| Description |
Borrelia burgdorferi and Borrelia hermsii represent two vector-borne bacterial pathogens that are causative agents for Lyme disease and relapsing fever, respectively. Though related, these pathogens occupy distinct niches within a host upon infection and cause unique clinical symptoms and disease. B. burgdorferi resides predominantly within tissues during infection whereas B. hermsii is notably a blood-borne pathogen. The research described in this dissertation focuses on examining a role for the Toll-like receptor (TLR) signaling pathway, a major signaling pathway of the innate immune response, in host defense to B. burgdorferi and B. hermsii. In multiple infection models, TLR signaling has been shown to be involved in host defense and play an important role in the control of pathogen burden. TLR signaling is also central to inflammation during infection and can contribute to pathology associated with infection. To determine if Toll-like receptor signaling influences the host response during challenge with B. burgdorferi or B. hermsii, mice deficient in TLR2, involved in the host response to bacterial lipoproteins, or mice deficient in the common Toll-like receptor adaptor protein, MyD88, were infected. TLR2-deficient mice and, to a greater extent, MyD88-deficient mice exhibited a severe defect in the ability to control B. burgdorferi levels in multiple tissues during the course of infection. Elevated levels of B. burgdorferi were detected in multiple tissues as early as 2 weeks following infection and were consistently higher through 8 weeks of infection. The inability to control B. burgdorferi levels early during infection supports a crucial role for TLR signaling in the innate immune response against B. burgdorferi that was determined to be independent of the host antibody response. Similarly, MyD88-deficient and TLR2-deficient mice also revealed a role for TLR signaling in host defense to B. hermsii, as evidenced by increased levels of B. hermsii in the blood. Interestingly, the defect in control of B. hermsii in MyD88-deficient mice consisted of two factors, altered kinetics of IgM antibody production against B. hermsii lipoproteins and an additional defect in the innate response to the bacterium. |
