The meninges are important mediators of immune cell trafficking in response to infection in the central nervous system (CNS). A recently identified tick-borne human pathogen, Borrelia miyamotoi, causes an acute febrile illness, and may have serious complications in immunocompromised patients. Specifically, these patients are deficient in B cells and develop meningoencephalitis upon infection with B. miyamotoi. Our long-term goal is to determine the physiological mechanisms that underlie the neuropathologies associated with severe Borrelia miyamotoi disease (BMD). Our central hypothesis is that B. miyamotoi colonization of the meninges routinely occurs only in the absence of B cells. We will address this hypothesis with 2 Specific Aims: 1) Determining the kinetics of B. miyamotoi dissemination into the meninges in the absence of B cells; and, 2) Identifying immune responses that contribute to pathogen control. In Aim 1 of this proposal we will determine a) the kinetics of meningeal infection; b) the effects of inoculation site variation; and c) the spatial and temporal colonization patterns of meningeal infection. In Aim 2, we will determine the role of T-dependent B cell responses; and changes in brain microglial activation in response to B. miyamotoi infection. Completion of these aims will define the kinetics of B. miyamotoi colonization of the meninges and will determine if B cell responses are indeed required for control of infection. Overall, this proposal is relevant to the mission of NIAID because a greater understanding of severe BMD will enable healthcare providers to target at-risk patients with information about alternative treatments for their conditions and preventative strategies to avoid BMD and other tick-borne diseases.