Locally up-regulated lymphotoxin alpha, not systemic tumor necrosis factor alpha, is the principle mediator of murine cerebral malaria.
Cerebral malaria (CM) causes death in children and nonimmune adults. TNF-alpha has been thought to play a key role in the development of CM. In contrast, the role of the related cyto-kine lymphotoxin alpha (LTalpha) in CM has been overlooked. Here we show that LTalpha, not TNFalpha, is the principal mediator of murine CM. Mice deficient in TNFalpha (B6.TNFalpha-/-) were as susceptible to CM caused by Plasmodium berghei (ANKA) as C57BL/6 mice, and died 6 to 8 d after infection after developing neurological signs of CM, associated with perivascular brain hemorrhage. Significantly, the development of CM in B6.TNFalpha-/- mice was not associated with increased intracellular adhesion molecule (ICAM)-1 expression on cerebral vasculature and the intraluminal accumulation of complement receptor 3 (CR3)-positive leukocytes was moderate. In contrast, mice deficient in LTalpha (B6.LTalpha-/-) were completely resistant to CM and died 11 to 14 d after infection with severe anemia and hyperparasitemia. No difference in blood parasite burden was found between C57BL/6, B6.TNFalpha-/-, and B6.LTalpha-/- mice at the onset of CM symptoms in the two susceptible strains. In addition, studies in bone marrow (BM) chimeric mice showed the persistence of cerebral LTalpha mRNA after irradiation and engraftment of LTalpha-deficient BM, indicating that LTalpha originated from a radiation-resistant cell population.
Engwerda
Christian R
CR
Department of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, London WC1E 7HT, United Kingdom. christian.engwerda@lshtm.ac.uk
Mynott
Tracey L
TL
Sawhney
Sanjeet
S
De Souza
J Brian
JB
Bickle
Quentin D
QD
Kaye
Paul M
PM
D000818:Animals; D016026:Bone Marrow Transplantation; D001921:Brain / Q000098:blood supply / Q000469:parasitology / Q000473:pathology; D017353:Gene Deletion; D007150:Immunohistochemistry; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D007962:Leukocytes / Q000378:metabolism / Q000528:radiation effects; D008233:Lymphotoxin-alpha / Q000235:genetics / Q000378:metabolism*; D016177:Macrophage-1 Antigen / Q000378:metabolism; D016779:Malaria, Cerebral / Q000097:blood* / Q000378:metabolism* / Q000469:parasitology; D051379:Mice; D008810:Mice, Inbred C57BL; D010962:Plasmodium berghei / Q000502:physiology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011828:Radiation Chimera; D011836:Radiation Tolerance; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014409:Tumor Necrosis Factor-alpha / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation
D008233:Lymphotoxin-alpha; D016177:Macrophage-1 Antigen; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D018799:Intercellular Adhesion Molecule-1