Abstract
Macrophages (MØ) and mononuclear phagocytes are major targets of infection by dengue virus (DV), a mosquito-borne flavivirus that can cause haemorrhagic fever in humans. To our knowledge, we show for the first time that the MØ mannose receptor (MR) binds to all four serotypes of DV and specifically to the envelope glycoprotein. Glycan analysis, ELISA, and blot overlay assays demonstrate that MR binds via its carbohydrate recognition domains to mosquito and human cell–produced DV antigen. This binding is abrogated by deglycosylation of the DV envelope glycoprotein. Surface expression of recombinant MR on NIH3T3 cells confers DV binding. Furthermore, DV infection of primary human MØ can be blocked by anti-MR antibodies. MR is a prototypic marker of alternatively activated MØ, and pre-treatment of human monocytes or MØ with type 2 cytokines (IL-4 or IL-13) enhances their susceptibility to productive DV infection. Our findings indicate a new functional role for the MR in DV infection.
Highlights
Dengue is the most prevalent mosquito-borne viral disease worldwide and in the past 40 years has undergone a global resurgence such that almost half the world’s population are currently living at risk in dengue-endemic areas [1]
The vascular leakage associated with dengue haemorrhagic fever is believed to be immune mediated
Our work on the interaction of dengue virus (DV) with human macrophages has led to two major findings; first, we have identified that the macrophage mannose receptor is important for mediating the infection of human macrophages by DV, and second, that the type 2 cytokines IL-4 and IL-13 enhance macrophage susceptibility to DV infection
Summary
Dengue is the most prevalent mosquito-borne viral disease worldwide and in the past 40 years has undergone a global resurgence such that almost half the world’s population are currently living at risk in dengue-endemic areas [1]. DV pathogenesis is complex and multifactorial [2], and macrophages (MØ) are thought to play an important role in disease both as primary targets of viral infection and as a source of immunomodulatory cytokines. The four serotypes of DV (DV1-DV4) bind to a number of opsonic and non-opsonic receptors on cells of the mononuclear phagocyte lineage including DC-SIGN [3,4], glycosaminoglycans [5], and when in complex with specific antibody, Fc and complement receptors [6]. DCSIGN, a lectin with similar sugar specificity to that of the MR, can mediate DV attachment to dendritic cells [3,4]. Even though DV binding to DC-SIGN on these cells is important for attachment, DC-SIGN-mediated viral endocytosis is not required for DV entry [9]
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