Immunomodulatory mechanisms of wild bird reservoir hosts that facilitate persistence of Lyme disease bacteria - Project Summary. Lyme disease (LD) is the most common vector-borne illness in the northern hemisphere, with an estimated 476,000 new cases annually in the US. No effective prevention is currently available. The disease is caused by infection with Borrelia burgdorferi (Bb) which is transmission by Ixodes ticks. After inoculation in the skin, Bb disseminates to different organs, presumably by evading host immune responses, including complement- and antibody-mediated killing. While Bb does not cause symptoms in reservoir hosts, such as Peromyscus mice (white footed mice) and wild birds, it persists in these animals and can thus be transmitted to humans by tick bite. Our overreaching goal is to identify the mechanisms that facilitate persistence of Bb in natural reservoir hosts, which can ultimately facilitate the understanding of bird-specific responses to carry avian-transmitted pathogens, informing the public health intervention against those pathogens. Our recent field findings demonstrate that wild birds frequently carry certain Bb ospC genotypes (e.g., ospC-E, -I, -N) which are rarely found in Peromyscus. In contrast, birds less often carry genotypes (e.g., ospC-K) which are common in Peromyscus. This is consistent with our laboratory findings in Peromyscus, or American robins as a model avian reservoir: ospC-E-infected robins transmitted Bb to fed larvae more efficiently than ospC-E-infected Peromyscus, whereas the opposite was true for ospC-K. These findings highlight the role of birds as a reservoir for Bb strains that are rarely carried by Peromyscus. In addition, they validate robins as a model of avian reservoir host which allows us to recapitulate the field findings in a controlled laboratory environment. Using this model, we found that during early infection, robins induced robust inflammatory (e.g., IFNγ, TNF) and antibody responses to less competent bird genotypes (ospC-K), but only minimal responses to bird-adapted genotypes (ospC-E). Interestingly, antibody responses to ospC-E or ospC-K were indistinguishable late in the infection. Additionally, ospC-E strain escaped robin complement-mediated killing more efficiently than ospC-K strain. Thus, these heightened immune responses were associated with Bb clearance, implying that modulation of early host immune responses may facilitate the persistence of certain Bb genotypes in birds. In this proposal we are testing the hypothesis that wild birds maintain certain Bb genotypes by modulating early immune responses in a strain-specific manner. We thus will 1) Ascertain the role of complement on survival and persistence of bird-adapted Bb strains in birds. 2) Determine the impact of delayed antibody response on survival of bird-adapted Bb strains in birds. 3) Investigate the role of immune tolerance on survival and persistence of bird-adapted Bb strains in birds. This study will define a new paradigm in pathogen maintenance in animal reservoir hosts, identifying the immune mechanisms that allow wild birds to serve as a unique reservoir of human-relevant Bb. Such knowledge will ultimately inform intervention for the transmission of Bb and other bird-transmitted pathogens and reducing human exposure to those pathogens.
