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Molecular mechanisms of Ebola virus pathogenesis: focus on cell death.

Falasca L, Agrati C, Petrosillo N, Di Caro A, Capobianchi MR, Ippolito G, Piacentini M - Cell Death Differ. (2015)

Bottom Line: 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.We also discuss how the treatment of the infection can benefit from the recent experience of blocking/modulating cell death in human degenerative diseases.

View Article: PubMed Central - PubMed

Affiliation: National Institute for Infectious Diseases, Lazzaro Spallanzani, Rome, Italy.

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.

No MeSH data available.


Related in: MedlinePlus

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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fig4: 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

Mentions: Analyses of human samples obtained from succumbed patients or from experimentally infected animal models indicated that monocytes/macrophages, DCs, fibroblasts, hepatocytes, adrenal cells and epithelial cells can be productively infected by this virus. Furthermore, various studies suggested that monocytes/macrophages and DC are the early replication sites during EBOV infection.26, 27, 28 These cells also have key roles in the dissemination of the virus by migrating out of the spleen and lymph nodes to other tissues.29 Several immunological mechanisms are involved in the pathogenesis of EBOV infection involving both innate and adaptive immune response. In particular, innate immune deregulation (Figure 3) involves inhibition of type-I IFNs response, perturbation of cytokines/chemokines network, functional impairment of DC and natural killer (NK) cells. Adaptive immune deregulation involves both humoral and cell mediated immune arms (Figure 4).


Molecular mechanisms of Ebola virus pathogenesis: focus on cell death.

Falasca L, Agrati C, Petrosillo N, Di Caro A, Capobianchi MR, Ippolito G, Piacentini M - Cell Death Differ. (2015)

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
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4495366&req=5

fig4: 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
Mentions: Analyses of human samples obtained from succumbed patients or from experimentally infected animal models indicated that monocytes/macrophages, DCs, fibroblasts, hepatocytes, adrenal cells and epithelial cells can be productively infected by this virus. Furthermore, various studies suggested that monocytes/macrophages and DC are the early replication sites during EBOV infection.26, 27, 28 These cells also have key roles in the dissemination of the virus by migrating out of the spleen and lymph nodes to other tissues.29 Several immunological mechanisms are involved in the pathogenesis of EBOV infection involving both innate and adaptive immune response. In particular, innate immune deregulation (Figure 3) involves inhibition of type-I IFNs response, perturbation of cytokines/chemokines network, functional impairment of DC and natural killer (NK) cells. Adaptive immune deregulation involves both humoral and cell mediated immune arms (Figure 4).

Bottom Line: 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.We also discuss how the treatment of the infection can benefit from the recent experience of blocking/modulating cell death in human degenerative diseases.

View Article: PubMed Central - PubMed

Affiliation: National Institute for Infectious Diseases, Lazzaro Spallanzani, Rome, Italy.

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.

No MeSH data available.


Related in: MedlinePlus