Members of the filoviridae family of RNA viruses are causative agents of viral hemorrhagic fever and represent some of the most deadly human pathogens. A fundamental feature of filovirus virulence is the ability of these viruses to evade the host immune response. An associated critical determinant for disease progression is early and sustained viral replication in monocytes (macrophages and dendritic cells). Recent evidence has demonstrated that replication in monocytes, which are vital interfaces of innate and adaptive immune responses, results in the inhibition of normal monocyte activation and maturation, cytokine expression, antigen presentation, and apoptosis. In this application, we propose to use traditional virological methods to study viral replication, coagulation factor protein expression, and apoptosis coupled with high-throughput genomic technologies to identify changes in monocyte gene expression programs that result from filovirus infection. For this collaborative application, infections of human macrophages will be performed under high bio-containment (BSL4) conditions at the Institute for Virology at Philipps University in Marburg Germany. All samples will be decontaminated thoroughly to destroy all viral particles and will be tested rigorously for infectious agent before shipment to the University of Washington. The ability to hijack host cell gene expression and control macrophage function is crucial strategies for filoviruses to evade the innate and adaptive immune response. Therefore, knowledge of the transcriptional changes induced by filovirus infection of these cells at the genomic level will increase our understanding of the mechanisms employed by these highly pathogenic viruses to circumvent these responses and may lead to new diagnostic markers and new targets for therapeutic intervention. ? ? ?
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