TY - JOUR
T1 - The glycosylphosphatidylinositol transamidase complex subunit PbGPI16 of Plasmodium berghei is important for inducing experimental cerebral malaria
AU - Liu, Qingyang
AU - Zhao, Yan
AU - Zheng, Li
AU - Zhu, Xiaotong
AU - Cui, Liwang
AU - Cao, Yaming
N1 - Funding Information:
This study was supported by grants from the National Natural Science Foundation of China (81429004) and the U.S. National Institutes of Health (R01AI099611 and R01AI104946). We declare that we have no competing interests.
Publisher Copyright:
© 2018 American Society for Microbiology.
PY - 2018/8/1
Y1 - 2018/8/1
N2 - In animal models of experimental cerebral malaria (ECM), the glycosylphosphatidylinositols (GPIs) and GPI anchors are the major factors that induce nuclear factor kappa B (NF-κB) activation and proinflammatory responses, which contribute to malaria pathogenesis. GPIs and GPI anchors are transported to the cell surface via a process called GPI transamidation, which involves the GPI transamidase (GPI-T) complex. In this study, we showed that GPI16, one of the GPI-T subunits, is highly conserved among Plasmodium species. Genetic knockout of pbgpi16 (Δpbgpi16) in the rodent malaria parasite Plasmodium berghei strain ANKA led to a significant reduction of the amounts of GPIs in the membranes of merozoites, as well as surface display of several GPI-anchored merozoite surface proteins. Compared with the wild-type parasites, pbgpi16 parasites in C57BL/6 mice caused much less NF-κB activation and elicited a substantially attenuated T helper type 1 response. As a result, Δpbgpi16 mutant-infected mice displayed much less severe brain pathology, and considerably fewer Δpbgpi16 mutant-infected mice died from ECM. This study corroborated the GPI toxin as a significant inducer of ECM and further suggested that vaccines against parasite GPIs may be a promising strategy to limit the severity of malaria.
AB - In animal models of experimental cerebral malaria (ECM), the glycosylphosphatidylinositols (GPIs) and GPI anchors are the major factors that induce nuclear factor kappa B (NF-κB) activation and proinflammatory responses, which contribute to malaria pathogenesis. GPIs and GPI anchors are transported to the cell surface via a process called GPI transamidation, which involves the GPI transamidase (GPI-T) complex. In this study, we showed that GPI16, one of the GPI-T subunits, is highly conserved among Plasmodium species. Genetic knockout of pbgpi16 (Δpbgpi16) in the rodent malaria parasite Plasmodium berghei strain ANKA led to a significant reduction of the amounts of GPIs in the membranes of merozoites, as well as surface display of several GPI-anchored merozoite surface proteins. Compared with the wild-type parasites, pbgpi16 parasites in C57BL/6 mice caused much less NF-κB activation and elicited a substantially attenuated T helper type 1 response. As a result, Δpbgpi16 mutant-infected mice displayed much less severe brain pathology, and considerably fewer Δpbgpi16 mutant-infected mice died from ECM. This study corroborated the GPI toxin as a significant inducer of ECM and further suggested that vaccines against parasite GPIs may be a promising strategy to limit the severity of malaria.
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U2 - 10.1128/IAI.00929-17
DO - 10.1128/IAI.00929-17
M3 - Article
C2 - 29784863
AN - SCOPUS:85054936658
SN - 0019-9567
VL - 86
JO - Infection and Immunity
JF - Infection and Immunity
IS - 8
M1 - e00929-17
ER -