Exploring the Collaborative Cross resource to identify different phenotypes of Lyme neuroborreliosis and disease-contributing genetic factors

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PROJECT SUMMARY Lyme disease (LD), the most prevalent tick-borne illness in the US (~300,000-475,000 annual cases), is caused by spirochetes of Borreliella burgdorferi (Bb) sensu lato (s.l.) complex. When early LD diagnosis is missed, it is left untreated and LD becomes chronic. Human vaccine is unavailable. Antimicrobial treatment of chronic/persistent infection is often unrewarding. LD may last for years, presenting itself as skin lesions, arthritis, carditis, and/or Lyme neuroborreliosis (LNB). Both central (CNS) and peripheral nervous systems (PNS) are affected, which results in headache, fatigue, memory loss, depression, facial nerve palsy among others. The main reason for incomplete understanding of LNB is the limited availability of adequate animal models. Nonhuman primates are the only model that demonstrates similarities to clinical manifestations of human LNB. However, issues of cost, reagents availability, non-reproducible genetic backgrounds, and ethical concerns limit their use. Laboratory mouse strains do not develop neurological clinical signs and encephalitis. The current knowledge gap is the lack of suitable mouse models of LNB. The overall objective is to develop mouse model that will be permissive to Bb entry into the CNS/PNS, develop inflammatory lesions in the neural tissues, and exhibit neurological signs. In the preliminary 3-year-long study, the Collaborative Cross (CC) resource (32 lines; ~230 mice) was extensively used to identify the mouse model of LNB. The data showed that over 30% of mice of CC line E, which were infected with Bb for 6 months, including the mouse that exhibited neurological signs upon Bb infection, developed significant inflammatory lesions in the brain, spinal cord, and peripheral nerves. In this application, it is proposed to test 4 different Bb strains using the 9 lines that have already shown Bb infection-induced inflammation in the neural tissues. It is also proposed to include new 8 CC lines that have not been tested, so that a total of 40 CC lines (32+8) will be used to identify genetic factors contributing to LNB via quantitative trait locus anlaysis. The following Specific Aims will be pursued: SA1: Determine if CC lines infected with various strains of Bb s.l. will produce distinct LNB phenotypes. SA2: Localize genetic factors contributing to LNB. This approach is innovative s the CC resource has never been utilized in the LD research field. Identifying a single CC line that consistently shows the presence of inflammation and/or spirochetes in the neural tissues will be considered a substantial advance in the field of LNB. The mapping resolution is expected to identify causal regions with confidence, and the number, effect sizes, and relationship among QTL identified will help guide subsequent investigations and provide the foundation for a future R01 application. The proposed research is significant because a mouse model of LNB will allow the scientific community to study the LNB pathogenesis in much greater detail and and provide the foundation for a R01 applications.