Tick (Ixodes scapularis) vector saliva-induced Lyme disease...

Details Tick (Ixodes scapularis) vector saliva-induced Lyme disease... Tick (Ixodes scapularis) vector saliva-induced Lyme disease...

1997-01-29

2001-11-06

Navarro, Albert (Department: 1645)

Chemistry: molecular biology and microbiology

Measuring or testing process involving enzymes or...

Involving antigen-antibody binding, specific binding protein...

C435S007220, C435S007320, C435S007920, C435S034000, C435S041000, C436S506000

Reexamination Certificate

active

06312915

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates to the use of the saliva of a member of the family Ixodidae to induce the expression of proteins by
Borrelia burgdorferi
. Novel tick saliva-induced
B. burgdorferi
proteins can be used for the potential development of a vaccine against Lyme disease and for improved diagnostic kits for the detection of Lyme disease.
BACKGROUND OF THE INVENTION
Borrelia burgdorferi
, a spirochete, is the causative agent of Lyme disease. It is a vector borne pathogen, transmitted by ticks of the
Ixodes scapularis
and
Ixodes pacificus
complexes in the United States. Burgdorfer W.,
B. burgdorferi
: Its Relationships to Tick Vectors, In Staken (ed): Lyme Borreliosis, II, Zbl Bakt Supplement 18, Stuttgart-New York, Gustav Fischer, 8-13, 1989. Infection with
B. burgdorferi
is the most common tick-borne infectious disease in the United States. In endemic areas, between 30 and 90% of Ixodes ticks are infected with this organism.
The illness caused by
B. burgdorferi
is a multisystem infection that affects the skin, central nervous system, peripheral nerves, the heart and the joints, with nerve and joint involvement being the most common. Steere, A. C., S. E. Malawista, J. A. Hardin, S. Ruddy, W. Askenase, and W. A. Andiman, Erythema Chronicum Migrans and Lyme Arthritis: the Enlarging Spectrum, Ann Intern Med. 86:685-698, 1977a. The dissemination of spirochetes over time from the site of infection has been documented in a mouse model. Barthold, S. W., D. H. Persing, A. L. Armstrong, and R. A. Peeples, Kinetics of
B. burgdorferi
Dissemination and Evolution of Disease after Intradermal Inoculation of Mice, AM J. Pathol, 139:263-273, 1991. In these experiments it was shown that the spirochetes were multifocal in distribution with a predilection for collagenous connective tissue of joints, heart, arteries, nerves, muscles, skin and other tissues. In humans, nerve, joint and heart involvement is usually manifested when the disease reaches a chronic state. The pathogensis to a chronic state of nerve involvement, termed neuroborreliosis, is unclear, but may be due to a direct effect of the spirochetes at the site of infection, the host response to
B. burgdorferi
, or the host response to tissue antigens that may mimic those of
Borrelia burgdorferi
. Fikrig, E., R. Berland, M. Chen, S. Williams, L. H. Signal, and R. A. Flavell, Serological Response to
B. burgdorferi
Flagellin Demonstrates an Epitope Common to a Neuroblastoma Cell Line, Proc. Natl. Acad. Sci. 90:183-187, 1993. For example, spirochetes can be detected in the cerebrospinal fluid of patients with neuroborreliosis with a corresponding high level of antigen specific T-cells which suggests that a local immune response may be involved in the disease. However, the presence of spirochetes has yet to be demonstrated in biopsy specimens of affected nerve tissue suggesting that clinical manifestations may be due to some type of molecular mimicry. Indeed, it has been shown that antibodies reactive to a certain epitope of the
B. burgdorferi
flagellin molecule cross react with a neuroblastoma cell line. Fikrig, E., R. Berland, , M. Chen, S. Williams, L. H. Sigal , and R. A. Flavell, Serological Response to
B. burgdorferi
Flagellin Demonstrates an Epitope Common to a Neuroblastoma Cell Line, Proc. Natl. Acad. Sci. 90:183-187, 1993. Development of arthritic symptoms is similarly complex. Patients who develop arthritis usually show involvement of the knee joint with an increase of polymorphonuclear granulocytes in the synovial fluid. Steere, A. C., S. E. Malawista, and D. R. Snydman, Lyme Arthritis: An Epidemic of oligoarticular Arthritis in Children and Adults in Three Connecticut Communities, Arthritis Rheum. 20:7-17, 1977. It has been hypothesized that spirochetes trigger a local immune response with autoreactive features in the joint, symptoms which may continue after the organisms no larger are viable. Girouard, L., D. C. Laux, S. Jindal, and D. R. Nelson, Immune Recognition of Human Hsp60 by Lyme Disease Patient Sra, Microb. Pathog. 14:287-297, 1993; and Steere, A. C., J. Feld, and R. Winchester, Association of Chronic Lyme Arthritis with Increased Frequencies of DR4 and 3, Arthritis Rheum. 31:98 (Abstract), 1988. As with nerve biopsies, culturing of spirochetes from synovial fluid of the joints is exceedingly difficult, being reported only twice, and direct observation is also rare. These phenomena are especially true as the disease progresses. Recent advances in the ability to detect small amounts of DNA using polymerase chain reaction (PCR) has led to conflicting results regarding the presence of spirochetes in the joint. Nocton, J. J., F. Dressler, B. J. Rutledge, P. N. Rys, D. H. Persing, and A. C. Steere, Detection of
B. burgdorferi
DNA by Polymerase Chain Reaction in Synovial Fluid in Lyme Arthritis, N. Engl. J. Med. (In press); and Malawista, S. E., T. L. Moore, D. E. Dodge, T. J. White, R. T. Schoen, and D. H. Persing, Failure of Multitarget Detection of
Borrelia burgdorferi
-Associated DNA Sequences in Synovial Fluids of Patients with Juvenile Rheumatoid Arthritis: A Cautionary Note, Arthritis Rheum. 35:246-247, 1992. Thus, as with neuroborreliosis, there appear to be two possibilities: septic arthritis with live organisms in the joint, and reactive arthritis where a microbial antigen at a remote site stimulates an immune response involving either antibodies or cytotoxic mononuclear cells that cross-react with a compartment of host tissue.
The humoral response to
B. burgdorferi
has been well documented. There is a potent response to the 41 kDa flagellar protein early during the course of infection followed by an antibody response to various other proteins, notably Hsp60, Hsp70, a 66 kDa protein and other lower molecular weight proteins. Chronic infection generally results in development of an antibody response to the outer surface lipoproteins A and B (OspA and OspB). Barbour, A. G., W. Burgdorfer, E. Grunwaldt, and A. C. Steere, Antibodies of Patient with Lyme Disease to Components of the Ixodes Dammini Spirochete, J. Clin. Invest. 72:504-510, 1983. These and other outer surface proteins have been given a great deal of attention because of their potential as vaccine candidates and because of their possible virulence functions. Antibodies against OspA have been shown to be protective against Lyme disease—mice immunized with recombinant OspA are resistant to infection with
Borrelia burgdorferi
. Fikrig, E., S. W. Barthold, F. S. Kantor, and R. A. Flavell, Protection of Mice Against the Lyme Disease Agent by Immunization with Recombinant OspA, Science. 250:553-556, 1990, and sera containing antibodies against OspA has been shown to exhibit borreliacidal activity independent of complement. Callister, S. M., R. F. Schell, K. L. Case, S. D. Lovrich, and S. P. Day, Characterization of the Borreliacidal Antibody Response to
B. burgdorferi
in Humans: A Serodiagnostic Test, J. Infect. Dis. 167:158-164, 1992. Similarly, a bactericidal antibody directed against OspB has also been reported. Sadziene, A., M. Jonsson, S. Bergstrom, R. K. Bright, R. C. Kennedy, and A. G. Barbour, A Bactericidal Antibody to
B. burgdorferi
is Directed Against a Variable Region of the OspB Protein, Infect. Immun. 62:2037-2045, 1994.
Despite the appearance of a humoral immune response to OspA and OspB during the course of infection and the proven effectiveness of antibodies against these proteins in killing
B. burgdorferi
and preventing infection, disease symptoms generally do not resolve without treatment. Vaccination of mice after infection with
B. burgdorferi
has been shown to partially clear spirochetes from the bloodstream and also to reduce the severity of disease symptoms, however, it did not eliminate them from other tissues, nor did it alter the course of joint and heart involvement. Fikrig, E., S. W. Barthold, and R. A. Flavell, OspA Vaccination of Mice with Established
B. burgdorferi
Infection Alters Disease but not Infection, Infect. Immun. 61:2553-2557, 1993. This implies that
B.

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