Brugia malayi asparaginyl-transfer RNA synthetase induces chemotaxis of human leukocytes and activates G-protein-coupled receptors CXCR1 and CXCR2.
Background. Lymphatic filariasis is a chronic human parasitic disease in which the parasites repeatedly provoke acute and chronic inflammatory reactions in the host bloodstream and lymphatics. Excretory-secretory products derived from filariae are believed to play an important role in the development of associated immunologic conditions; however, the specific mechanisms involved in these changes are not well understood. Recently, human cytoplasmic aminoacyl-transfer (t) RNA synthetases, which are autoantigens in idiopathic inflammatory myopathies, were shown to activate chemokine receptors on T lymphocytes, monocytes, and immature dendritic cells by recruiting immune cells that could induce innate and adaptive immune responses. Filarial (Brugia malayi) asparaginyl-tRNA synthetase (AsnRS) is known to be an immunodominant antigen that induces strong human immunoglobulin G3 responses.Methods. Recombinant B. malayi AsnRS was used to perform cellular function assays--for example, chemotaxis and kinase activation assays.Results. Unlike human AsnRS, parasite AsnRS is chemotactic for neutrophils and eosinophils. Recombinant B. malayi AsnRS but not recombinant human AsnRS induced chemotaxis of CXCR1 and CXCR2 single-receptor-transfected HEK-293 cell lines, blocked CXCL1-induced calcium flux, and induced mitogen-activated protein kinase.Conclusions. Our findings suggest that a filarial parasite chemoattractant protein may contribute to the development of chronic inflammatory disease and that chemokine receptors may be therapeutic targets to ameliorate parasite-induced pathology.
Department of Biochemistry and Molecular Biology, College of Medicine, University of the Philippines, Manila, the Philippines.
Bernadette L
BL
Ramirez
O M Zack
OM
Howard
Hui Fang
HF
Dong
Takeo
T
Edamatsu
Ping
P
Gao
Michael
M
Hartlein
Michael
M
Kron
D000818:Animals; D000909:Antibodies, Helminth / Q000378:metabolism; D001226:Aspartate-tRNA Ligase / Q000187:drug effects / Q000502:physiology*; D017178:Brugia malayi / Q000201:enzymology* / Q000472:pathogenicity; D002118:Calcium / Q000502:physiology; D002460:Cell Line; D002634:Chemotaxis, Leukocyte / Q000502:physiology*; D005368:Filariasis / Q000469:parasitology / Q000503:physiopathology*; D019204:GTP-Binding Proteins / Q000378:metabolism; D006801:Humans; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D009504:Neutrophils / Q000502:physiology; D037342:Pertussis Toxin / Q000494:pharmacology; D017434:Protein Structure, Tertiary / Q000502:physiology; D012346:RNA, Transfer, Amino Acyl / Q000187:drug effects / Q000502:physiology*; D023062:Receptors, Interleukin-8A / Q000378:metabolism*; D023063:Receptors, Interleukin-8B / Q000378:metabolism*; D011994:Recombinant Proteins
D000909:Antibodies, Helminth; D012346:RNA, Transfer, Amino Acyl; D023062:Receptors, Interleukin-8A; D023063:Receptors, Interleukin-8B; D011994:Recombinant Proteins; D037342:Pertussis Toxin; D020929:Mitogen-Activated Protein Kinase Kinases; D019204:GTP-Binding Proteins; D001226:Aspartate-tRNA Ligase; C029194:asparaginyl-tRNA synthetase; D002118:Calcium