Ebola virion attachment and entry into human macrophages profoundly effects early cellular gene expression.
Zaire ebolavirus (ZEBOV) infections are associated with high lethality in primates. ZEBOV primarily targets mononuclear phagocytes, which are activated upon infection and secrete mediators believed to trigger initial stages of pathogenesis. The characterization of the responses of target cells to ZEBOV infection may therefore not only further understanding of pathogenesis but also suggest possible points of therapeutic intervention. Gene expression profiles of primary human macrophages exposed to ZEBOV were determined using DNA microarrays and quantitative PCR to gain insight into the cellular response immediately after cell entry. Significant changes in mRNA concentrations encoding for 88 cellular proteins were observed. Most of these proteins have not yet been implicated in ZEBOV infection. Some, however, are inflammatory mediators known to be elevated during the acute phase of disease in the blood of ZEBOV-infected humans. Interestingly, the cellular response occurred within the first hour of Ebola virion exposure, i.e. prior to virus gene expression. This observation supports the hypothesis that virion binding or entry mediated by the spike glycoprotein (GP(1,2)) is the primary stimulus for an initial response. Indeed, ZEBOV virions, LPS, and virus-like particles consisting of only the ZEBOV matrix protein VP40 and GP(1,2) (VLP(VP40-GP)) triggered comparable responses in macrophages, including pro-inflammatory and pro-apoptotic signals. In contrast, VLP(VP40) (particles lacking GP(1,2)) caused an aberrant response. This suggests that GP(1,2) binding to macrophages plays an important role in the immediate cellular response.
Integrated Research Facility at Fort Detrick, Division of Clinical Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Fort Detrick, Maryland, United States of America. victoriajensen@nih.gov
Victoria
V
Wahl-Jensen
Sabine
S
Kurz
Friedericke
F
Feldmann
Lukas K
LK
Buehler
Jason
J
Kindrachuk
Victor
V
DeFilippis
Jean
J
da Silva Correia
Klaus
K
Früh
Jens H
JH
Kuhn
Dennis R
DR
Burton
Heinz
H
Feldmann
D002478:Cells, Cultured; D029043:Ebolavirus / Q000276:immunology* / Q000472:pathogenicity*; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D006801:Humans; D008264:Macrophages / Q000276:immunology* / Q000821:virology*; D046228:Microarray Analysis; D060888:Real-Time Polymerase Chain Reaction; D014771:Virion / Q000276:immunology / Q000472:pathogenicity; D053586:Virus Internalization