Pro- and anti-inflammatory mechanisms regulating the mammalian response to Borrelia burgdorferi.
burgdorferi stimulates a strong inflammatory response during infection of a mammalian
host. Toll-like receptors (TLRs), especially TLR2/1 heterodimers which recognize
bacterial lipopeptides, play the major role in the induction of the inflammatory
response to B. burgdorferi. Adaptors and co-receptors that mediate this process, as well
as the mechanisms by which these adapto... read morers and co-receptors function, are still being
discovered. Here we identify integrin α3β1 as a novel regulator for the
recognition of bacterial lipopeptides. We demonstrate that the induction of a specific
subset of cytokines is dependent upon integrin α3β1-mediated endocytosis of
the lipopeptides. In addition, we address an ongoing controversy regarding endosomal
recognition of bacterial lipopeptides by demonstrating that TLR2/1 signals from within
endosomal compartments as well as from the plasma membrane, and that downstream
responses may differ depending upon receptor localization. We propose that the
regulation of endosomal TLR2/1 signaling by integrin α3β1 serves as a
mechanism for modulating inflammatory responses. This inflammatory response is important
for the control and clearance of the infection, but if left unchecked, inflammation
damages the host tissue and causes the clinical manifestations of Lyme disease including
neuroborreliosis, carditis, or arthritis. To understand the mechanisms of immune
regulation employed by the host to control this inflammatory response, we focused
additional studies on adrenomedullin, a peptide produced in response to bacterial
stimuli that regulates inflammatory responses by modulating the expression of
inflammatory cytokines. Specifically, we investigated the effect of B. burgdorferi on
the expression of adrenomedullin in vitro and in vivo , as well as the ability of
adrenomedullin to dampen host inflammatory responses to the spirochete. Our results
suggest that B. burgdorferi increases the production of adrenomedullin, which in turn
negatively regulates the B. burgdorferi-stimulated inflammatory response. These data
identify a novel mechanism by which the host regulates the response to B.
Thesis (Ph.D.)--Tufts University, 2011.
Submitted to the Dept. of Immunology.
Advisors: Linden Hu, and Thereza Imanishi-Kari.
Committee: Stephen Bunnell, Joan Mecsas, and Lynda Stuart.
Keywords: Immunology, and Microbiology.read less