Ebola Virion Attachment and Entry into Human Macrophages Profoundly Effects Early Cellular Gene Expression

Abstract

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 (GP1,2) 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 GP1,2 (VLPVP40-GP) triggered comparable responses in macrophages, including pro-inflammatory and pro-apoptotic signals. In contrast, VLPVP40 (particles lacking GP1,2) caused an aberrant response. This suggests that GP1,2 binding to macrophages plays an important role in the immediate cellular response.

Transcriptional Profiling of the Immune Response to Marburg Virus Infection

“…To identify genes that showed significant transcriptional regulation following exposure to Marburg virus, we used criteria similar to those previously used to analyze the transcriptional response in other filovirus infections (28)(29)(30). This analysis showed that when experimental arrays were compared to the preinfection controls, 1,754 probes (1,213 genes) showed at least a 2-log-fold change in their expression pattern in at least 3 arrays (see Fig.…”

Bovine viral diarrhea virus type 2 in vivo infection modulates TLR4 responsiveness in differentiated myeloid cells which is associated with decreased MyD88 expression

“…Furthermore, it has been reported that proinflammatory cytokine mRNAs induced by LPS are more stabilized than in the absence of LPS (Dai et al, 2003;Kishore et al, 1999). Hypersensitivity of PRRs in response to their cognate ligands and enhanced expression of proinflammatory cytokines are contributing factors to severe clinical disease and a prolonged period of recovery (Cheng et al, 2012;Totura and Baric, 2012;Villinger et al, 1999;Wahl-Jensen et al, 2011). Thus, in cases of BRDC that involve BVDV-bacterial co-infections, enhanced pro-inflammatory cytokine secretion in response to bacterial LPS could contribute to more severe clinical disease.…”

The Role of Viral Protein Phosphorylation During Filovirus Infection

“…EBOV infection also resulted in the upregulation of IFN-regulated genes starting early during the course of infection (day 2) and remained upregulated through to the endpoint of the study (day 6). More recently, Wahl-Jensen and colleagues demonstrated that EBOV particle attachment and entry into human macrophages induce pro-infl ammatory mediators (including IL-6, IL-8, and TNF-α) 1 h post-inoculation [ 61 ]. While such studies of global gene expression have been informative, many questions remain regarding the molecular pathogenesis of fi lovirus infection.…”