Helicobactor pylori

Helicobacter pylori is one of the most common bacterial pathogens, affecting more than half of the population
worldwide
This bacterium was first described as a member of the genus Campylobacter;

however, because of differences in taxonomy, it was classified as a member of the genus Helicobacter in 1989

Helicobacter pylori is the most common cause of gastric and duodenal ulcers.
In individuals infected with H pylori, there is a 10% to 20% lifetime risk of Peptic Ulcer Disease (PUD) and
1% to 2% risk of gastric cancer.
Specifically, patients infected with cytotoxin-associated gene A H pylori strains are at higher risk of PUD
and gastric cancer because of greater inflammation.
Epidemiology

In developing countries, infection commonly develops in children and chronic infection continues into adulthood;

in the developed world, infection is rare in children and develops more commonly in adulthood.

Early exposure to H pylori is associated with gastric pathologic changes, progressing from atrophic gastritis to
gastric ulcers and carcinoma.

Later-onset infection most commonly presents with duodenal pathology.

The most common route of transmission is person-to-person spread through fecal-oral and oral-oral exposures.

The seroprevalence of H pylori is approximately 30% in individuals younger than 30 years and 63% for individuals
aged 55 to 65 years.

Risk factors for transmission are related to living conditions that promote close person-to-person contact such as
crowded homes
2017
 2022

Journal of Biosciences 2020. 45(1):110

 Diagnosis

Serologic testing is not recommended to detect active infection, as it cannot distinguish between active disease and
previous exposure.

Antibodies to H pylori can remain elevated for a long time even after treatment, potentially increasing the number of
false-positive results.

The 1 positive aspect of serologic testing is that it is the only test for H pylori that is not affected by PPI (Proton
Pump Inhibitor) therapy, antibiotics, or by the presence of blood in the stomach.

Invasive testing strategies require upper endoscopy and include the biopsy urease (campylobacter-like organism)
test, histologic assessment, and culture.
The biopsy urease test is a good first-line test, as it is accurate, rapid, and inexpensive.

This test relies on H pylori urease to convert urea into ammonia, increase the pH, and change the color of the pH
indicator.
 Treatment

There are various proposed treatment regimens for H pylori infection.

It consists of a PPI, bismuth, metronidazole, and tetracycline (PBMT) or a 10- to 14-day course of a PPI,
clarithromycin, and metronidazole
Bismuth salt is bacteriostatic and bactericidal against Helicobacter pylori (H. pylori)

Over the past several years, clarithromycin resistance is increasing worldwide while H pylori eradication rates are
decreasing.

Data on clarithromycin resistance in the United States remains limited, but estimates approach 30%.
Consequently, alternative regimens have been suggested to counteract this increase in resistance.

One proposed regimen is sequential therapy, which consists of a Proton Pump Inhibitors (PPi) and amoxicillin for the
first half of treatment duration and a PPI, metronidazole, and clarithromycin for the second half.

The principle behind sequential therapy is that amoxicillin first weakens the bacterial cell wall, which then allows
clarithromycin and metronidazole to directly attack the bacteria and prevent efflux of antibiotics through drug efflux
channels
Helicobacter pylori colonization and disruption of the gastric barrier

Helicobacter pylori colonization of the gastric mucosa is mediated by surface adhesins, which preferentially interact
with mucin 5 (MUC5AC).

The elevated production of MUC5AC in response to H pylori infection could be considered as a potential mechanism
facilitating bacterial adherence.

Recently, by using guinea pigs, it was revealed that during H pylori infection the production of MUC5AC in the
gastric mucosa was upregulated.

These phenomena were confirmed in vitro in cell cultures of guinea pig primary gastric epithelial cells co‐cultured
with the following H pylori component

One study confirmed the role of the transferrin receptor (TFRC) in H pylori attachment to gastric epithelial cells,
which facilitates iron capture.

In the same study, an overexpression of ferritin light chain (FTL) in the gastric mucosa of H pylori‐infected patients
was found to be important.
Virulence Factors
Virulence Factors
Virulence Factors
Virulence Factors
In general, disintegration of the gastric barrier by H pylori and its soluble compounds leads to the development of
inflammatory response and proliferation of gastric cells to resolve homeostasis.

Nevertheless, enhanced cell proliferation may increase the risk of genetic instability of cells and the development
of gastric cancer.

Recently, it was shown that H pylori promotes the invasion and metastasis of gastric cancer by enhancing the
expression of heparanase (HPA), which is involved in tissue remodeling and cell migration.
The upregulation of HPA in MKN‐45 human gastric cells exposed to H pylori was reported in relation to increased
cell proliferation on MAPK and NF‐κB‐dependent signaling pathway.
H. pylori IV secretion system (T4SS)
 Outer membrane vesicles

Helicobacter pylori virulence factors are soluble, cell‐surface‐bound, or injected into the host cells via the type IV
secretion system (T4SS).

Recently, the central role of outer membrane vesicles (OMVs) produced by H pylori on the distribution of bacterial
antigens was suggested.

Various biologically active compounds of H pylori, which are present in OMVs, can be internalized into host cells,

That consequently influence signaling pathways and promote apoptosis of gastric epithelial cells as well as
immunocompetent cells, and thus strengthen or downregulate the immune responses leading to disease
development.

Protonography and mass spectrometry confirmed the presence of α‐carbonic anhydrase (CA) in OMVs generated

by planktonic and biofilm phenotypes of H pylori strains. This work suggested that CA, together with urease, may
play a pivotal role in decreasing gastric juice acidity by H pylori

OMVs determine the protein content, immunogenicity, and mechanisms of entrance into the host cells,
which can occur via caveolin‐dependent endocytosis (OMVs 20‐100 nm) or macropinocytosis and endocytosis
(OMVs 90‐150 nm).

These results suggest a critical role for OMVs in pathogenesis and their possibility as vaccine candidates.
NH4Cl increased the toxicity of vacuolating cytotoxin A (VacA) by increasing the intracellular VacA stability.

This study also confirmed that ammonia, which is generated by a bacterial urease during H pylori infection,
enhances VacA toxicity.

Certain vacA subtypes correlated with chronic gastritis in up to 90.0% of patients.

Molecular characterization of the vacA gene in H pylori clinical isolates from patients with gastroduodenal
diseases was also carried out in Assam, India.

CagA‐dependent downregulated cathepsin C (CtsC) via Src/ERK and Janus kinase (JAK) and activated STAT3
pathways, leading to impairment of neutrophil activation and thus promoting the persistence of bacteria in the
gastric mucosa.

H. pylori CagA+VacA+ strains are able to induce differentiation of fibroblasts into cells with characteristics of
cancer‐associated fibroblasts (CAFs).

This in turn induced epithelial‐mesenchymal transition (EMT) of normal rat gastric epithelial cells.

This process allows polarized epithelial cells to differentiate into a mesenchymal phenotype with enhanced
migration activity and invasiveness.
 H. pylori impairs T-cell-mediated immunity via direct and
indirect mechanisms

All strains express the secreted virulence factors VacA and GGT to
directly inhibit T-cell activation, proliferation and effector
functions.

Hexameric VacA binds to the β2 integrin subunit of LFA-1; the

receptor complex is internalized upon protein kinase C-mediated
serine/threonine phosphorylation of the β2 integrin cytoplasmic
tail.

Cytoplasmic VacA prevents nuclear translocation of NF-AT by

inhibiting its dephosphorylation by calcineurin, and thereby
blocks IL-2 production and subsequent T-cell activation and
proliferation.

GGT arrests T-cells in the G1 phase of the cell cycle and thus
prevents their proliferation.

Both VacA and GGT also indirectly prevent T-cell immunity

via re-programming of DCs;

VacA/GGT-exposed DCs produce IL-10, and induce the FoxP3-

and contact-dependent differentiation of T-cells into regulatory T-
cells while at the same time preventing Th1 and Th17
differentiation.

DC-derived and/or Treg-derived IL-10 further suppresses Th1

Nat Rev Microbiol. 2013 Jun; 11(6): 385–399. and Th17 effector functions.
 Tumor Associated Macrophages (TAMs) Myeloid Derived Supprsor Cells (MSDCs)

Mesenchymal Stem Cells (MSCs)

Cancer Associated Fibroblasts (CAFs)

 H. pylori colonization and persistence factors

During initial infection of the stomach lumen, urease-dependent

ammonia production locally raises the pH

which promotes bacterial survival and solubilizes the mucus gel to

facilitate bacterial motility.

Chemotaxis (driven by pH and possibly other gradients) and helical

rod shape promote flagellar-based motility away from the acidic
lumen to H. pylori's preferred niche, on and adjacent to gastric
epithelial cells.

Variably expressed adhesins may shift the balance to cell-associated

bacteria.

This includes CagA and VacA dependent disruption of cell

polarity by iron acquisition.

CagA and CagL dependent induction of chemokines and/or the

gastric hormone gastrin, CagL dependent inhibition of acid secretion
Cell-associated bacteria alter gastric epithelial cell behavior through VacA, by the H+/K+ ATPase, and affects on proliferation, apoptosis and
CagA and CagL which all have multiple cellular targets. differentiation mediated by all three effectors.

fla, flagella; che, chemotaxis; ure, urease; T4SS, Cag Type IV secretion In addition to CagL, CagA and CagY have also been shown to bind
system; PS, phosphatidylserine; α5β1 and αvβ5, indicated integrin subunits. α5β1 integrins.
 H. pylori subversion of innate immune recognition

H. pylori harbors PAMPs that have evolved to evade

detection by pro-inflammatory TLRs.

H. pylori expresses tetra-acylated LPS, which is less

bioactive than the hexa-acylated form typical of other
Gram-negative pathogens

due to specific lipid A modifications that prevent detection

by TLR4.

H. pylori flagella are not detected by TLR5 due to

Nat Rev Microbiol. 2013 Jun; 11(6): 385–399. mutations in the TLR5 binding site of flagellin.
 H. pylori activation of NLRs, NF-κB signalling and
caspase-1.

H. pylori peptidoglycan is delivered to the cytoplasmic

NLR Nod1 through either the type IV secretion system
(T4SS; via its interaction with α5β1 integrin at
cholesterol-rich lipid rafts) or via outer membrane
vesicles.
Activated Nod1 induces the AP1/NF-κB-dependent
expression of pro-inflammatory cytokines and defensins,
and the IRF3/7-dependent expression of type I IFNs.

Additional unidentified H. pylori NLR ligands activate

the inflammasome to induce autoproteolytic pro-
caspase-1 cleavage and the subsequent processing and
release of mature IL-1β and IL-18.

IL-18 binds to its receptor on naive T-cells and promotes

FoxP3-dependent Treg differentiation and immune
tolerance, which in turn prevents clearance and ensures
persistent colonization of H. pylori.
Nat Rev Microbiol. 2013 Jun; 11(6): 385–399.
In contrast, IL-1β binding to its receptor induces T-bet-
and RORγT-dependent Th1 and Th17 differentiation and
the expression of the respective signature cytokines IFN-γ
and IL-17.