The innate immune response to Entamoeba histolytica lipopeptidophosphoglycan is mediated by toll-like receptors 2 and 4.
Entamoeba histolytica is a human pathogen that may invade the intestinal mucosa, causing amoebic colitis or hepatic abscesses when the trophozoites travel through the portal circulation to the liver. Lipopeptidophosphoglycan (LPPG) is a molecular pattern of E. histolytica recognized by the human immune system. Here we report that LPPG is exposed on the cell surface of E. histolytica trophozoites, and is recognized by the host through toll-like receptor (TLR) 2 and TLR4. Correspondingly, human embryonic kidney (HEK)-293 cells were rendered LPPG responsive through overexpression of TLR2 or TLR4/MD2. Moreover, co-expression of CD14 enhanced LPPG signal transmission through TLR2 and TLR4. The interaction of LPPG with TLR2 and TLR4 resulted in activation of NF-kappaB and release of interleukin (IL)-10, IL-12p40, tumour necrosis factor (TNF)-alpha, and IL-8 from human monocytes. Consistent with these findings, responsiveness of mouse macrophages lacking TLR2 expression (TLR2-/-) or functional TLR4 (TLR4d/d) to E. histolytica LPPG challenge was impaired while double deficient macrophages were unresponsive. In contrast to wild-type control and TLR2-/- animals succumbing to lethal shock syndrome, TLR4d/d mice were resistant to systemic LPPG challenge-induced pathology.
Maldonado-Bernal
C
C
Infectious Disease Medical Research Unit, Hospital de Pediatría, Centro Médico Nacional Siglo XXI, IMSS, Mexico City, México.
Kirschning
C J
CJ
Rosenstein
Y
Y
Rocha
L M
LM
Rios-Sarabia
N
N
Espinosa-Cantellano
M
M
Becker
I
I
Estrada
I
I
Salazar-González
R M
RM
López-Macías
C
C
Wagner
H
H
Sánchez
J
J
Isibasi
A
A
D000818:Animals; D000953:Antigens, Protozoan / Q000276:immunology*; D002460:Cell Line; D004748:Entamoeba histolytica / Q000276:immunology*; D005260:Female; D006801:Humans; D007113:Immunity, Innate; D016753:Interleukin-10 / Q000378:metabolism; D018664:Interleukin-12 / Q000378:metabolism; D053762:Interleukin-12 Subunit p40; D016209:Interleukin-8 / Q000378:metabolism; D008264:Macrophages / Q000276:immunology; D008562:Membrane Glycoproteins / Q000276:immunology*; D051379:Mice; D008809:Mice, Inbred C3H; D009000:Monocytes / Q000276:immunology; D016328:NF-kappa B / Q000378:metabolism; D010457:Peptidoglycan / Q000276:immunology*; D010743:Phospholipids / Q000276:immunology*; D021122:Protein Subunits / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000276:immunology*; D011971:Receptors, Immunologic / Q000276:immunology*; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D000953:Antigens, Protozoan; D053762:Interleukin-12 Subunit p40; D016209:Interleukin-8; D008562:Membrane Glycoproteins; D016328:NF-kappa B; D010457:Peptidoglycan; D010743:Phospholipids; D021122:Protein Subunits; D011956:Receptors, Cell Surface; D011971:Receptors, Immunologic; C495342:TLR2 protein, human; C495345:TLR4 protein, human; C493486:Tlr2 protein, mouse; C493487:Tlr4 protein, mouse; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors; D014409:Tumor Necrosis Factor-alpha; C014643:lipopeptidophosphoglycan; D016753:Interleukin-10; D018664:Interleukin-12