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
2000-06-16
2003-10-14
Duffy, Patricia A. (Department: 1645)
Chemistry: molecular biology and microbiology
Micro-organism, tissue cell culture or enzyme using process...
Recombinant dna technique included in method of making a...
C435S070100, C435S071100, C435S189000, C435S252300, C435S254110, C435S320100, C435S325000, C435S440000, C536S023200, C536S024320
Reexamination Certificate
active
06632636
ABSTRACT:
FIELD OF INVENTION
The present invention discloses nucleotide sequences from the genome of
Moraxella catarrhalis
. These sequences may be used in various assays and in the development of diagnostic and therapeutic agents.
BACKGROUND OF INVENTION
All animals coexist with an indigenous microflora. Beginning shortly after birth, the gastrointestinal tract, lungs, and other areas of the human body are colonized by different bacterial species. A large number of factors operate to maintain symbiotic, host-microbe balance. These include the physical barriers of skin and mucosal surfaces and both nonspecific and highly specific aspects of the immune system. When host-microbe balance becomes disturbed, infection may ensue. Virulence, the ability of a microbe to produce infection, is related to a variety of complex mechanisms of disease induction. Some organisms are highly virulent and cause clinical illness when they colonize most or all hosts. Alternatively, when host defenses are compromised, normally symbiotic microbes can induce serious, or even life-threatening, infections. Thus, infection is generally a consequence of the interaction between a relatively virulent microbe and a normal host or between a relatively less virulent microbe and a host with some degree of transient or permanent immunological impairment.
M. catarrhalis (Branhamella catarrhalis
) is a large, aerobic, gram-negative diplococcus normally found among the bacterial flora of human upper airways. It is nonmotile and possesses fimbriae. Collonies are regularly friable and nonadherent and grow well on blood or chocolate agar. Unlike many other pathogenic bacteria,
M. catarrhalis
shows a high degree of homogeneity in its outer membrane proteins. This usually harmless parasite of the mucous membranes may behave as an opportunistic pathogen when microbe-host balance is perturbed. Following infection, host antibodies directed against one or more of the microbial outer-membrane proteins are detectable-in the serum.
M. catarrhalis
is known to cause acute, localized infections such as otitis media, sinusitis, and bronchopulmonary infection and life-threatening, systemic diseases including endocarditis and meningitis. The presence of bacterial endotoxin and host histamine and chemotactic factors are major indicators of
M. catarrhalis
pathogenicity.
M. catarrhalis
can be isolated from the upper respiratory tract of 50% of healthy school children and 7% of healthy adults. In children with otitis media, colonization increases to 86%, and it is the third most common bacterial isolate. It causes 10-15% of otitis media and sinusitis. Infections of the maxillary sinuses, middle ears, or bronchi may occur through contiguous spread of the microbes.
M. catarrhalis
causes a large proportion of lower respiratory tract infections in elderly patients with chronic obstructive pulmonary diseases and is exceeded only by
Haemophilus influenzae
and
Streptococcus pneumoniae
as a causative agent of acute purulent exacerbations of chronic bronchitis.
Pneumonia due to
M. catarrhalis
, like that of
H. influenzae
or
S. pneumoniae
, begins with aspiration of the bacteria. Failure or absence of appropriate host defense allows the bacteria to replicate and produce an inflammatory response in the alveoli. Because of mandatory immunosuppression, organ transplant recipients can develop moderate to severe
M. catarrhalis
pneumonia very rapidly. Bloodstream invasion is less characteristic of
M. catarrhalis
than pneumococcal infection, but nearly 50% of
M. catarrhalis
pneumonia patients die within 3 months of onset.
M. catarrhalis
is treated with antibiotic agents including penicillin-clavulanic acid combinations, cephalosporins, tetracycline, erythromycin, chloramphenicol, trimethoprim-sulfamethoxazole, and quinolones. Over 85% of
M. catarrhalis
clinical isolates have been reported to be resistant to penicillin. Moreover, the microbe protects itself by binding to the first subcomponent of the complement system (Clq) which inactivates the C1 complex or by inactivating the terminal, lytic complement complex via a protein on the outer cell wall surface. Resistance is mediated by two closely related &bgr;-lactamases, BRO-1, present in 90% of resistant isolates and BRO-2, present in 10%. These enzymes are active against penicillin, ampicillin, and amoxicillin, less active against cephalosporins, and bind avidly to clavulanic acid and sublactam. Tetracycline resistant strains are increasing in Europe and Asia and have been documented in the United States. Ampicillin, which had been universally effective in treating
M. catarrhalis
pneumonia, can no longer be used.
M. catarrhalis
physiology and pathogenicity are reviewed in: Holt et al. (1994)
Bergey's Manual of Determinative Bacteriology
, Williams and Wilkins, Baltimore Md.; Cullmann (1997) Med Klin 92(3):162-166; Isselbacher et al. (1994)
Harrison's Principles of Internal Medicine
, McGraw-Hill, New York N.Y.; Murray (1995)
Manual of Clinical Microbiology
, ASM Press, Washington D.C.; and Shulman et al. (1997)
The Biologic and Clinical Basis of Infectious Diseases
, W B Saunders, Philadelphia Pa.
In view of the conditions or diseases associated with
M. catarrhalis
, it would be advantageous to provide specific methods for the diagnosis, prevention, and treatment of diseases attributed to
M. catarrhalis
. Relevant methods would be based on the expression of
M. catarrhalis
-derived nucleic acid sequences. Such traits as virulence, acquisition of resistance factors, and effects of treatment using particular therapeutic agents may be characterized by under- or over-expression of nucleic acid sequences as revealed using PCR, hybridization or microarray technologies. Treatment for diseases attributed to
M. catarrhalis
can then be based on expression of these identified sequences or their expressed proteins, and efficacy of any particular therapy and development of resistance monitored. The information provided herein provides the basis for understanding the pathogenicity of
M. catarrhalis
and treating and monitoring the treatment of diseases caused by
M. catarrhalis.
SUMMARY OF THE INVENTION
The present invention relates to a genomic library comprising the combination of nucleic acid molecules from
Moraxella catarrhalis
, presented as SEQ ID NOs: 1-41. The library substantially provides the nucleic acid molecules comprising the genome of
M. catarrhalis
, and the nucleic acid molecules provide a plurality of open reading frames (ORFs). The ORFs uniquely identify structural, functional, and regulatory genes of
M. catarrhalis
. The invention encompasses oligonucleotides, fragments, and derivatives of the
M. catarrhalis
nucleic acid molecules, and sequences complementary to the nucleic acid molecules listed in the Sequence Listing.
M. catarrhalis
nucleic acid molecules, fragments, derivatives, oligonucleotides, and complementary sequences thereof, can be used as probes to detect, amplify, or quantify
M. catarrhalis
genes, ORFs, cDNAs, or RNAs in biological, solution or substrate-based, assays or as compositions in diagnostic kits. The invention contemplates the use of such diagnostic probes to identify the presence of
M. catarrhalis
sequence in a sample or to screen for virulence factors and mutations.
The invention also provides for the comparison of the
M. catarrhalis
genomic library or the encoded proteins with genomes, individual DNA sequences, or proteins from other
Moraxella
species or strains, other bacteria, and other organisms to identify virulence factors, regulatory elements, drug targets, and to characterize genomic organization. In another aspect, the present invention provides for the use of computer databases to make such comparisons.
The invention further provides host cells and expression vectors comprising nucleic acid molecules of the invention and methods for the production of the proteins they encode. Such methods include culturing the host cells under conditions for expression of
M. catarrhalis
protein and recovering the protein fr
Berg Kim L.
Lagace Robert E.
Patterson Chandra
Duffy Patricia A.
Elitra Pharmaceuticals Inc.
Knobbe Martens Olson & Bear LLP
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