TY - JOUR
T1 - Murine cerebral malaria development is independent of toll-like receptor signaling
AU - Togbe, Dieudonnée
AU - Schofield, Louis
AU - Grau, Georges E.
AU - Schnyder, Bruno
AU - Boissay, Victorine
AU - Charron, Sabine
AU - Rose, Stéphanie
AU - Beutler, Bruce
AU - Quesniaux, Valérie F J
AU - Ryffel, Bernhard
N1 - Funding Information:
Supported by Le Studium (Orleans, France); the Medical Research Foundation (FRM), Orleans, France; the Biomedical Research Foundation SBF, Matzingen, Switzerland; the European FP6 MPCM (no. 037749) project, and the French Ministère de l'Education National de la Recherche et de la Technologie.
PY - 2007/5
Y1 - 2007/5
N2 - Malaria pigment hemozoin was reported to activate the innate immunity by Toll-like receptor (TLR)-9 engagement. However, the role of TLR activation for the development of cerebral malaria (CM), a lethal complication of malaria infection in humans, is unknown. Using Plasmodium berghei ANKA (PbA) infection in mice as a model of CM, we report here that TLR9-deficient mice are not protected from CM. To exclude the role of other members of the TLR family in PbA recognition, we infected mice deficient for single TLR1, -2,-3,-4,-6,-7, or -9 and their adapter proteins MyD88, TIRAP, and TRIF. In contrast to lymphotoxin α-deficient mice, which are resistant to CM, all TLR-deficient mice were as sensitive to fatal CM development as wild-type control mice and developed typical microvascular damage with vascular leak and hemorrhage in the brain and lung, together with comparable parasitemia, thrombocytopenia, neutrophilia, and lymphopenia. In conclusion, the present data do not exclude the possibility that malarial molecular motifs may activate the innate immune system. However, TLR-dependent activation of innate immunity is unlikely to contribute significantly to the proinflammatory response to PbA infection and the development of fatal CM.
AB - Malaria pigment hemozoin was reported to activate the innate immunity by Toll-like receptor (TLR)-9 engagement. However, the role of TLR activation for the development of cerebral malaria (CM), a lethal complication of malaria infection in humans, is unknown. Using Plasmodium berghei ANKA (PbA) infection in mice as a model of CM, we report here that TLR9-deficient mice are not protected from CM. To exclude the role of other members of the TLR family in PbA recognition, we infected mice deficient for single TLR1, -2,-3,-4,-6,-7, or -9 and their adapter proteins MyD88, TIRAP, and TRIF. In contrast to lymphotoxin α-deficient mice, which are resistant to CM, all TLR-deficient mice were as sensitive to fatal CM development as wild-type control mice and developed typical microvascular damage with vascular leak and hemorrhage in the brain and lung, together with comparable parasitemia, thrombocytopenia, neutrophilia, and lymphopenia. In conclusion, the present data do not exclude the possibility that malarial molecular motifs may activate the innate immune system. However, TLR-dependent activation of innate immunity is unlikely to contribute significantly to the proinflammatory response to PbA infection and the development of fatal CM.
UR - http://www.scopus.com/inward/record.url?scp=34250866255&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=34250866255&partnerID=8YFLogxK
U2 - 10.2353/ajpath.2007.060889
DO - 10.2353/ajpath.2007.060889
M3 - Article
C2 - 17456769
AN - SCOPUS:34250866255
SN - 0002-9440
VL - 170
SP - 1640
EP - 1648
JO - American Journal of Pathology
JF - American Journal of Pathology
IS - 5
ER -