RESUMO
A recent (2007 to 2009) dengue outbreak caused by dengue virus (DENV) in Paraguay presented unusual severe clinical outcomes associated with 50% mortality rates. Although it has been reported that inflammatory responses influence the severity of dengue virus infection (T. Pang, M. J. Cardosa, and M. G. Guzman, Immunol. Cell Biol. 85:43-45, 2007), there remains a paucity of information on virus-innate immunity interactions influencing clinical outcome. Using human dendritic cells from a major innate immune cell population as an in vitro model, we have investigated signature cytokine responses as well as infectivity-replicative profiles of DENV clinical isolates from either a nonfatal case of classical dengue fever (strain DENV3/290; isolated in Brazil in 2002) or a fatal case of dengue fever with visceral complications isolated in Paraguay in 2007 (strain DENV3/5532). Strain DENV3/5532 was found to display significantly higher replicative ability than DENV3/290 in monocyte-derived dendritic cells (mdDCs). In addition, compared to DENV3/290 results, mdDCs exposed to DENV3/5532 showed increased production of proinflammatory cytokines associated with higher rates of programmed cell death, as shown by annexin V staining. The observed phenotype was due to viral replication, and tumor necrosis factor alpha (TNF-α) appears to exert a protective effect on virus-induced mdDC apoptosis. These results suggest that the DENV3/5532 strain isolated from the fatal case replicates within human dendritic cells, modulating cell survival and synthesis of inflammatory mediators.
Assuntos
Apoptose , Citocinas/metabolismo , Células Dendríticas/imunologia , Células Dendríticas/virologia , Vírus da Dengue/patogenicidade , Dengue/virologia , Brasil , Vírus da Dengue/isolamento & purificação , Humanos , Dados de Sequência Molecular , Paraguai , RNA Viral/genética , Análise de Sequência de DNA , Replicação ViralRESUMO
Dengue virus (DENV) infection can cause a self-limiting disease (dengue fever) or a more severe clinical presentation known as dengue hemorrhagic fever (DHF)/dengue shock syndrome (DSS). Furthermore, data from recent dengue epidemics in Brazil indicate that the neurological manifestations are becoming more prevalent. However, the neuropathogenesis of dengue are not well understood. The balance between viral replication efficiency and innate immunity--in opposition during the early stages of infection--determines the clinical outcome of DENV infection. In this study, we investigated the effects of DENV infection on the transcription profile of the central nervous system (CNS) of mice. We observed in infected mice the up-regulation of 151 genes possibly involved in neuropathogenesis of dengue. Conversely, they may have a protective effect. Ingenuity Systems software analysis demonstrated, that the main pathways modulated by DENV infection in the mouse CNS are involved in interferon signaling and antigen presentation.
Assuntos
Sistema Nervoso Central/efeitos dos fármacos , Vírus da Dengue/imunologia , Dengue/patologia , Perfilação da Expressão Gênica , Interferons/farmacologia , Animais , Sistema Nervoso Central/virologia , Dengue/imunologia , Vírus da Dengue/patogenicidade , Camundongos , Software , Transcrição GênicaRESUMO
Recent observations indicate that the clinical profile of dengue virus (DENV) infection is changing, and that neurological manifestations are becoming frequent. The neuro pathogenesis of dengue, and the contribution of viral and host factors to the disease are not well understood. To define the amino acid substitutions in DENV potentially implicated in the acquisition of a neurovirulent phenotype we used a murine model to characterize two neuroadapted strains of DENV-1, FGA/NA a5c (previously obtained), and FGA/NA P6 (recently obtained). Only three amino acid substitutions were identified in the neurovirulent strains, mapping to the E and NS3 helicase domains. These mutations enhanced the ability of neuroadapted viral strains to replicate in the CNS of infected mice, causing extensive damage with leptomeningitis and encephalitis.