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Effective resolution of malaria infection by avoiding pathogenesis requires regulated pro- to anti-inflammatory responses and the development of protective immunity. TLRs are known to be critical for initiating innate immune responses, but their roles in the regulation of immune responses and development of protective immunity to malaria remain poorly understood. In this study, using wild-type, TLR2(-/-), TLR4(-/-), TLR9(-/-), and MyD88(-/-) mice infected with Plasmodium yoelii, we show that TLR9 and MyD88 regulate pro/anti-inflammatory cytokines, Th1/Th2 development, and cellular and humoral responses. Dendritic cells from TLR9(-/-) and MyD88(-/-) mice produced significantly lower levels of proinflammatory cytokines and higher levels of anti-inflammatory cytokines than dendritic cells from wild-type mice. NK and CD8(+) T cells from TLR9(-/-) and MyD88(-/-) mice showed markedly impaired cytotoxic activity. Furthermore, mice deficient in TLR9 and MyD88 showed higher Th2-type and lower Th1-type IgGs. Consequently, TLR9(-/-) and MyD88(-/-) mice exhibited compromised ability to control parasitemia and were susceptible to death. Our data also show that TLR9 and MyD88 distinctively regulate immune responses to malaria infection. TLR9(-/-) but not MyD88(-/-) mice produced significant levels of both pro- and anti-inflammatory cytokines, including IL-1β and IL-18, by other TLRs/inflammasome- and/or IL-1R/IL-18R-mediated signaling. Thus, whereas MyD88(-/-) mice completely lacked cell-mediated immunity, TLR9(-/-) mice showed low levels of cell-mediated immunity and were slightly more resistant to malaria infection than MyD88(-/-) mice. Overall, our findings demonstrate that TLR9 and MyD88 play central roles in the immune regulation and development of protective immunity to malaria, and have implications in understanding immune responses to other pathogens.
Department of Biochemistry and Molecular Biology, Pennsylvania State University College of Medicine, Hershey, PA 17033.
This article was published in the following journal.
Name: Journal of immunology (Baltimore, Md. : 1950)
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Malaria caused by PLASMODIUM VIVAX. This form of malaria is less severe than MALARIA, FALCIPARUM, but there is a higher probability for relapses to occur. Febrile paroxysms often occur every other day.
Vaccines made from antigens arising from any of the four strains of Plasmodium which cause malaria in humans, or from P. berghei which causes malaria in rodents.
A biguanide compound which has little antimalarial activity until metabolized in the body to the active antimalarial agent cycloguanil. The usefulness of proguanil is limited by the rapid development of drug resistance by the malarial parasite. The hydrochloride is used for the casual prophylaxis of falciparum malaria, to suppress other forms of malaria, and to reduce transmission of infection (From Martindale, The Extra Pharmacopoeia, 30th ed, p405)
A protozoan parasite that causes vivax malaria (MALARIA, VIVAX). This species is found almost everywhere malaria is endemic and is the only one that has a range extending into the temperate regions.
Malaria caused by PLASMODIUM FALCIPARUM. This is the severest form of malaria and is associated with the highest levels of parasites in the blood. This disease is characterized by irregularly recurring febrile paroxysms that in extreme cases occur with acute cerebral, renal, or gastrointestinal manifestations.
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