Genetic architecture of host response to tickborne disease in Peromyscus leucopus

点击翻译按钮获取中文摘要

PROJECT SUMMARY (Administrative supplement) For the administrative supplement a fourth specific aim is added to the project: Functional consequences of naturally-occurring genetic variants for responses of Peromyscus to Borreliella burgdorferi. The parent project principally entails forward genetics approaches to identify the traits and ultimately characterize the mechanisms for the white-footed deermouse's capacity to serve as a major reservoir for several zoonotic agents, including the cause of Lyme disease, while maintaining fitness in the presence of persistent infection. In the course of the project to date, we have made discoveries that justify a new line of investigation that takes a reverse genetics approach. The discoveries represent both innate and aquired immunity in Peromyscus immunity: (1) Structural variants in the Nos2 gene of P. leucopus populations that could account for an attenuated production of nitric oxide and reactive nitrogen species during infection. (2) Evidence in Peromyscus of an inactivated Fcgr1 gene that encodes the high-affinity IgG Fc receptor protein (FcγR1 or CD64) of macrophages and other phagocytes. (3) An association between a MHC class II gene and the antibody response to the OspA protein of Borreliella burgdorferi. The new aim comprises four sub- aims: (A) host response phenotypes of variants of the Nos2 gene and its 3’-UTR in P. leucopus, (B) functional effects of mutant Fcgr1 of Peromyscus, (C) variation of MHC II genes and antibodies to OspA after immunization, and (D) high-throughput discovery and annotation of structural variants segregating in the colony. The new research supported by this administrative supplement is anticipated to have both basic research and translational research and application impacts. The findings may also guide clinical research on persisting illness in patients with Lyme disease and other tickborne infections.