Ebola virus glycoprotein directly triggers T lymphocyte death despite of the lack of infection

Autor: Richard A. Koup, Patrick Younan, Mathieu Iampietro, Andrew Nishida, Mukta Dutta, Ndongala Michel Lubaki, Michael G. Katze, Rodrigo I. Santos, Alexander Bukreyev
Jazyk: angličtina
Rok vydání: 2017
Předmět:
0301 basic medicine
CD4-Positive T-Lymphocytes
Cellular differentiation
Apoptosis
Monocytes
White Blood Cells
Spectrum Analysis Techniques
Viral Envelope Proteins
Cell Signaling
Interferon
Animal Cells
Medicine and Health Sciences
Cytotoxic T cell
Membrane Receptor Signaling
lcsh:QH301-705.5
Cells
Cultured
Cell Death
T Cells
Cell Differentiation
Ebolavirus
Flow Cytometry
Immune Receptor Signaling
3. Good health
medicine.anatomical_structure
Cell Processes
Spectrophotometry
Host-Pathogen Interactions
Cytophotometry
Cellular Types
medicine.drug
Protein Binding
Research Article
Signal Transduction
lcsh:Immunologic diseases. Allergy
Programmed cell death
T cell
Immune Cells
030106 microbiology
Immunology
Biology
Research and Analysis Methods
Microbiology
Necrotic Cell Death
03 medical and health sciences
Immune system
Virology
Genetics
medicine
Humans
Molecular Biology
Blood Cells
Biology and Life Sciences
T lymphocyte
Cell Biology
Hemorrhagic Fever
Ebola
Toll-Like Receptor 4
030104 developmental biology
lcsh:Biology (General)
Parasitology
lcsh:RC581-607
Developmental Biology
Zdroj: PLoS Pathogens, Vol 13, Iss 5, p e1006397 (2017)
PLoS Pathogens
ISSN: 1553-7374
1553-7366
Popis: Fatal outcomes of Ebola virus (EBOV) infections are typically preceded by a ‘sepsis-like’ syndrome and lymphopenia despite T cells being resistant to Ebola infection. The mechanisms that lead to T lymphocytes death remain largely unknown; however, the degree of lymphopenia is highly correlative with fatalities. Here we investigated whether the addition of EBOV or its envelope glycoprotein (GP) to isolated primary human CD4+ T cells induced cell death. We observed a significant decrease in cell viability in a GP-dependent manner, which is suggestive of a direct role of GP in T cell death. Using immunoprecipitation assays and flow cytometry, we demonstrate that EBOV directly binds to CD4+ T cells through interaction of GP with TLR4. Transcriptome analysis revealed that the addition of EBOV to CD4+ T cells results in the significant upregulation of pathways associated with interferon signaling, pattern recognition receptors and intracellular activation of NFκB signaling pathway. Both transcriptome analysis and specific inhibitors allowed identification of apoptosis and necrosis as mechanisms associated with the observed T cell death following exposure to EBOV. The addition of the TLR4 inhibitor CLI-095 significantly reduced CD4+ T cell death induced by GP. EBOV stimulation of primary CD4+ T cells resulted in a significant increase in secreted TNFα; inhibition of TNFα-mediated signaling events significantly reduced T cell death while inhibitors of both necrosis and apoptosis similarly reduced EBOV-induced T cell death. Lastly, we show that stimulation with EBOV or GP augments monocyte maturation as determined by an overall increase in expression levels of markers of differentiation. Subsequently, the increased rates of cellular differentiation resulted in higher rates of infection further contributing to T cell death. These results demonstrate that GP directly subverts the host’s immune response by increasing the susceptibility of monocytes to EBOV infection and triggering lymphopenia through direct and indirect mechanisms.
Author summary The latest outbreak of Ebola virus (EBOV) in West Africa resulted in more than 28,000 human infections including more than 11,000 deaths thus highlighting the necessity for the development of countermeasures. Monocytes and dendritic cells are among the primary targets of EBOV infection; infection of these critical antigen presenting cells contributes to the immune deficiency observed in Ebola virus disease (EVD). In contrast, lymphocytes are resistant to EBOV infection; however, in fatal EVD, pronounced lymphopenia is uniformly observed. Here we report that T lymphocyte cell death in the absence of detectable infection was observed in an EBOV glycoprotein (GP)-dependent manner. Using transcriptome analysis of EBOV-stimulated CD4+ T cells we show upregulation of both toll-like receptor 4 (TLR4) and cell death associated pathways. Furthermore, we demonstrate that EBOV increases susceptibility of monocytes to infection by promoting cellular differentiation. Both EBOV-induced monocyte differentiation and cell death of T lymphocytes result from a direct interaction between GP and TLR4. Blocking of TLR4 signaling significantly reduced both EBOV-induced T cell death and infection of monocytes. These data contribute to understanding of the ‘immune paralysis’ during EBOV infections and provide evidence for the development of targeted therapies for the treatment of EVD.
Databáze: OpenAIRE
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