Chemistry: molecular biology and microbiology – Measuring or testing process involving enzymes or... – Involving nucleic acid
Reexamination Certificate
1998-03-11
2002-10-22
McGarry, Sean (Department: 1635)
Chemistry: molecular biology and microbiology
Measuring or testing process involving enzymes or...
Involving nucleic acid
C435S069100, C435S069800, C435S320100, C536S023100, C536S023700
Reexamination Certificate
active
06468739
ABSTRACT:
DESCRIPTION
The present invention concerns a method for identifying secretory genes and in particular adherence genes from
Helicobacter pylori
. In addition the invention concerns a gene bank suitable for identifying secretory genes from
H. pylori
, polynucleotides and polypeptides obtainable from this gene bank, in particular the alpA-gene from
Helicobacter pylori
and the polypeptide which it codes. These polynucleotides and polypeptides can be used to diagnose, prevent and treat a Helicobacter infection.
The occurrence of spiral bacteria in the human gastric mucous membrane has been known for a long time (Bizzozero, 1893). The fact that these are pathogenic germs was, however, not realized until the successful isolation and culture of this bacterium by Marshall and Warren (Warren and Marshall, 1983; Marshall et al., 1984) from the gastric mucous membrane of a patient with a gastric ulcer (ulcus ventriculi). As the first analyses showed the isolated microorganisms were gram-negative, spiral bacteria with an extremely high motility and the unusual ability of being able to survive in a strongly acidic environment (up to ca. pH 1.5). The germs which were originally denoted
Campylobacter pylori
were finally classified on the basis of biochemical and morphological characteristics in the newly established genus “Helicobacter” (Goodwin et al., 1989).
The importance of
Helicobacter pylori
infection and the implications of this discovery already became clear within a few years. Epidemiological investigations by Taylor and Blaser (1991) showed that the
H. pylori
infection occurs world-wide and that ca. 50% of the population are infected with this bacterium, the infection rate being higher in the developing countries than in industrialized countries. Furthermore it was observed that the probability of a chronic
H. pylori
infection increases drastically with increasing age. Hence the
H. pylori
infection is among the most frequent chronic bacterial infections of humans.
Today it is known that the infection inevitably leads to the induction of a bacterial gastritis (type B gastritis) in humans. Moreover it is assumed that
H. pylori
also plays a causal role in the development of gastric and duodenal ulcers (ulcus ventriculi and ulcus duodeni) as well as some forms of gastric carcinoma (adenocarcinoma) (Lee et al., 1993; Solnick and Tompkins, 1993). Even the MALT (mucosa associated lymphoid tissue) lymphomas of the stomach which occur more rarely and are regarded as a precursor of B cell tumours of the immune system are also presumably a result of
H. pylori
infection. An antibacterial treatment of such patients with the successful eradication (total elimination) of
H. pylori
leads to a healing of gastric ulcers as well as of low grade MALT lymphomas (Sipponen and Hyvärinen, 1993; Isaacson and Spencer, 1993; Stolte and Eidt, 1993).
A sequel of a long-term infection with
H. pylori
is atrophic gastritis, a degeneration of the mucous, acid or pepsin-producing cells of the stomach epithelium which has to be regarded as a pre-cancerous lesion. According to statistics of the types of cancer which occurred world-wide most frequently in 1980, gastric carcinoma is in second place but with a declining tendency (Parkin et al., 1988). Two studies have recently shown a statistically significant correlation between
H. pylori
infection and the occurrence of gastric carcinoma (intestinal type); both came to the conclusion that ca. 60% of all gastric carcinomas that occur are probably due to a
H. pylori
infection (Parsonnet et al., 1991; Nomura et al., 1991). Furthermore investigations by Sipponen (1992) show that in many industrialized countries more than 20% of infected persons contract an ulcer of the stomach or of the duodenum during their life whereas this risk is negligibly small in persons with a normal gastric mucosa. This means that these frequent gastro-duodenal diseases must be regarded as infectious diseases and treated appropriately (Alper, 1993). A treatment which eliminates a chronic
H. pylori
infection that is already present leads to a healing of a gastritis, a gastric or duodenal ulcer or a MALT lymphoma. Thus a prophylactic treatment which prevents a
H. pylori
infection (e.g. immunization) as well as a treatment which eliminates a
H. pylori
infection that is already present can be used to treat these frequent gastro-duodenal diseases.
Apart from some higher primates, humans were previously the only known natural host for
H. pylori
. The relatively recent discovery that the domestic cat can also be infected with
H. pylori
throws new light onto the question of transmission and a possible reservoir for the bacteria outside the human organism. The occasionally successful culture of
H. pylori
from the faeces of infected persons and the ability of the bacteria to survive for months in water support the hypothesis of a faecal-oral transmission. Also direct oral-oral transmission is regarded as probable on the basis of family studies. The infection usually occurs in childhood within the family, cramped living conditions and a poor standard of hygiene correlating positively with the frequency of the infection.
After oral uptake the bacteria first reach the extremely acid stomach lumen (pH 1-2). Here the survival of the bacteria is made possible by the production of the enzyme urease which leads to cleavage of the urea that is present and thus to a local neutralization of the acidic pH value in the stomach. By means of chemotactic orientation and flagella-dependent motility the microorganisms then move into the bicarbonate-buffered mucosal layer of the antrum region of the stomach which is in fact their natural habitat. Here they are in a unique ecological niche which, due to the acid barrier, is accessible only to a few competing bacterial species. The microorganisms presumably orientate themselves by means of the pH gradient between the lumen (pH 1-2) and epithelial cell surface (pH 6-7) in order to reach the epithelium. Due to their spiral shape, their motility in viscous mucous, the production of mucous-modifying enzymes and finally their microaerophilic way of living, these germs are optimally adapted to the living conditions in this habitat.
They usually spend their time in the deep crypts of the antrum region where they are protected from external influences such as e.g. acid, pepsin and also from medicines for their eradication such as e.g. antibiotics. Part of the population (ca. 20%) is closely associated with epithelial cells especially with mucous-producing cells. Under the condition of a gastral metaplasia i.e. the acid-induced formation of gastral epithelium in the duodenum, the metaplastic areas in the duodenum are also colonized which creates the prerequisites for the development of a duodenal ulcer (ulcus duodeni). A complete excretion of the Helicobacter with the shed mucous is probably prevented by their ability to adhere so that the bacteria can persist for years, decades or even for a life time (chronic infection).
Before the existence and the significance of
H. pylori
for ulcerous diseases was known, these were treated with so-called antacids or H
2
-receptor antagonists. These are substances which inhibit the acid secretion of the parietal cells of the stomach. The action of these pharmaceutical agents usually leads to a healing of the ulcers but, since one of the causes of these ulcers i.e.
H. pylori
infection, is not eliminated by this, in most cases a re-occurrence of the ulceration (relapse) occurs within a short period.
A further frequently used therapy in ulcerations is bismuth treatment. Various bismuth salts (CBS, BSS) have a bactericidal effect on
H. pylori
. However, a total eradication of these germs is only achieved in 8-32% of the cases. The treatment apparently leads to a temporary suppression of the germs but after discontinuing the treatment the infection flares up again in most cases. A long-term therapy with high doses leads to an accumulation of the substance in the liver, kidney and nervous system and has considerab
Haas Rainer
Meyer Thomas
Odenbreit Stefan
Arent Fox Kintner Plotkin & Kahn LLC
Max-Planck-Gesellschaft zur Förderung der Wissenschaften e.V.
McGarry Sean
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