transforming-growth-factor-beta and Hemorrhagic-Fever--Ebola

The filoviruses, Ebola (EBOV) and Marburg (MARV), are among the deadliest of human pathogens, causing acute diseases typified by rapidly fatal hemorrhagic fevers. Upon filoviral infection, innate immune cells become paralyzed and lose the capacity to properly co-stimulate and activate filovirus-specific, T-cell responses. Deleterious inflammation and upregulation of co-inhibitory molecules expressed by monocytic lineage cells (e.g., dendritic cells) and their co-inhibitory receptors on T- and B-cells may lead to incomplete humoral and T-cell immunity, anergy, exhaustion, apoptosis, and subsequent immune subversion. Hence, the dysregulation of inflammatory and co-inhibitory molecules may be exploited by filoviruses to further deteriorate host immune responses, ultimately leading to fulminant infections in susceptible species. Thus, in light of accumulating scientific observations, the challenge is now to characterize the molecular mechanisms that may result in rational strategies leading to new therapeutics and vaccines.

Topics: Animals; Filoviridae; Hemorrhagic Fever, Ebola; Humans; Immunity, Innate; Interleukin-10; Marburg Virus Disease; Membrane Glycoproteins; Receptors, Immunologic; T-Lymphocyte Subsets; T-Lymphocytes; Transforming Growth Factor beta; Triggering Receptor Expressed on Myeloid Cells-1

Ebola virus (EBOV) causes a severe hemorrhagic disease in humans and nonhuman primates, with a median case fatality rate of 78.4%. Although EBOV is considered a public health concern, there is a relative paucity of information regarding the modulation of the functional host response during infection. We employed temporal kinome analysis to investigate the relative early, intermediate, and late host kinome responses to EBOV infection in human hepatocytes. Pathway overrepresentation analysis and functional network analysis of kinome data revealed that transforming growth factor (TGF-β)-mediated signaling responses were temporally modulated in response to EBOV infection. Upregulation of TGF-β signaling in the kinome data sets correlated with the upregulation of TGF-β secretion from EBOV-infected cells. Kinase inhibitors targeting TGF-β signaling, or additional cell receptors and downstream signaling pathway intermediates identified from our kinome analysis, also inhibited EBOV replication. Further, the inhibition of select cell signaling intermediates identified from our kinome analysis provided partial protection in a lethal model of EBOV infection. To gain perspective on the cellular consequence of TGF-β signaling modulation during EBOV infection, we assessed cellular markers associated with upregulation of TGF-β signaling. We observed upregulation of matrix metalloproteinase 9, N-cadherin, and fibronectin expression with concomitant reductions in the expression of E-cadherin and claudin-1, responses that are standard characteristics of an epithelium-to-mesenchyme-like transition. Additionally, we identified phosphorylation events downstream of TGF-β that may contribute to this process. From these observations, we propose a model for a broader role of TGF-β-mediated signaling responses in the pathogenesis of Ebola virus disease.. Ebola virus (EBOV), formerly Zaire ebolavirus, causes a severe hemorrhagic disease in humans and nonhuman primates and is the most lethal Ebola virus species, with case fatality rates of up to 90%. Although EBOV is considered a worldwide concern, many questions remain regarding EBOV molecular pathogenesis. As it is appreciated that many cellular processes are regulated through kinase-mediated phosphorylation events, we employed temporal kinome analysis to investigate the functional responses of human hepatocytes to EBOV infection. Administration of kinase inhibitors targeting signaling pathway intermediates identified in our kinome analysis inhibited viral replication in vitro and reduced EBOV pathogenesis in vivo. Further analysis of our data also demonstrated that EBOV infection modulated TGF-β-mediated signaling responses and promoted "mesenchyme-like" phenotypic changes. Taken together, these results demonstrated that EBOV infection specifically modulates TGF-β-mediated signaling responses in epithelial cells and may have broader implications in EBOV pathogenesis.

Topics: Animals; Cell Differentiation; Disease Models, Animal; Ebolavirus; Gene Expression Profiling; Hemorrhagic Fever, Ebola; Hepatocytes; Host-Pathogen Interactions; Humans; Mesoderm; Mice, Inbred BALB C; Signal Transduction; Transforming Growth Factor beta