RESUMO
BACKGROUND: Dengue Virus (DENV) is the most common mosquito-borne viral infection worldwide. Important target cells during DENV infection are macrophages, monocytes, and immature dendritic cells (imDCs). DENV-infected cells are known to secrete a large number of partially immature and fully immature particles alongside mature virions. Fully immature DENV particles are considered non-infectious, but antibodies have been shown to rescue their infectious properties. This suggests that immature DENV particles only contribute to the viral load observed in patients with a heterologous DENV re-infection. METHODOLOGY/PRINCIPAL FINDINGS: In this study, we re-evaluated the infectious properties of fully immature particles in absence and presence of anti-DENV human serum. We show that immature DENV is infectious in cells expressing DC-SIGN. Furthermore, we demonstrate that immature dendritic cells, in contrast to macrophage-like cells, do not support antibody-dependent enhancement of immature DENV. CONCLUSIONS/SIGNIFICANCE: Our data shows that immature DENV can infect imDCs through interaction with DC-SIGN, suggesting that immature and partially immature DENV particles may contribute to dengue pathogenesis during primary infection. Furthermore, since antibodies do not further stimulate DENV infectivity on imDCs we propose that macrophages/monocytes rather than imDCs contribute to the increased viral load observed during severe heterotypic DENV re-infections.
Assuntos
Moléculas de Adesão Celular/metabolismo , Células Dendríticas/virologia , Vírus da Dengue/patogenicidade , Lectinas Tipo C/metabolismo , Receptores de Superfície Celular/metabolismo , Células Cultivadas , Humanos , Ligação Proteica , VirulênciaRESUMO
Pattern recognition receptors are the main sensors of the innate immune response. Their function is to recognize pathogen-associated molecular patterns, which are molecules essential for the survival of microbial pathogens, but are not produced by the host. The recognition of pathogen-associated molecular patterns by pattern recognition receptors leads to the expression of cytokines, chemokines, and co-stimulatory molecules that eliminate pathogens, such as viruses, for the activation of antigen presenting cells and for the activation of specific adaptive immunity. Among the most thoroughly studied pattern recognition receptors implicated in viral infections, there are the toll-like receptors (TLRs) and the RNA helicase-type retinoic acid-inducible gene-1 receptors [or RIG-like receptors (RLRs)]. Moreover, other proteins such as PKR, 2-5 OAS, and ADAR also act as effector proteins in antiviral responses. The identification and characterization of pattern recognition receptors have contributed to our knowledge of the role of innate immunity in viral infections and has led us to better understand host-pathogen interactions. The most recent findings concerning the role of TLRs and RLRs in viral infections, the molecular mechanisms of viral ligand recognition through pattern recognition receptors, and the activation of their signaling pathways are discussed in this review.
Los receptores de reconocimiento de patrones (PRR) son los principales sensores de la respuesta inmune innata. Su función es reconocer moléculas indispensables para la sobrevivencia de los patógenos, conocidas como patrones moleculares asociados a patógenos (PAMP). El reconocimiento de los PAMP por los PRR conlleva a la expresión de citoquinas, quimioquinas, y moléculas coestimuladoras implicadas en la eliminación de patógenos como virus, en la activación de células presentadoras de antígenos y en la inducción de una inmunidad adaptativa específica. Entre los PRR mejor descritos y con implicaciones en infecciones virales se encuentran los receptores tipo toll (TLR) y receptores tipo RNA helicasas inducibles por ácido retinoico (RLR); además las proteínas efectoras PKR, 2´-5´ OAS y ADAR también participan activamente en la respuesta antiviral. La descripción y caracterización de los PRR ha contribuido enormemente al entendimiento del papel de la respuesta inmune innata en las infecciones virales y han sido usados para comprender mejor las interacciones hospedero-patógenos. Se discuten en la presente revisión los más recientes conocimientos de los TLR y RLR, el mecanismo de reconocimiento de los virus vía PRRs y las vías de señalización activadas por dicho reconocimiento.