TY - JOUR
T1 - TLR9 and MyD88 are crucial for the development of protective immunity to malaria
AU - Gowda, Nagaraj M.
AU - Wu, Xianzhu
AU - Gowda, D. Channe
PY - 2012/5/15
Y1 - 2012/5/15
N2 - 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.
AB - 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.
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U2 - 10.4049/jimmunol.1102143
DO - 10.4049/jimmunol.1102143
M3 - Article
C2 - 22516959
AN - SCOPUS:84861159419
SN - 0022-1767
VL - 188
SP - 5073
EP - 5085
JO - Journal of Immunology
JF - Journal of Immunology
IS - 10
ER -