Structural and functional comparison of MIF ortholog from Plasmodium yoelii with MIF from its rodent host.
Host-derived macrophage migration inhibitory factor (MIF) has been implicated in the pathogenesis of malaria infection, especially in malarial anemia. Although two Plasmodium parasite-derived MIF orthologs, Plasmodium falciparum MIF and P. berghei MIF were identified recently, the crystal structure and the precise roles of Plasmodium-derived MIFs, particularly in combination with the host MIF, remain unknown. In this study, we identified another MIF ortholog from a rodent-specific P. yoelii (PyMIF). This molecule shares a conserved three-dimensional structure with murine MIF (MmMIF), but with a different substrate binding pattern and much lower tautomerase activity. It could activate host cells via several signaling pathways in vitro, and inhibiting macrophage apoptosis, also similarly to MmMIF. However, we found that PyMIF and MmMIF acted synergistically to activate the MAPK-ERK1/2 signaling pathway at very low concentration but acted antagonistically at higher concentration. Furthermore, we detected PyMIF in the sera of infected mice and found that injection of recombinant PyMIF (rPyMIF) during infection could up-regulate several pro-inflammatory cytokines in vivo and slightly delay the death of infected mice. These data suggest that PyMIF modulates host immune responses together with host MIF and has potential to prolong parasitemia or the chronicity of malaria infection.
Shao
Dingding
D
Department of Microbiology and Parasitology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and School of Basic Medicine, Peking Union Medical College, 5# Dong Dan 3 Tiao, Beijing 100005, China.
Zhong
Xiang
X
Zhou
Yan-Feng
YF
Han
Zhifu
Z
Lin
Yahui
Y
Wang
Zhensheng
Z
Bu
Lingyi
L
Zhang
Lianhui
L
Su
Xiao-Dong
XD
Wang
Heng
H
D000595:Amino Acid Sequence; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D018360:Crystallography, X-Ray; D004789:Enzyme Activation / Q000187:drug effects; D006790:Host-Parasite Interactions; D018836:Inflammation Mediators / Q000378:metabolism; D007275:Injections, Intravenous; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008262:Macrophage Activation / Q000187:drug effects; D008263:Macrophage Migration-Inhibitory Factors / Q000097:blood / Q000737:chemistry* / Q000235:genetics / Q000276:immunology*; D008264:Macrophages / Q000166:cytology / Q000187:drug effects / Q000201:enzymology; D008288:Malaria / Q000097:blood / Q000469:parasitology; D051379:Mice; D008969:Molecular Sequence Data; D010967:Plasmodium yoelii / Q000737:chemistry* / Q000187:drug effects / Q000276:immunology*; D017433:Protein Structure, Secondary; D011518:Proto-Oncogene Proteins / Q000235:genetics; D019253:Proto-Oncogene Proteins c-bcl-2; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D040681:Structural Homology, Protein; D015854:Up-Regulation / Q000187:drug effects
D018836:Inflammation Mediators; D008263:Macrophage Migration-Inhibitory Factors; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D011994:Recombinant Proteins; C052617:Bcl2 protein, mouse