Chemistry: molecular biology and microbiology – Micro-organism – tissue cell culture or enzyme using process... – Recombinant dna technique included in method of making a...
Reexamination Certificate
1997-10-30
2002-07-16
Ketter, James (Department: 1632)
Chemistry: molecular biology and microbiology
Micro-organism, tissue cell culture or enzyme using process...
Recombinant dna technique included in method of making a...
C435S252300, C435S320100, C435S325000, C536S023700
Reexamination Certificate
active
06420135
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to the field of molecular biology. In particular, it relates to, among other things, nucleotide sequences of
Streptococcus pneumoniae
, contigs, ORFs, fragments, probes, primers and related polynucleotides thereof, peptides and polypeptides encoded by the sequences, and uses of the polynucleotides and sequences thereof, such as in fermentation, polypeptide production, assays and pharmaceutical development, among others.
BACKGROUND OF THE INVENTION
Streptococcus pneumoniae
has been one of the most extensively studied microorganisms since its first isolation in 1881. It was the object of many investigations that led to important scientific discoveries. In 1928, Griffith observed that when heat-killed encapsulated pneumococci and live strains constitutively lacking any capsule were concomitantly injected into mice, the nonencapsulated could be converted into encapsulated pneumococci with the same capsular type as the heat-killed strain. Years later, the nature of this “transforming principle,” or carrier of genetic information, was shown to be DNA. (Avery, O. T., et al.,
J. Exp. Med
., 79:137-157 (1944)).
In spite of the vast number of publications on
S. pneumoniae
many questions about its virulence are still unanswered, and this pathogen remains a major causative agent of serious human disease, especially community-acquired pneumonia. (Johnston, R. B., et al.,
Rev. Infect. Dis
. 13(Suppl. 6):S509-517 (1991)). In addition, in developing countries, the pneumococcus is responsible for the death of a large number of children under the age of 5 years from pneumococcal pneumonia. The incidence of pneumococcal disease is highest in infants under 2 years of age and in people over 60 years of age. Pneumococci are the second most frequent cause (after
Haemophilus influenzae
type b) of bacterial meningitis and otitis media in children. With the recent introduction of conjugate vaccines for
H. influenzae
type b, pneumococcal meningitis is likely to become increasingly prominent.
S. pneumoniae
is the most important etiologic agent of community-acquired pneumonia in adults and is the second most common cause of bacterial meningitis behind
Neisseria meningitidis.
The antibiotic generally prescribed to treat
S. pneumoniae
is benzylpenicillin, although resistance to this and to other antibiotics is found occasionally. Pneumococcal resistance to penicillin results from mutations in its penicillin-binding proteins. In uncomplicated pneumococcal pneumonia caused by a sensitive strain, treatment with penicillin is usually successful unless started too late. Erythromycin or clindamycin can be used to treat pneumonia in patients hypersensitive to penicillin, but resistant strains to these drugs exist. Broad spectrum antibiotics (e.g., the tetracyclines) may also be effective, although tetracycline-resistant strains are not rare. In spite of the availability of antibiotics, the mortality of pneumococcal bacteremia in the last four decades has remained stable between 25 and 29%. (Gillespie, S. H., et al.,
J. Med. Microbiol
. 28:237-248 (1989).
S. pneumoniae
is carried in the upper respiratory tract by many healthy individuals. It has been suggested that attachment of pneumococci is mediated by a disaccharide receptor on fibronectin, present on human pharyngeal epithelial cells. (Anderson, B. J., et al.,
J. Immunol
. 142:2464-2468 (1989). The mechanisms by which pneumococci translocate from the nasopharynx to the lung, thereby causing pneumonia, or migrate to the blood, giving rise to bacteremia or septicemia, are poorly understood. (Johnston, R. B., et al.,
Rev. Infect. Dis
. 13(Suppl. 6):S509-517 (1991).
Various proteins have been suggested to be involved in the pathogenicity of
S. pneumoniae
, however, only a few of them have actually been confirmed as virulence factors. Pneumococci produce an IgA1 protease that might interfere with host defense at mucosal surfaces. (Kornfield, S. J., et al.,
Rev. Inf. Dis
. 3:521-534 (1981).
S. pneumoniae
also produces neuraminidase, an enzyme that may facilitate attachment to epithelial cells by cleaving sialic acid from the host glycolipids and gangliosides. Partially purified neuraminidase was observed to induce meningitis-like symptoms in mice; however, the reliability of this finding has been questioned because the neuraminidase preparations used were probably contaminated with cell wall products. Other pneumococcal proteins besides neuraminidase are involved in the adhesion of pneumococci to epithelial and endothelial cells. These pneumococcal proteins have as yet not been identified. Recently, Cundell et al., reported that peptide permeases can modulate pneumococcal adherence to epithelial and endothelial cells. It was, however, unclear whether these permeases function directly as adhesions or whether they enhance adherence by modulating the expression of pneumococcal adhesions. (DeVelasco, E. A., et al.,
Micro. Rev
. 59:591-603 (1995). A better understanding of the virulence factors determining its pathogenicity will need to be developed to cope with the devastating effects of pneumococcal disease in humans.
Ironically, despite the prominent role of
S. pneumoniae
in the discovery of DNA, little is known about the molecular genetics of the organism. The
S. pneumoniae
genome consists of one circular, covalently closed, double-stranded DNA and a collection of so-called variable accessory elements, such as prophages, plasmids, transposons and the like. Most physical characteristics and almost all of the genes of
S. pneumoniae
are unknown. Among the few that have been identified, most have not been physically mapped or characterized in detail. Only a few genes of this organism have been sequenced. (See, for instance current versions of GENBANK and other nucleic acid databases, and references that relate to the genome of
S. pneumoniae
such as those set out elsewhere herein.)
It is clear that the etiology of diseases mediated or exacerbated by
S. pneumoniae
, infection involves the programmed expression of
S. pneumoniae
genes, and that characterizing the genes and their patterns of expression would add dramatically to our understanding of the organism and its host interactions. Knowledge of
S. pneumoniae
genes and genomic organization would improve our understanding of disease etiology and lead to improved and new ways of preventing, ameliorating, arresting and reversing diseases. Moreover, characterized genes and genomic fragments of
S. pneumoniae
would provide reagents for, among other things, detecting, characterizing and controlling
S. pneumoniae
infections. There is a need to characterize the genome of
S. pneumoniae
and for polynucleotides of this organism.
SUMMARY OF THE INVENTION
The present invention is based on the sequencing of fragments of the
Streptococcus pneumoniae
genome. The primary nucleotide sequences which were generated are provided in SEQ ID NOS:1-391.
The present invention provides the nucleotide sequence of several hundred contigs of the
Streptococcus pneumoniae
genome, which are listed in tables below and set out in the Sequence Listing submitted herewith, and representative fragments thereof, in a form which can be readily used, analyzed, and interpreted by a skilled artisan. In one embodiment, the present invention is provided as contiguous strings of primary sequence information corresponding to the nucleotide sequences depicted in SEQ ID NOS:1-391.
The present invention further provides nucleotide sequences which are at least 95% identical to the nucleotide sequences of SEQ ID NOS:1-391.
The nucleotide sequence of SEQ ID NOS:1-391, a representative fragment thereof, or a nucleotide sequence which is at least 95% identical to the nucleotide sequence of SEQ ID NOS; 1-391 may be provided in a variety of mediums to facilitate its use. In one application of this embodiment, the sequences of the present invention are recorded on computer readable media. Such media includes, but is not limited to: magnetic storage media, such as floppy discs, ha
Barash Steven C.
Choi Gil H.
Dillon Patrick S.
Dougherty Brian A.
Fannon Michael R.
Human Genome Sciences Inc.
Human Genome Sciences Inc.
Ketter James
Schnizer Richard
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