Disordered lymphoid purine metabolism contributes to the pathogenesis of persistent Borrelia garinii infection in mice.
Extracellular ATP and adenosine are important regulators of immune responses; however, contribution of purinergic signaling to host defense during persistent microbial infections remains obscure. Lyme borreliosis is a common arthropod-borne infection caused by Borrelia burgdorferi sensu lato. In this study, we investigated whether lymphoid purinergic signaling contributes to the mechanisms by which borreliae species evade the immune system and trigger joint inflammation. Intracutaneous inoculation of Borrelia garinii to C3H/He mice induced symptomatic infection manifested in elevated levels of borrelia-specific IgG Abs, persistent spirochete dissemination into the tissues and joint swelling, as well as approximately 2- to 2.5-fold enlargement of draining lymph nodes with hyperplasia of B cell follicle area and L-selectin shedding from activated T lymphocytes. Purine catabolism was also activated in lymph nodes but not spleen and blood of infected C3H/He mice within the first 4 postinfection weeks, particularly manifested in transient upregulations of adenosine triphosphatase/ectonucleoside triphosphate diphosphohydrolase and ecto-5'-nucleotidase/CD73 on CD4(+)CD8(+) T lymphocytes and adenosine deaminase activity on B220(+) B lymphocytes. Compared with borrelia-susceptible C3H/He strain, lymphocytes from C57BL/6 mice displayed markedly enhanced adenosine-generating capability due to approximately three times higher ratio of ecto-5'-nucleotidase to adenosine deaminase. Borrelia-infected C57BL/6 mice efficiently eradicated the inoculated spirochetes at more chronic stage without any signs of arthritis. Strikingly, deletion of key adenosine-generating enzyme, ecto-5'-nucleotidase/CD73, was accompanied by significantly enhanced joint swelling in borrelia-infected CD73-deficient C57BL/6 mice. Collectively, these data suggest that insufficient basal adenosine level and/or pathogen-induced disordered lymphoid purine homeostasis may serve as important prerequisite for promotion of inflammatory responses and further host's commitment to persistence of bacterial infection and arthritis development.
Yegutkin
Gennady G
GG
MediCity Research Laboratory, University of Turku, Tykistökatu 6A, 20520 Turku, Finland. genyeg@utu.fi
Hytönen
Jukka
J
Samburski
Sergei S
SS
Yrjänäinen
Heta
H
Jalkanen
Sirpa
S
Viljanen
Matti K
MK
D000208:Acute Disease; D000243:Adenosine Deaminase / Q000096:biosynthesis; D000255:Adenosine Triphosphate / Q000378:metabolism*; D000818:Animals; D001170:Arthritis, Infectious / Q000201:enzymology / Q000276:immunology / Q000378:metabolism / Q000382:microbiology; D015748:Borrelia burgdorferi Group / Q000276:immunology*; D005110:Extracellular Space / Q000201:enzymology / Q000276:immunology / Q000382:microbiology; D005260:Female; D057131:Immune Evasion / Q000276:immunology; D008193:Lyme Disease / Q000201:enzymology / Q000276:immunology* / Q000378:metabolism*; D008198:Lymph Nodes / Q000201:enzymology / Q000276:immunology* / Q000378:metabolism* / Q000382:microbiology; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010761:Phosphorus Radioisotopes; D011755:Pyrophosphatases / Q000096:biosynthesis; D015398:Signal Transduction / Q000276:immunology; D015854:Up-Regulation / Q000276:immunology
D010761:Phosphorus Radioisotopes; D000255:Adenosine Triphosphate; D000243:Adenosine Deaminase; D011755:Pyrophosphatases; C092064:ectonucleotide pyrophosphohydrolase