Human Lyme disease symptoms are inexplicably ephemeral, with spontaneous resolution and episodic recurrences during the course of persistent infection with Borrelia burgdorferi. The investigators have developed a mouse model for human Lyme disease in which mice develop heart and joint disease that undergo spontaneous resolution and episodic recurrence during the course of persistent infection. Immune serum from infected mice, when passively transferred, will protect naive mice against challenge inoculation, as well as selectively induce arthritis resolution in mice with ongoing infection. Compartmentalization of activity to serum facilitates the search for B. burgdorferi antigens responsible for eliciting host immune responses involved in arthritis resolution. They will screen a genomic expression library with immune serum, as well as with monoclonal antibodies generated from infected mice. Monoclonal antibodies will be tested for arthritis-resolving activity in an infant mouse bioassay, and arthritis-resolving monoclonals will be used to directly incriminate the responsible antigen in the expression library. Clones with genes of interest will be sequenced and expressed as recombinant proteins and antisera to recombinant proteins generated. They will then modify the course of infection and arthritis in infected, immunodeficient mice by passive immunization with specific antisera; in infected, immunocompetent mice by active immunization with specific proteins; and in infected, transgenic mice that are immunologically tolerant to the proteins of interest. These studies will be based on the N40 strain of B. burgdorferi. They will then evaluate the specificity of arthritis-resolving antigens/antibodies by examining the effects of antisera against specific proteins of interest in mice infected with homologous or heterologous strains of B. burgdorferi. They will examine the specificity of arthritis-resolving immunity among selected B. burgdorferi sensu stricto, B. afzelii, and B. garinii isolates that are cloned and mouse-adapted. They will also examine the specificity of arthritis-resolving immunity among different B. burgdorferi sensu stricto isolates, selecting members of branches of the B. burgdorferi dendrogram. These studies, for the first time, will investigate antigens involved in disease expression and persistent infection. They offer the potential for development of a therapeutic vaccine for Lyme disease and development of a model for chronic arthritis.
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