Chemistry: molecular biology and microbiology – Micro-organism – tissue cell culture or enzyme using process... – Recombinant dna technique included in method of making a...
Patent
1996-04-10
1999-11-09
Priebe, Scott D.
Chemistry: molecular biology and microbiology
Micro-organism, tissue cell culture or enzyme using process...
Recombinant dna technique included in method of making a...
4352523, 43525411, 4353201, 435 691, 536 231, 536 237, C12N 1531, C12N 1574, C12N 1570, C12N 1581, C07H 2104
Patent
active
059812290
DESCRIPTION:
BRIEF SUMMARY
FIELD OF THE INVENTION
The present invention relates to the identification of bacterial exported proteins, and the genes encoding such proteins. The invention also relates to acellular vaccines to provide protection from bacterial infection using such proteins, and to antibodies against such proteins for use in diagnosis and passive immune therapy.
BACKGROUND OF THE INVENTION
Exported proteins in bacteria participate in many diverse and essential cell functions such as motility, signal transduction, macromolecular transport and assembly, and the acquisition of essential nutrients. For pathogenic bacteria, many exported proteins are virulence determinants that function as adhesins to colonize and thus infect the host or as toxins to protect the bacteria against the host's immune system (for a review, see Hoepelman and Tuomanen, 1992, Infect. Immun. 60:1729-33).
Since the development of the smallpox vaccine by Jenner in the 18th century, vaccination has been an important armament in the arsenal against infectious microorganisms. Prior to the introduction of antibiotics, vaccination was the major hope for protecting populations against viral or bacterial infection. With the advent of antibiotics in the early 20th century, vaccination against bacterial infections became much less important. However, the recent insurgence of antibiotic-resistant strains of infectious bacteria has resulted in the reestablishment of the importance of anti-bacterial vaccines.
One possibility for an anti-bacterial vaccine is the use of killed or attenuated bacteria. However, there are several disadvantages of whole bacterial vaccines, including the possibility of a reversion of killed or attenuated bacteria to virulence due to incomplete killing or attenuation and the inclusion of toxic components as contaminants.
Another vaccine alternative is to immunize with the bacterial carbohydrate capsule. Presently, vaccines against Streptococcus pneumoniae employ conjugates composed of the capsules of the 23 most common serotypes of this bacterium, these vaccines are ineffective in individuals most susceptible to pathological infection--the young, the old, and the immune compromised--because of its inability to elicit a T cell immune response. A recent study has shown that this vaccine is only 50% protective for these individuals (Shapiro et al., 1991, N. Engl. J. Med. 325:1453-60).
An alternative to whole bacterial vaccines are acellular vaccines or subunit vaccines in which the antigen includes a bacterial surface protein. These vaccines could potentially overcome the deficiencies of whole bacterial or capsule-based vaccines. Moreover, given the importance of exported proteins to bacterial virulence, these proteins are an important target for therapeutic intervention. Of particular importance are proteins that represent a common antigen of all strains of a particular species of bacteria for use in a vaccine that would protect against all strains of the bacteria. However, to date only a small number of exported proteins of Gram positive bacteria have been identified, and none of these represent a common antigen for a particular species of bacteria.
A strategy for the genetic analysis of exported proteins in E. coli was suggested following the description of translational fusions to a truncated gene for alkaline phosphatase (phoA) that lacked a functional signal sequence (Hoffman and Wright, 1985, Proc. Natl. Acad. Sci. U.S.A. 82:5107-5111). In this study, enzyme activity was readily detected in strains that had gene fusions between the coding regions of heterologous signal sequences and phoA indicating that translocation across the cytoplasmic membrane was required for enzyme activity. Subsequently, a modified transposon, TnphoA, was constructed to facilitate the rapid screening for translational gene fusions (Manoil and Beckwith, 1985, Proc. Natl. Acad. Sci. U.S.A. 82:8129-8133). This powerful tool has been modified and used in many Gram negative pathogens such as Escherichia coli (Guitierrez et al., 1987, J. Mol. Biol. 195:289-297),
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Masure H. Robert
Pearce Barbara J.
Tuomanen Elaine
Priebe Scott D.
The Rockefeller University
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