Borrelia burgdorferi polypeptides and uses thereof

Details Borrelia burgdorferi polypeptides and uses thereof Borrelia burgdorferi polypeptides and uses thereof

2001-03-20

2004-02-10

Swartz, Rodney P (Department: 1645)

Drug, bio-affecting and body treating compositions

Antigen, epitope, or other immunospecific immunoeffector

Amino acid sequence disclosed in whole or in part; or...

C424S009100, C424S009200, C424S184100, C424S185100, C424S200100, C424S234100, C424S278100, C530S300000, C530S350000, C536S023100, C536S023700

Reexamination Certificate

active

06689364

ABSTRACT:

FIELD OF THE INVENTION
The present invention is directed to novel
Borrelia burgdorferi
polypeptides and uses thereof.
BACKGROUND OF THE INVENTION
Lyme borreliosis (Lyme disease) is the most common vector-borne infection in the United States [S. W. Barthold, et al., “An Animal Model For Lyme Arthritis”, Ann. N.Y. Acad. Sci., 539, pp. 264-73 (1988)]. It has been reported in every continent except Antarctica. The clinical hallmark of Lyme Disease is an early expanding skin lesion known as erythema migrans, which may be followed weeks to months later by neurologic, cardiac, and joint abnormalities.
The causative agent of Lyme disease is a spirochete known as
Borrelia burgdorferi
, transmitted primarily by Ixodes ticks of the
Ixodes ricinus
complex.
B. burgdorferi
has also been shown to be carried in other species of ticks and in mosquitoes and deer flies, but it appears that only ticks of the
I. ricinus
complex are able to transmit the disease to humans.
Lyme disease generally occurs in three stages. Stage one involves localized skin lesions (erythema migrans) from which the spirochete is cultured more readily than at any other time during infection [B. W. Berger et al., “Isolation And Characterization Of The Lyme Disease Spirochete From The Skin Of Patients With Erythema Chronicum Migrans”, J. Am. Acad. Dermatol., 3, pp. 444-49 (1985)]. Flu-like or meningitis-like symptoms are common at this time. Stage two occurs within days or weeks, and involves spread of the spirochete through the patient's blood or lymph to many different sites in the body including the brain and joints. Varied symptoms of this disseminated infection occur in the skin, nervous system, and musculoskeletal system, although they are typically intermittent. Stage three, or late infection, is defined as persistent infection, and can be severely disabling. Chronic arthritis, and syndromes of the central and peripheral nervous system appear during this stage, as a result of the ongoing infection and perhaps a resulting auto-immune disease [R. Martin et al., “Borrelia burgdorferi-Specific And Autoreactive T-Cell Lines From Cerebrospinal Fluid In Lyme Radiculomyelitis”, Ann Neurol., 24, pp. 509-16 (1988); D. Gross et al., “Identification of LFA-1 as a Candidate Autoantigen in Treatment-Resistant Lyme Arthritis”, Science 281, pp. 703-706 (1998)].
B. burgdorferi
is much easier to culture from the tick than from humans, therefore at present, Lyme disease is diagnosed primarily by serology. The enzyme-linked immunosorbent assay (ELISA) is one method of detection, using sonicated whole spirochetes as the antigen [J. E. Craft et al., “The Antibody Response In Lyme Disease: Evaluation Of Diagnostic Tests”, J. Infect. Dis., 149, pp. 789-95 (1984)]. However, false negative and, more commonly, false positive results are associated with currently available tests.
At present, all stages of Lyme disease are treated with antibiotics. Treatment of early disease is usually effective, however the cardiac, arthritic, and nervous system disorders associated with the later stages often do not respond to therapy [A. C. Steere, “Lyme Disease”, New Eng. J. Med., 321, pp. 586-96 (1989)].
Like
Treponema pallidum
, which causes syphilis, and leptospirae, which cause an infectious jaundice, Borrelia belong to the eubacterial phylum of spirochetes [A. G. Barbour and S. F. Hayes, “Biology of Borrelia Species”, Microbiol. Rev., 50, pp. 381-400 (1986)].
Borrelia burgdorferi
have a protoplasmic cylinder that is surrounded by a cell membrane, then by flagella, and then by an outer membrane.
The
B. burgdorferi
outer surface proteins identified to date are believed to be lipoproteins, as demonstrated by labeling with [
3
H]palmitate [M. E. Brandt et al., “Immunogenic Integral membrane Proteins of
Borrelia burgdorferi
Are Lipoproteins”, Infect. Immun., 58, pp. 983-91 (1990)]. The two major outer surface proteins are the 31 kd outer-surface protein A (OspA) and the 34 kd outer surface protein B (OspB). Both proteins have been shown to vary from different isolates or from different passages of the same isolate as determined by their molecular weights and reactivity with monoclonal antibodies. OspC is a 22 kDa membrane lipoprotein previously identified as pC [R. Fuchs et al., “Molecular Analysis and Expression of a Borrelia burgdorferi Gene Encoding a 22 kDa Protein (pC) in Escherichia coli”, Mol. Microbiol., 6, pp. 503-09 (1992)]. OspD is said to be preferentially expressed by low-passage, virulent strains of
B. burgdorferi
B31 [S. J. Norris et al., “Low-Passage-Associated Proteins of Borrelia burgdorferi B31: Characterization and Molecular Cloning of OspD, A Surfaced-Exposed, Plasmid-Encoded Lipoprotein”, Infect. Immun., 60, pp. 4662-4672 (1992)].
Additional
B. burgdorferi
proteins identified to date include the 41 kD flagellin protein, which is known to contain regions of homology with other bacterial flagellins [G. S. Gassman et al., “Analysis of the Borrelia burgdorferi GeHo fla Gene and Antigenic Characterization of Its Gene Product”, J. Bacteriol., 173, pp. 1452-59 (1991)] and a 93 kDa protein said to be localized to the periplasmic space [D. J. Volkman et al., “Characterization of an Immunoreactive 93 kDa Core Protein of Borrelia burgdorferi With a Human IgG Monoclonal Antibody”, J. Immun., 146, pp. 3177-82 (1991)].
Recently, immunization of mice with recombinant OspA has been shown to be effective to confer long-lasting protection against subsequent infection with
B. burgdorferi
[E. Fikrig et al., “Long-Term Protection of Mice from Lyme Disease by Vaccination with OspA”, Infec. Immun., 60, pp. 773-77 (1992)]. Protection by the OspA immunogens used to date appears to be somewhat strain specific, probably due to the heterogeneity of the OspA gene among different
B. burgdorferi
isolates. For example, immunization with OspA from
B. burgdorferi
strain N40 confers protection against subsequent infection with strains N40, B31 and CD 16, but not against strain 25015 [E. Fikrig et al., “Borrelia burgdorferi Strain 25015: Characterization of Outer Surface Protein A and Vaccination Against Infection”, J. Immun., 148, pp. 2256-60 (1992)].
An additional problem with OspA as a protective immunogen is cross-reactivity at the T cell level observed between OspA
165-173
and LFA-1&agr;. [D. Gross et al., “Identification of LFA-1 as a Candidate Autoantigen in Treatment-Resistant Lyme Arthritis”, Science 281, pp. 703-706 (1998)]. As described above, a prominent late manifestation of infection with
B. burgdorferi
is Lyme arthritis[A. C. Steere, et al.,
Ann. Int. Med
90: 896 (1979); A. C. Steere, et al.,
Ann. Int. Med
. 107: 725 (1987); A. C. Steere, et al.,
N. Eng. J. Med
. 321: 586 (1989); A. C. Steere, et al.,
N. Eng. J. Med
. 323: 219 (1990); A. C. Steere, et al.,
Arthritis Rheum
. 37: 878 (1994)]. About 10% of patients with Lyme arthritis develop a condition known as antibiotic-resistant Lyme arthritis, which typically affects one knee for months to years after multiple courses of antibiotics [A. C. Steere, et al.,
Ann. Int. Med
. 90: 896 (1979); A. C. Steere, et al.,
Ann. Int. Med
. 107: 725 (1987); A. C. Steere, et al.,
N. Eng. J. Med
. 321: 586 (1989); A. C. Steere, et al.,
Arthritis Rheum
. 37: 878 (1994)]. Such patients have no detectable spirochetal DNA in joint fluid after antibiotic therapy, which suggests that the spirochete has been eliminated by this treatment [J. F. Bradley, et al.,
Ann. Int. Med
. 120: 487 (1994); J. J. Nocton et al.,
N. Eng. J. Med
. 330: 229 (1994)]. The increased frequency of the HLA-DRB1*0401 allele in these patients suggests an autoimmune etiology [unpublished data] (Kalish et al., 1993 Infect Immun 61:2774-9).
Recent work has identified LFA-1&agr; as a candidate autoantigen in treatment-resistant Lyme arthritis [D. Gross et al., “Identification of LFA-1 as a Candidate Autoantigen in Treatme

Affiliated with

Also associated with

Rating

Borrelia burgdorferi polypeptides and uses thereof does not yet have a rating. At this time, there are no reviews or comments for this patent.

If you have personal experience with Borrelia burgdorferi polypeptides and uses thereof, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Borrelia burgdorferi polypeptides and uses thereof will most certainly appreciate the feedback.

Rate now

Comments { 0 }

Profile ID: LFUS-PAI-O-3349456