Helicobacter pylori haemagglutinin protease protein, nucleic aci

Details Helicobacter pylori haemagglutinin protease protein, nucleic aci Helicobacter pylori haemagglutinin protease protein, nucleic aci

1996-09-16

1998-11-17

Horlick, Kenneth R.

Chemistry: molecular biology and microbiology

Micro-organism, tissue cell culture or enzyme using process...

Preparing compound containing saccharide radical

4353201, 435 6, 4352523, 435325, 530350, 5303881, 536 2432, 536 221, 536 237, C12P 1934, C12N 1500, C07K 1300, C07K 1528

Patent

active

058375023

DESCRIPTION:

BRIEF SUMMARY
The present invention relates to Helicobacter pylori (H.pylori) haemagglutinin/protease protein, nucleic acids encoding therefor and antibodies specific thereto and, in particular, to their use in the identification of H.pylori and in the diagnosis of H.pylori infection.
H.pylori (formerly Campylobacter pyloridis or C.pylori) is a spiral-shaped Gram negative microorganism which appears to live beneath the mucus layer of the stomach. Since its first isolation in 1982 H.pylori has been associated with gastric and duodenal ulcer disease and gastric cancer. H.pylori has been described as the most chronic infectious agent of man. Reviews on the state of the art include those by C. A. M. McNulty in J. Infection, 1986, 13, 107-113, C. S. Goodwin et al. in J. Clin. Pathol., 1986, 39, 353-365 and the Eurogast Study Group, Lancet, 1993, 341, 1359-1362.
The number of genes that encode proteins that are involved in the ability of H.pylori to cause disease is unknown and virulence determinants of H.pylori have so far not been identified. A number of determinants possessed by this organism have been proposed as possible pathogenic factors. For example, multiple flagella allow the microorganism to move rapidly by a corkscrew-like motion through highly viscous fluids such as the mucus layer of the gut which normally poses a barrier to bacteria en route to the gut epithelium. Also, the ability of H.pylori to produce mucinase digesting enzymes allows the organism to spread in the stomach. Microscopic studies of gastric biopsies from patients with H.pylori infection have shown the H.pylori organisms at specific sites on the gastric epithelial cells. Biochemical studies have reported the identification of haemagglutinins that allow H.pylori to adhere to these sites.
Extracellular metalloprotease enzymes are common microbial pathogenicity factors in bacteria causing disease in mammals. Zinc metalloprotease enzymes are known to have rapid substrate turnover and broad substrate profiles. Reviews on the state of the art are by Frausto da Silva J. J. R and Williams R. J. P in, The Biological Chemistry of the Elements, 1993, Clarendon Press, Oxford, Chapter 11, and Vallee, B. L. and Auld D. S., Biochemistry, 29, 5647-5659.
The zinc metalloprotease enzyme of Pseudomonas aeruginosa (also known as the elastase enzyme) has been shown to be important in the lung tissue-destructive processes caused by this organism in cystic fibrosis patients, (Bever R. A. and Iglewski B. H., J.Bacteriol., 1988, 170, 4309-4314). Similarly, the zinc metalloprotease enzyme of Vibrio cholerae (V.cholerae) (also known as the mucinase enzyme or haemagglutinin/protease (HAP) enzyme) has been shown to be important in the attachment and detachment of these organisms during the disease cholera. References on the state of the art include: Hase C. C. and Finkelstein R. A., J. Bacteriol., 1991, 173, 3311-3317; and Finkelstein R. A. et al., Infect.Immunol. 1992, 60 472-478.
We have now surprisingly found that a virulance gene almost identical to the V.cholerae hap gene, which we have termed the H.pylori hap gene, is present in the H.pylori genome. The detection of the H.pylori hap nucleic acid sequence by polymerase chain reaction (PCR) or other hybridization methods, the detection of H.pylori HAP protein epitopes by antibody detection methods, or the detection of antibodies to the H.pylori HAP protein by, for example ELISA, have utility in the diagnosis of H.pylori mediated gastroduodenal disorders in mammals.
Prior art in the diagnosis of H.pylori mediated gastric diseases include Campylobacter DNA probes capable of hybridizing H.pylori RNA (EP-A-0350205). H.pylori oligonucleotides specific for the H.pylori urease gene sequences are disclosed in WO 91/09049. Serological detection and diagnosis of H.pylori infection by serological immunoassays and detection of H.pylori antigens and antigenic fragments are disclosed in WO 89/08843, WO 89/09497 and EP-A-0329570.
It would be highly desirable to have a reliable means of detecting H.pylori DNA, RNA or antibodies directed

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"Zinc: Lewis acid catalysis and regulation", Chapter 11 of The Biological Chemistry of the Elements, by Frausto da Silva, J.J.R. and Williams R.J.P., 1993, pp. 299-318.

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