Desvendando o papel do receptor CCR5 em modelo experimental de dengue em camundongos

Abstract

Dengue is an important human arbovirosis, a public health problem faced by 2.5 billion people. Infection is characterized by a systemic inflammatory response and hematological alterations that may evolve with shock and death in severe cases. Recent clinical and experimental data have shown an association between components of the chemokine network and severity of Dengue, and previous data from our group indicates that CC chemokine receptor 5 deficient mice (CCR5-/-), are markedly protected against dengue virus disease, leading to the investigation of the role of CCR5 receptor in a mice model of dengue. Wild-type (WT) and CCR5-/- mice were inoculated with 10 LD50 for lethality assays and evaluation of disease signs. CCR5-/- mice are resistant to infection by different DENV serotypes, and resistance can be conferred to WT mice by treatment with CCR5 antagonists before infection, but not after. Infection of primary macrophages cultures from WT and CCR5-/- mice with DENV-2 reveal that CCR5 is not involved in viral entry in macrophages, but deficiency in CCR5 delays DENV replication in these cells. The viral replication delay observed in the in vitro assays, responsible for a 10-fold decrease in viral load in CCR5-/- macrophages, was also observed in vivo by the reduced viral load in CCR5-/- mice tissues at early phases of infection. Analysis of the inflammatory parameters showed that WT mice present a discrete disease at day 5 post-infection (p.i.), which becomes severe and lead to shock and death at day 7 p.i. CCR5-/- never present disease, besides being infected with DENV. The immune response generated by CCR5-/- mice can eliminate DENV from host without causing tissue damage. Together, these data indicate that the CCR5 receptor is a host factor required for proper DENV replication in macrophages. CCR5 receptor participates in disease pathogenesis and impacts infection outcome. Investigation of the mechanisms underlying the requirement of the CCR5 receptor by DENV, as well as how such effective immune response is generated in CCR5-/- mice, could lead to the development of preventive and therapeutic approaches for dengue treatment.