title: How antibodies alter the cell entry pathway of dengue virus particles in macrophages.
abstract: Antibody-dependent enhancement of dengue virus (DENV) infection plays an important role in the exacerbation of DENV-induced disease. To understand how antibodies influence the fate of DENV particles, we explored the cell entry pathway of DENV in the absence and presence of antibodies in macrophage-like P388D1 cells. Recent studies unraveled that both mature and immature DENV particles contribute to ADE, hence, both particles were studied. We observed that antibody-opsonized DENV enters P388D1 cells through a different pathway than non-opsonized DENV. Antibody-mediated DENV entry was dependent on FcγRs, pH, Eps15, dynamin, actin, PI3K, Rab5, and Rab7. In the absence of antibodies, DENV cell entry was FcγR, PI3K, and Rab5-independent. Live-cell imaging of fluorescently-labeled particles revealed that actin-mediated membrane protrusions facilitate virus uptake. In fact, actin protrusions were found to actively search and capture antibody-bound virus particles distantly located from the cell body, a phenomenon that is not observed in the absence of antibodies. Overall, similar results were seen for antibody-opsonized standard and antibody-bound immature DENV preparations, indicating that the maturation status of the virus does not control the entry pathway. Collectively, our findings suggest that antibodies alter the cell entry pathway of DENV and trigger a novel mechanism of initial virus-cell contact.
authors.affiliation: Dept. of Medical Microbiology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: Nilda V
authors.initials: NV
authors.lastname: Ayala-Nunez
authors.affiliation: Dept. of Medical Microbiology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: Tabitha E
authors.initials: TE
authors.lastname: Hoornweg
authors.affiliation: Dept. of Medical Microbiology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: Denise P I
authors.initials: DP
authors.lastname: van de Pol
authors.affiliation: Dept. of Cell Biology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: Klaas A
authors.initials: KA
authors.lastname: Sjollema
authors.affiliation: Dept. of Medical Microbiology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: Jacky
authors.initials: J
authors.lastname: Flipse
authors.affiliation: Dept. of Infectious Diseases &Immunology, Virology Division, Faculty of Veterinary Medicine, Utrecht University, Utrecht, The Netherlands.
authors.forename: Hilde M
authors.initials: HM
authors.lastname: van der Schaar
authors.affiliation: Dept. of Medical Microbiology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: Jolanda M
authors.initials: JM
authors.lastname: Smit
mesh_terms: D008841:Actin Cytoskeleton / Q000473:pathology; D000818:Animals; D000906:Antibodies / Q000502:physiology*; D019067:Antibody-Dependent Enhancement; D002460:Cell Line; D002462:Cell Membrane / Q000473:pathology / Q000821:virology; D009033:Culicidae; D003715:Dengue / Q000821:virology*; D003716:Dengue Virus / Q000502:physiology*; D004705:Endocytosis; D006801:Humans; D007700:Kinetics; D008264:Macrophages / Q000821:virology*; D051379:Mice; D017452:Receptors, IgG / Q000378:metabolism; D053586:Virus Internalization
chemical_list: D000906:Antibodies; D017452:Receptors, IgG