Contribution of macrophage migration inhibitory factor to the pathogenesis of dengue virus infection

被引:98
作者
Assuncao-Miranda, Iranaia [2 ,3 ]
Amaral, Flavio A. [4 ]
Bozza, Fernando A. [5 ]
Fagundes, Caio T. [4 ]
Sousa, Lirlandia P.
Souza, Danielle G. [4 ]
Pacheco, Patricia [6 ]
Barbosa-Lima, Giselle [6 ]
Gomes, Rachel N. [6 ]
Bozza, Patricia T. [6 ]
Da Poian, Andrea T. [2 ]
Teixeira, Mauro M. [1 ]
Bozza, Marcelo T. [3 ]
机构
[1] Univ Fed Minas Gerais, Inst Ciencias Biol, Dept Bioquim & Imunol, BR-31270901 Belo Horizonte, MG, Brazil
[2] Univ Fed Rio de Janeiro, Programa Biol Estrutural, Inst Bioquim Med, Rio De Janeiro, Brazil
[3] Univ Fed Rio de Janeiro, Inst Microbiol, Dept Imunol, BR-21941 Rio De Janeiro, Brazil
[4] Univ Fed Minas Gerais, Dept Microbiol, BR-31270901 Belo Horizonte, MG, Brazil
[5] Fundacao Oswaldo Cruz, Inst Oswaldo Cruz, Inst Pesquisa Clin Evandro Chagas, Intens Care Unit, Rio De Janeiro, Brazil
[6] Fundacao Oswaldo Cruz, Inst Oswaldo Cruz, Lab Imunofarmacol, Rio De Janeiro, Brazil
关键词
MIF; cytokine; lipid droplets; inflammation; hemorrhagic fever; sepsis; FACTOR MIF; HEMORRHAGIC-FEVER; JAPANESE ENCEPHALITIS; CHEMOKINE RECEPTORS; DISEASE SEVERITY; INNATE IMMUNITY; REGULATORY ROLE; SHOCK-SYNDROME; SEPTIC SHOCK; SERUM-LEVELS;
D O I
10.1096/fj.09-139469
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Dengue fever is an emerging viral disease transmitted by arthropods to humans in tropical countries. Dengue hemorrhagic fever (DHF) is escalating in frequency and mortality rates. Here we studied the involvement of macrophage migration inhibitory factor (MIF) in dengue virus (DENV) infection and its pathogenesis. Patients with DHF had elevated plasma concentrations of MIF. Both leukocytes from these patients and macrophages from healthy donors infected in vitro with DENV showed a substantial amount of MIF within lipid droplets. The secretion of MIF by macrophages and hepatocytes required a productive infection and occurred without an increase in gene transcription or cell death, thus indicating active secretion from preformed stocks. In vivo infection of wildtype and mif-deficient (Mif(-/-)) mice demonstrated a role of MIF in dengue pathogenesis. Clinical disease was less severe in Mif(-/-) mice, and they exhibited a significant delay in lethality, lower viremia, and lower viral load in the spleen than wild-type mice. This reduction in all parameters of severity on DENV infection in Mif(-/-) mice correlated with reduced proinflammatory cytokine concentrations. These results demonstrated the contribution of MIF to the pathogenesis of dengue and pointed to a possible beneficial role of neutralizing MIF as an adjunctive therapeutic approach to treat the severe forms of the disease.-Assuncao-Miranda, I., Amaral, F. A., Bozza, F. A., Fagundes, C. T., Sousa, L. P., Souza, D. G., Pacheco, P., Barbosa-Lima, G., Gomes, R. N., Bozza, P. T., Da Poian, A. T., Teixeira, M. M., Bozza, M. T. Contribution of macrophage migration inhibitory factor to the pathogenesis of dengue virus infection. FASEB J. 24, 218-228 (2010). www.fasebj.org
引用
收藏
页码:218 / 228
页数:11
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