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
1994-06-22
2001-10-09
Housel, James C. (Department: 1641)
Chemistry: molecular biology and microbiology
Micro-organism, tissue cell culture or enzyme using process...
Recombinant dna technique included in method of making a...
C424S234100, C530S402000, C530S825000
Reexamination Certificate
active
06300101
ABSTRACT:
BACKGROUND OF THE INVENTION
Lyme disease is a complex, multisystemic illness caused by at least three genomic species of the spirochete
Borrelia burgdorferi
sensu lato (reviewed in Barbour and Fish, 1993). Virtually all North American isolates have been classified as
B. burgdorferi
sensu stricto (Baranton et al., 1992; Boerlin et al., 1992; Welsh et al., 1992). European isolates also include two other genomic species,
B. garinii
and
B. afzelii
(Baranton et al., 1992; Canica et al., 1993). The clinical features and epidemiology of Lyme disease have been well characterized (reviewed review in Barbour and Fish, 1993). Comparatively less, however, is known about the pathogenic features of Lyme disease borrelias and immunopathological responses to them in the host.
Ignorance of precise mechanisms of Lyme disease pathogenesis is partly attributable to the paucity of basic information about all spirochetes. The spirochete cell is unique in several aspects (Holt, 1978). One of the features of borrelia is the abundance of one or several lipoproteins in the outer cell membrane (Bergstrom et al., 1989; Brandt et al., 1990; Brusca et al., 1991; Howe et al., 1985; Norris et al., 1992). Much has been learned about immunogenicity, as well as biochemical and genetic aspects, of these lipoproteins in Lyme disease and relapsing fever borrelias (Barbour, 1993; Bergstrom et al., 1989; Brandt et al., 1990; Johnson et al., 1992; Kitten and Barbour, 1990; Meier et al., 1985; Wilske et al., 1993).
The lipoproteins OspA and OspB are major contributors to antigenic distinctness of Lyme disease borrelias (Barbour and Fish, 1993). Both OspA and OspB are co-transcribed from a single operon located on linear plasmid of 49 kb in
B. burgdorferi
sensu stricto (Bergstrom et al., 1989). Many of European and some North American
B. burgdorferi
sensu lato strains express a third immunodominant major protein, OspC (Wilske et al., 1993). Another protein of this group, OspD, has been also reported (Norris et al., 1992). Proteins called “OspE” and “OspF” have been reported, but their surface exposure and location in the outer membrane have not been established (Lam et al., 1994).
OspA and OspB may contribute to the spirochete's ability to adhere to or invade host cells (Benach et al., 1988; Comstock et al., 1992; Thomas and Comstock, 1989). It has been suggested that OspA may affect the chemotactic response of human neutrophils in vitro (Benach et al., 1988). Mitogenic and cytokine-stimulatory properties of OspA and OspB have been also shown (Ma and Weis, 1993). It was found that reduced size and amounts of OspB was associated with lowered infectivity (Sadziene et al., 1993A). The findings of Cadavid et al. indicated that differences in invasive properties and tissues tropism between serotypes of related spirochete
Borrelia turicatae
, a relapsing fever agent, may be determined by the expression of a single surface protein that is analogous to Osp proteins of
B. burgdorferi
(Cadavid et al., 1994).
These studies of function of Osp proteins, however, are still limited in number. More information is needed regarding the function of these proteins, in particular their roles in infectivity and their contributions to the microorganism's ability to survive in the host. One approach to obtain these insights is selection and characterization of mutants with altered surface lipoproteins. There were several compelling reasons for studying
B. burgdorferi
cells that lacked all known Osp proteins (Sadziene et al., 1992, Sadziene et al., 1993B). First the morphology and function of the Osp-less mutant were characterized to determine whether borrelias lacking OspA, B, C, and D would be altered in such functional properties, as (i) generation time, (ii) ability to form colonies on solid medium, (iii) adherence to cells, (iv) serum and complement sensitivity, (v) potential to evoke immune response after intradermal live cell inoculation, and (vi) ability to survive in the skin. Among pathogenic borrelias the role of surface lipoproteins in these respects have not yet been reported.
Another intriguing aspect was the immunological characterization of the Osp-less mutant. There have been several studies describing low molecular weight lipoproteins that have not been identified as Osps. Katona et al. showed the presence of a major low-molecular-weight lipoprotein specific for
B. burgdorferi
and raised the possibility that it was a borrelial equivalent of Braun's lipoprotein (Katona et al., 1992). Another study reported an immunogenic 14 kDa surface protein of
B. burgdorferi
recognized by sera from Lyme disease patients (Sambri et al., 1991). These findings encouraged us to determine whether other proteins are present on the surface in the absence of Osp proteins.
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Barbour Alan G.
Sadziene Ariadna
Board of Regents , The University of Texas System
Frommer & Lawrence & Haug LLP
Housel James C.
Kowalski Thomas J.
Swartz Rodney P.
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