Pathogenesis of Lyme neuroborreliosis: Borrelia burgdorferi lipoproteins induce both proliferation and apoptosis in rhesus monkey astrocytes.
Brain invasion by Borrelia burgdorferi, the agent of Lyme disease, results in an inflammatory and neurodegenerative disorder called neuroborreliosis. In humans, neuroborreliosis has been correlated with enhanced concentration of glial fibrillary acidic protein in the cerebrospinal fluid, a sign of astrogliosis. Rhesus monkeys infected by us with B. burgdorferi showed evidence of astrogliosis, namely astrocyte proliferation and apoptosis. We formulated the hypothesis that astrogliosis could be caused by spirochetal lipoproteins. We established primary cultures of rhesus monkey astrocytes and stimulated the cells with recombinant lipidated outer surface protein A (L-OspA), a model B. burgdorferi lipoprotein, and tripalmitoyl-S-glyceryl-Cys-Ser-Lys(4)-OH (Pam(3)Cys), a synthetic lipopeptide that mimics the structure of the lipoprotein lipid moiety. L-OspA elicited not only astrocyte proliferation but also apoptosis, two features observed during astrogliosis. Astrocytes produced both IL-6 and TNF-alpha in response to L-OspA and Pam(3)Cys. Proliferation induced by L-OspA was diminished in the presence of an excess of anti-IL-6 antibody, and apoptosis induced by this lipoprotein was completely suppressed with anti-TNF-alpha antibody. Hence, IL-6 contributes to, and TNF-alpha determines, astrocyte proliferation and apoptosis, respectively, as elicited by lipoproteins. Our results provide proof of the principle that spirochetal lipoproteins could be key virulence factors in Lyme neuroborreliosis, and that astrogliosis might contribute to neuroborreliosis pathogenesis.
Ramesh
Geeta
G
Division of Bacteriology and Parasitology, Tulane National Primate Research Center, Tulane University Health Sciences Center, Covington, LA 70433, USA.
Alvarez
Alida L
AL
Roberts
E Donald
ED
Dennis
Vida A
VA
Lasater
Barbara L
BL
Alvarez
Xavier
X
Philipp
Mario T
MT
D000818:Animals; D000954:Antigens, Surface / Q000378:metabolism*; D017209:Apoptosis / Q000502:physiology*; D001253:Astrocytes / Q000378:metabolism*; D001425:Bacterial Outer Membrane Proteins / Q000378:metabolism*; D001428:Bacterial Vaccines; D025065:Borrelia burgdorferi / Q000472:pathogenicity*; D002455:Cell Division / Q000502:physiology*; D008074:Lipoproteins; D020852:Lyme Neuroborreliosis / Q000209:etiology / Q000473:pathology; D008253:Macaca mulatta / Q000382:microbiology
D000954:Antigens, Surface; D001425:Bacterial Outer Membrane Proteins; D001428:Bacterial Vaccines; D008074:Lipoproteins; C072045:OspA protein