene-pathogenicity island
NOD1: nucleotide-binding oligomerization domain-1
FAK: focal adhesion kinase
dupA: duodenal ulcer promoting gene
BabA: Lewis blood group antigen binding adhesin
ORF: open reading frame
VEGF: vascular endothelial growth factor
TNFα: tumor necrosis factor alpha
GC: gastric cancer
DU: duodenal ulcer
MAPK: mitogen-activated protein kinase
Acknowledgments
The authors are indeed grateful to Prof. Siddhartha Roy, Director, CSIR-IICB, Kolkata, for encouraging and supporting. The authors are thankful to Mr. Sayantan Jana and Mr. Somnath Chatterjee for assisting in referencing and drawing figure respectively.References
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