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Review
. 2015 Aug;22(8):1250-9.
doi: 10.1038/cdd.2015.67. Epub 2015 May 29.

Molecular mechanisms of Ebola virus pathogenesis: focus on cell death

L Falasca  1 , C Agrati  1 , N Petrosillo  1 , A Di Caro  1 , M R Capobianchi  1 , G Ippolito  1 , M Piacentini  2
Affiliations
Review

Molecular mechanisms of Ebola virus pathogenesis: focus on cell death

L Falasca et al. Cell Death Differ. 2015 Aug.

Abstract

Ebola virus (EBOV) belongs to the Filoviridae family and is responsible for a severe disease characterized by the sudden onset of fever and malaise accompanied by other non-specific signs and symptoms; in 30-50% of cases hemorrhagic symptoms are present. Multiorgan dysfunction occurs in severe forms with a mortality up to 90%. The EBOV first attacks macrophages and dendritic immune cells. The innate immune reaction is characterized by a cytokine storm, with secretion of numerous pro-inflammatory cytokines, which induces a huge number of contradictory signals and hurts the immune cells, as well as other tissues. Other highly pathogenic viruses also trigger cytokine storms, but Filoviruses are thought to be particularly lethal because they affect a wide array of tissues. In addition to the immune system, EBOV attacks the spleen and kidneys, where it kills cells that help the body to regulate its fluid and chemical balance and that make proteins that help the blood to clot. In addition, EBOV causes liver, lungs and kidneys to shut down their functions and the blood vessels to leak fluid into surrounding tissues. In this review, we analyze the molecular mechanisms at the basis of Ebola pathogenesis with a particular focus on the cell death pathways induced by the virus. We also discuss how the treatment of the infection can benefit from the recent experience of blocking/modulating cell death in human degenerative diseases.

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Figures

Figure 1
Figure 1
Overview of EBOV gene products and their interactions with the host cell. There are seven genes in the Ebola virus: the NP, the viral proteins VP24-VP30-VP35-VP40, L (polymerase) and the GP. Figure summarizes the function of genes products within EBOV biology, together with the existing knowledge on host cell factors and functions affected by each EBOV proteins
Figure 2
Figure 2
Ebola virus entry. EBOV binds to receptors on the cell surface through the viral spike protein, GP. The virus is then internalized via macropinocytosis and trafficked to endosomal compartments, where the cysteine proteases cathepsin B (CatB) and cathepsin L (CatL) digest GP to a 19 kDa form (GP2). Within the late endosome/lysosome, the viral GP2 interacts with NPC1 allowing fusion between the viral and endosomal membranes. After fusion, the viral nucleocapsid is released into the cytoplasm, where the genome is replicated
Figure 3
Figure 3
EBOV infection induces innate immune cell dysfunctions. (a) EBOV infection is able to impair type-I IFNs production by infected cells and to block IFN response in uninfected cells; (b) EBOV infection is able to induce massive cytokines/chemokines production by monocytes/macrophages; (c) EBOV infection is able to impair DC maturation and to deregulate cytokine production. (d) EBOV infection is able to induce massive NK apoptosis, thus avoiding NK function and impairing NK-mediated DC maturation help
Figure 4
Figure 4
EBOV infection induces adaptive immune cell dysfunctions. (a) Antibodies production represents the best correlate of protection during EBOV infection. Two different forms of EBOV GP, soluble GP (sGP) and glycosylated-GP (GlycGP), are able to drive antibodies shielding and misdirection. (b) EBOV infection of DC results in a deregulated DC/T synapse, characterized by an effective MHC-peptide/TCR interaction (signal 1), in a high inflammatory microenvironment (deregulated signal 3) in the absence of co-stimulatory accessories molecules on DC surface (ineffective signal 2). The inappropriate DC/T-cell interaction induces T-cell apoptosis, avoids CD4 T-cell clonal expansion, thus blocking all CD4 T-cell helper functions such as CD8-mediated cytotoxicity and antibodies-production by B cells
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