title: MAPK phosphotase 5 deficiency contributes to protection against blood-stage Plasmodium yoelii 17XL infection in mice.
abstract: Cell-mediated immunity plays a crucial role in the development of host resistance to asexual blood-stage malaria infection. However, little is known of the regulatory factors involved in this process. In this study, we investigated the impact of MAPK phosphotase 5 (MKP5) on protective immunity against a lethal Plasmodium yoelii 17XL blood-stage infection using MKP5 knockout C57BL/6 mice. Compared with wild-type control mice, MKP5 knockout mice developed significantly lower parasite burdens with prolonged survival times. We found that this phenomenon correlated with a rapid and strong IFN-γ-dependent cellular immune response during the acute phase of infection. Inactivation of IFN-γ by the administration of a neutralizing Ab significantly reduced the protective effects in MKP5 knockout mice. By analyzing IFN-γ production in innate and adaptive lymphocyte subsets, we observed that MKP5 deficiency specifically enhanced the IFN-γ response mediated by CD4+ T cells, which was attributable to the increased stimulatory capacity of splenic CD11c+ dendritic cells. Furthermore, following vaccination with whole blood-stage soluble plasmodial Ag, MKP5 knockout mice acquired strongly enhanced Ag-specific immune responses and a higher level of protection against subsequent P. yoelii 17XL challenge. Finally, we found the enhanced response mediated by MKP5 deficiency resulted in a lethal consequence in mice when infected with nonlethal P. yoelii 17XNL. Thus, our data indicate that MKP5 is a potential regulator of immune resistance against Plasmodium infection in mice, and that an understanding of the role of MKP5 in manipulating anti-malaria immunity may provide valuable information on the development of better control strategies for human malaria.
authors.affiliation: Institute of Infectious Disease and Vaccine Development, Tongji University School of Medicine, Shanghai 200092, China;
authors.forename: Qianqian
authors.initials: Q
authors.lastname: Cheng
authors.forename: Qingfeng
authors.initials: Q
authors.lastname: Zhang
authors.forename: Xindong
authors.initials: X
authors.lastname: Xu
authors.forename: Lan
authors.initials: L
authors.lastname: Yin
authors.forename: Lin
authors.initials: L
authors.lastname: Sun
authors.forename: Xin
authors.initials: X
authors.lastname: Lin
authors.forename: Chen
authors.initials: C
authors.lastname: Dong
authors.forename: Weiqing
authors.initials: W
authors.lastname: Pan
mesh_terms: D000818:Animals; D000953:Antigens, Protozoan / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D016207:Cytokines / Q000097:blood / Q000378:metabolism; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism; D004195:Disease Models, Animal; D060467:Disease Resistance / Q000235:genetics / Q000276:immunology; D054637:Dual-Specificity Phosphatases / Q000172:deficiency* / Q000235:genetics; D007371:Interferon-gamma / Q000096:biosynthesis / Q000097:blood; D008018:Life Cycle Stages; D008288:Malaria / Q000235:genetics* / Q000276:immunology* / Q000378:metabolism / Q000401:mortality / Q000469:parasitology; D051379:Mice; D018345:Mice, Knockout; D010967:Plasmodium yoelii / Q000254:growth & development / Q000276:immunology*; D013154:Spleen / Q000276:immunology
chemical_list: D000953:Antigens, Protozoan; D016207:Cytokines; D007371:Interferon-gamma; C505617:Dusp10 protein, mouse; D054637:Dual-Specificity Phosphatases