Contribution of macrophage migration inhibitory factor to the pathogenesis of dengue virus infection.
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 wild-type 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.
Programa de Biologia Estrutural, Departamento de Imunologia, Instituto de Microbiologia, CCS Bloco I, Universidade Federal do Rio de Janeiro, Avenida Carlos Chagas Filho 373, Cidade Universitária, Rio de Janeiro/RJ, 21941-902 Brazil.
Iranaia
I
Assunção-Miranda
Flavio A
FA
Amaral
Fernando A
FA
Bozza
Caio T
CT
Fagundes
Lirlandia P
LP
Sousa
Danielle G
DG
Souza
Patrícia
P
Pacheco
Giselle
G
Barbosa-Lima
Rachel N
RN
Gomes
Patrícia T
PT
Bozza
Andrea T
AT
Da Poian
Mauro M
MM
Teixeira
Marcelo T
MT
Bozza
D000818:Animals; D001483:Base Sequence; D016207:Cytokines / Q000096:biosynthesis / Q000235:genetics; D017931:DNA Primers / Q000235:genetics; D003715:Dengue / Q000097:blood / Q000209:etiology* / Q000235:genetics / Q000503:physiopathology / Q000628:therapy; D003716:Dengue Virus / Q000472:pathogenicity; D004195:Disease Models, Animal; D015870:Gene Expression; D022781:Hepatocytes / Q000502:physiology / Q000821:virology; D054884:Host-Pathogen Interactions / Q000502:physiology; D006801:Humans; D066298:In Vitro Techniques; D018836:Inflammation Mediators / Q000378:metabolism; D019746:Intramolecular Oxidoreductases / Q000097:blood / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D007962:Leukocytes / Q000378:metabolism; D050356:Lipid Metabolism; D008263:Macrophage Migration-Inhibitory Factors / Q000097:blood / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D008264:Macrophages / Q000502:physiology / Q000821:virology; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D011446:Prospective Studies; D019595:Severe Dengue / Q000209:etiology / Q000235:genetics / Q000503:physiopathology
D016207:Cytokines; D017931:DNA Primers; D018836:Inflammation Mediators; D008263:Macrophage Migration-Inhibitory Factors; D019746:Intramolecular Oxidoreductases; C515598:MIF protein, human; C076231:Mif protein, mouse