Polynucleotides and polypeptides in pathogenic mycobacteria and

Details Polynucleotides and polypeptides in pathogenic mycobacteria and Polynucleotides and polypeptides in pathogenic mycobacteria and

1998-09-16

2000-12-05

Baskar, P.

Drug, bio-affecting and body treating compositions

Antigen, epitope, or other immunospecific immunoeffector

Bacterium or component thereof or substance produced by said...

424 691, 4241841, 4241851, 4241681, 4242341, 4242481, 4242531, 424863, 424864, 435 71, 435 72, 435 732, 530300, 5303841, A61K 3904, A61K 3902, A61K 3910, A61K 3800, G01N 3353

Patent

active

061563226

DESCRIPTION:

BRIEF SUMMARY
This invention relates to the novel polynucleotide sequence we have designated "GS" which we have identified in pathogenic mycobacteria. GS is a pathogenicity island within 8 kb of DNA comprising a core region of 5.75 kb and an adjacent transmissable element within 2.25 kb. GS is contained within Mycobacterium paratuberculosis, Mycobacterium avium subsp. silvaticum and some pathogenic isolates of M.avium. Functional portions of the core region of GS are also represented by regions with a high degree of homology that we have identified in cosmids containing genomic DNA from Mycobacterium tuberculosis.


BACKGROUND TO THE INVENTION

Mycobacterium tuberculosis (Mtb) is a major cause of global diseases of humans as well as animals. Although conventional methods of diagnosis including microscopy, culture and skin testing exist for the recognition of these diseases, improved methods particularly new immunodiagnostics and DNA-based detection systems are needed. Drugs used to treat tuberculosis are increasingly encountering the problem of resistant organisms. New drugs targeted at specific pathogenicity determinants as well as new vaccines for the prevention and treatment of tuberculosis are required. The importance of Mtb as a global pathogen is reflected in the commitment being made to sequencing the entire genome of this organism. This has generated a large amount of DNA sequence data of genomic DNA within cosmid and other libraries. Although the DNA sequence is known in the art, the functions of the vast majority of these sequences, the proteins they encode, the biological significance of these proteins, and the overall relevance and use of these genes and their products as diagnostics, vaccines and targets for chemotherapy for tuberculous disease, remains entirely unknown.
Mycobacterium avium subsp. silvaticum (Mavs) is a pathogenic mycobacterium causing diseases of animals and birds, but it can also affect humans. Mycobacterium paratuberculosis (Mptb) causes chronic inflammation of the intestine in many species of animals including primates and can also cause Crohn's disease in humans. Mptb is associated with other chronic inflammatory diseases of humans such as sarcoidosis. Subclinical Mptb infection is widespread in domestic livestock and is present in milk from infected animals. The organism is more resistant to pasteurisation than Mtb and can be conveyed to humans in retail milk supplies. Mptb is also present in water supplies, particularly those contaminated with run-off from heavily grazed pastures. Mptb and Mavs contain the insertion elements IS900 and IS902 respectively, and these are linked to pathogenicity in these organisms. IS900 and IS902 provide convenient highly specific multi-copy DNA targets for the sensitive detection of these organisms using DNA-based methods and for the diagnosis of infections in animals and humans. Much improvement is however required in the immunodiagnosis of Mptb and Mavs infections in animals and humans. Mptb and Mavs are in general, resistant in vivo to standard anti-tuberculous drugs. Although substantial clinical improvements in infections caused by Mptb, such as Crohn's disease, may result from treatment of patients with combinations of existing drugs such as Rifabutin, Clarithromycin or Azithromycin, additional effective drug treatments are required. Furthermore, there is an urgent need for effective vaccines for the prevention and treatment of Mptb and Mavs infections in animals and humans based upon the recognition of specific pathogenicity determinants.
Pathogenicity islands are, in general, 7-9 kb regions of DNA comprising a core domain with multiple ORFs and an adjacent transmissable element. The transmissable element also encodes proteins which may be linked to pathogenicity, such as by providing receptors for cellular recognition. Pathogenicity islands are envisaged as mobile packages of DNA which, when they enter an organism, assist in bringing about its convertion from a non-disease-causing to a disease-causing strain.


DESCRIPTION OF THE DRAWINGS

FIGS

REFERENCES:
Database EMBL, Entry MT024, Accession No. U00024, Jan. 5, 1995 nt. 15203-15934 100% homology with SeqID:36 nt. 14306-15133 100% homology with SeqID:38 XP002033471 cited in the application.
Database EMBL, Entry MTCY277, Accession No. Z79701, Sep. 18, 1996 nt:34705-36493 100% homology with SeqID:30 nt.31972-32994 100% homology with SeqID:32 nt.33956-34687 100% homology with SeqID:34 XP002033472 cited in the application.
Database EMBL, Entry MTAD1, Accession No. AD000001, Dec. 15, 1996 nt.6775-7562 100% homology with Seq.ID:30 nt.9273-10295 100% homology with Seq.ID:32 7580-8311 100% homology with Seq.ID:34 XP002033473.
Database EMBL, Entry MTCY349, Accession No. Z83018, Nov. 26, 1996 nt.34695-35426 100% homology with SeqID:36 nt.33797-34624 100% homology with SeqID:38 XP002033474.
Database EMBL, Entry MTAD9, Accession No. AD000009, Dec. 15, 1996 nt.15203-15934 100% homology with SeqID:36 nt.14306-15133 100% homology with SeqID:38 XP002033475.
Vaccine, vol. 12, No. 16, 1994, pp. 1537-1540, XP002026338 Lowrie D B et al: "Towards A DNA Vaccine Against Tuberculosis" see p. 1537-p. 1538.
Nature, vol. 351, No. 6326, Jun. 6, 1991, pp. 456-460, XP000605495 Stover C K et al: "New Use Of BCG For Recombinant Vaccines" see p. 456-p.457.

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