The current study represents the first broad analysis of initial transcriptional responses to Ebola virions of human macrophages, the primary target cells of ZEBOV [12, 13, 14, 15] . To assure accurate identification of cellular genes that responded significantly to virion exposure, DNA microarray data were scrutinized and stringently filtered by two different sets of selection criteria and statistical evaluations. In addition, the expression levels of selected genes were experimentally verified by real-time PCR analysis. Using these methods for statistical verification and assay evaluation, our study permitted the identification of a large number of genes not previously implicated in early cellular responses to ZEBOV infection. The detected changes of gene expression levels occurred within the first hours after primary human macrophages were exposed to Ebola virions in vitro. In addition, we identified genes whose expression is known to be upregulated during acute Ebola hemorrhagic fever. This not only validated the experimental approach and data screening criteria, it also demonstrated that elevated levels of gene products, such as cytokines, are already induced in primary target cells within the first hours of virion binding and entry. Lending further credence to these assertions, pathway ORA of the significantly differentially regulated genes identified from our gene expression studies demonstrated a strong upregulation of specific host signaling pathways related to cytokine/chemokine signaling during the immediate response to Ebola infection. Indeed, the upregulation of signaling pathways related to cytokine/chemokine signaling events suggests that specific innate immune responses are mounted during the acute phase of Ebola viral insult. Through multiple pathway ORA analyses we identified broad cellular functional networks that are modulated during the early course of Ebola infection and, importantly, have correlated this with specific cell signaling pathways. The identities of the individual signaling pathways modulated by Ebola infection will provide critical information regarding disease pathogenesis and as well information for the development of novel antiviral therapeutics.