Differential induction of TGF-beta regulates proinflammatory cytokine production and determines the outcome of lethal and nonlethal Plasmodium yoelii infections.
Transforming growth factor-beta is an essential moderator of malaria-induced inflammation in mice. In this study, we show that the virulence of malaria infections is dependent upon the cellular source of TGF-beta and the timing of its production. C57BL/6 mice infected with a nonlethal (Py17X) strain of Plasmodium yoelii produce TGF-beta from 5 days postinfection; this correlates with resolution of parasitemia, down-regulation of TNF-alpha, and full recovery. In contrast, infection with the lethal strain Py17XL induces high levels of circulating TGF-beta within 24 h; this is associated with delayed and blunted IFN-gamma and TNF-alpha responses, failure to clear parasites, and 100% mortality. Neutralization of early TGF-beta in Py17XL infection leads to a compensatory increase in IL-10 production, while simultaneous neutralization of TGF-beta and IL-10R signaling leads to up-regulation of TNF-alpha and IFN-gamma, prolonged survival in all, and ultimate resolution of infection in 40% of Py17XL-infected animals. TGF-beta production can be induced in an Ag-specific manner from splenocytes of infected mice, and by cross-linking surface CTLA-4. CD25(+) and CD8(+) cells are the primary source of TGF-beta following Py17X stimulation of splenocytes, whereas Py17XL induces significant production of TGF-beta from adherent cells. In mice immunized against Py17XL, the early TGF-beta response is inhibited and is accompanied by significant up-regulation of IFN-gamma and TNF-alpha and rapid resolution of challenge infections.
Omer
Fakhreldin M
FM
Department of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, London, United Kingdom.
de Souza
J Brian
JB
Riley
Eleanor M
EM
D000818:Animals; D002448:Cell Adhesion / Q000276:immunology; D002478:Cells, Cultured; D016207:Cytokines / Q000096:biosynthesis*; D015536:Down-Regulation / Q000276:immunology; D018984:Epitopes, T-Lymphocyte / Q000096:biosynthesis; D007106:Immune Sera / Q000008:administration & dosage; D018836:Inflammation Mediators / Q000378:metabolism*; D007371:Interferon-gamma / Q000096:biosynthesis; D008288:Malaria / Q000276:immunology* / Q000401:mortality* / Q000469:parasitology / Q000517:prevention & control; D017780:Malaria Vaccines / Q000008:administration & dosage / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018512:Parasitemia / Q000276:immunology / Q000401:mortality / Q000469:parasitology; D010967:Plasmodium yoelii / Q000254:growth & development / Q000276:immunology* / Q000472:pathogenicity; D015375:Receptors, Interleukin-2 / Q000096:biosynthesis; D013154:Spleen / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000276:immunology / Q000502:physiology; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis; D015854:Up-Regulation / Q000276:immunology
D016207:Cytokines; D018984:Epitopes, T-Lymphocyte; D007106:Immune Sera; D018836:Inflammation Mediators; D017780:Malaria Vaccines; D015375:Receptors, Interleukin-2; D016212:Transforming Growth Factor beta; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma