Host specialization in microparasites transmitted by generalist vectors: insights into the cellular and immunological mechanisms

Host specialization is an ecological and evolutionary process by which a pathogen becomes differentially adapted to a subset of hosts, restricting its host range. For parasites transmitted by generalist vectors, host specialization is not expected to evolve because of the decreased survival of those parasites in inadequate hosts. Thus, parasites may develop adaptation strategies, resulting in host specialization. The causative agents of Lyme disease are multiple species of bacteria, Borrelia burgdorferi sensu lato species complex ( Bb sl), and are suitable for examining host specialization as birds and rodents were found to carry different species of these bacteria. Debate exists on whether host specialization occurs among these strains within a particular species of Bb sl, such as B. burgdorferi sensu stricto ( Bb ss). Current evidence supports some Bb ss strains are widespread in white-footed mice but others are in non-rodent vertebrates, such as birds. To recapitulate specialization in the laboratory and define the mechanisms for host specialization, we introduced different genotypes of Bb ss via tick transmission to American robins and white-footed mice, the Lyme disease reservoirs in North America. Among these strains, we found distinct levels of spirochete presence in the bloodstream and tissues and maintenance by these animals in a host-dependent fashion. We showed that the late stage persistence of these strains largely corresponds to bacterial survival at early infection onsets. We also demonstrated that those early survival phenotypes correspond to spirochete adhesiveness, evasion of complement-mediated killing in sera, and/or not triggering high levels of pro-inflammatory cytokines and antibodies. Our findings thus link host competence to Bb ss with spirochete genotypic variation of adhesiveness and inducing/escaping host immune responses, illuminating the potential mechanisms that dictate host specialization. Such information will provide a foundation for further investigation into multi-disciplinary processes driving host specialization of microparasites. AUTHOR SUMMARY Host specialization arises when microparasites adapt to a subset of available hosts, restricting the host ranges they can infect. The mechanisms and selective pressures for the evolution of host specialization remain unclear. The causative agent of Lyme disease (LD), the bacteria species complex of Borrelia burgdorferi sensu lato, is adapted to different vertebrates. However, whether such a differential host adaption also applies to each genotype within the same species is under debate. Further, the mechanisms that drive such host specialization are unclear. We thus introduced three genotypes of one LD bacteria species (B. burgdorferi sensu stricto) individually via tick bite to American robins and white-footed mice, the most common LD reservoirs in North America. We found that these genotypes differed in the persistent maintenance by those reservoirs and occurred in a host-specific fashion. The ability of those bacteria for long-term maintenance was linked with their capability to attach to cells and a lack of induction of high levels of immune responses at early infection onsets. This work demonstrates the potential mechanisms that dictate host specialization of LD bacteria circulating in natural populations. Such information will pave the road to define the molecular, ecological, and evolutionary determinants that drive host-microparasite interactions. ### Competing Interest Statement The authors have declared no competing interest.