Bacterial and host factors in the pathogenesis of Lyme neuroborreliosis

The Lyme disease spirochete Borrelia burgdorferi causes an infection with diverse clinical outcomes, which can
include arthritis as well as cardiac and neurological involvement. Lyme neuroborreliosis can range from
headaches and mild meningitis to more serious manifestations including vasculitis. Despite antibiotic treatment,
a proportion of patients continue to suffer from debilitating symptoms including neurological effects. The
mechanisms of central nervous system (CNS) pathology as well as bacterial and host risk factors for these
manifestations are poorly understood, largely due to the lack of a tractable laboratory model for the study of
Lyme disease in the CNS.
Previously, we reported the ability of Bb to colonize the dura mater of mice during late disseminated infection
that was associated with an increase in T cells. We now show acute and persistent extravascular Bb colonization
of the dura mater after both needle inoculation and tick transmission, accompanied by increases in expression
of inflammatory cytokines; in addition, we observe a robust interferon (IFN) response in the dura mater
comparable to that seen during murine Lyme arthritis. Dura colonization is associated with perivascular leukocyte
infiltration and meningitis, demonstrating for the first time that Bb-infected mice can develop meningitis. We also
demonstrate an increase in IFN-stimulated genes in both the cortex and hippocampus of infected mice, despite
a lack of detectable spirochetes in the brain parenchyma. A sterile IFN response in the absence of Bb is
unique to the brain parenchyma and could provide insights into the mechanism of inflammatory CNS
pathology associated with this pathogen.
An unanswered question is how specific bacterial virulence factors, in concert with the host response, intersect
to cause CNS disease. Our tractable model will allow us to directly assess bacterial and host factors leading to
more severe inflammatory CNS involvement, as well as test potential interventions. Our innovative proposal
challenges existing paradigms, utilizes state-of-the-art technologies, and addresses critical barriers to Lyme
neuroborreliosis research. Our central hypothesis is that specific bacterial factors engage the host immune
response in a deleterious manner. We will address our central hypothesis with the following Specific Aims:
Characterize the role of Borrelia genetics on CNS bacterial burden and host response. Working
hypothesis: the severity of the CNS immune response during infection with Lyme disease Borrelia is dictated by
the genetics of the infecting isolate.
Delineate the role of immune signaling and other host responses in the CNS. Working hypothesis: IFN
signaling affects the local inflammatory and cellular activation responses in the CNS.
Modulate inflammation and pathology through targeted intervention. Working hypothesis: Decreasing
inflammation at early time points, regardless of spirochete burden, will reduce meningitis and deleterious immune
responses in the brain parenchyma.
Our proposal directly addresses the NIH Strategic Plan for Tickborne Disease Research, including understanding
both the fundamental biology of, and host interactions with, tickborne pathogens. Our proposal also addresses
outstanding questions identified by the Pathogenesis and Pathophysiology of Lyme Disease Subcommittee of
the HHS Tick Borne Disease Working Group, including what is the role of adhesins in dissemination to specific
tissues. Our robust small animal model will allow us to fully characterize the CNS immune response to Bb
infection, and to mechanistically define factors that contribute to neuroinflammation and disease. Identifying
these factors will elucidate pathways to target for therapeutic intervention. Importantly, the results of our work
will provide more sensitive and specific diagnostic criteria for Lyme neuroborreliosis and its sequalae.

Grant Number: 5R01AI158304-04
NIH Institute/Center: NIH
Principal Investigator: Catherine Brissette