Ebola Hemorrhagic Fever: The Role of the Immune System in Pathogenesis

1
Ebola Hemorrhagic Fever The Role of the Immune
System in Pathogenesis

• Josh Lizer
• VMPM 587
• Spring 2008

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Ebola Virus Overview

• Family Filoviridae
• Ss sense RNA
• Pleomorphic morphology
• enveloped

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4 subtypes

• Zaire (1976) 80-90 mortality
• Sudan (1976) 50-65 mortality
• Reston (1989) 0 mortality
• Ivory Coast (1994) 0 mortality based on one case

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Clinical disease

• Flu-like symptoms
• Abrupt fever and malaise
• Diarrhea
• Myalgia
• Intense abdominal pain
• Rash
• External bleeding
• vomiting

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Prevention and Control

• AVOID DIRECT CONTACT

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Entertainments infatuation with Ebola and white
suits

• Books
• The Hot Zone by Richard Preston (1994)
• Horrifying nonfiction bestseller describing the
  origins of incidents involving the hemorrhagic
  fevers caused by Ebola and Marburg viruses
• Stephen King "one of the most horrifying things
  I've ever read."
• Outbreak by Robin Cook
• Fictional Ebola outbreak in LA hospital
• Movies
• Outbreak (fiction)
• Military involvement in outbreak fashioned off
  Ebola, and based off The Hot Zone
• Students
• I chose this virus because it sounds sweet

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Ebola as biological weapon

• Unlikely to be used since infection kills so
  fast, virus would not be able to spread very far

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The Role of Immune System in Pathogenesis

• Macrophages
• Dendritic cells
• Septic shock
• DIC
• Apoptosis
• Surface glycoproteins

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General Pathogenesis
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Indicators of Infection Fatality
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Host defense good intentions with bad results

• DIC and septic shock are caused by body in
  response to Ebola

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The Role of Macrophages in Ebola Pathogenesis

• Monocytes, macrophages, endothelial cells are
  permissive for exponential viral replication
• Monocyte/macrophage first to be infected

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Viral Growth in Macrophages

• Viral products (ie dsRNA) bind pattern
  recognition molecules.
• Transcriptional activators (ie NF?B) to nucleus
• Secretion of proinflammatory cytokines

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Viral Growth in Macrophages

• Proinflammatory cytokines secreted

Monocyte chemotactic protein-1
IL-1ß
IL-6, IL-8
Oncogenic- a
TNFa
RANTES
NO
MIP1- a
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Viral Growth in Macrophages

• Immature neutrophils to site of infection from
  blood vessels, bone marrow
• Facilitates exit of inflammatory cells, proteins
  through vasodilation, increased endothelial
  permeability, expression of endothelial cell
  surface adhesion molecules

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CATASTROPHIC CIRCULATORY COLLAPSE
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Viral Growth in Macrophages

• Role in DIC

Tissue factor
VIIa

Coagulation pathway
X
(Fibrin)
cell
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Viral Growth in Macrophages
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Role of Dendritic Cells in Pathogenesis

• Link innate and adaptive immunity
• Secrete chemokines/proinflammatory cytokines
• Upregulate chemokine receptors
• Activate Th1 and/or Th2 T cell response

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Role of DCs in Pathogenesis

• Effects of infected DC
• No secretion of Proinflammatory, immunoregulatory
  cytokines
• No maturation
• Interference with allogenic T cell stimulatory
  capability
• Down regulate cell-surface markers
• Poor T cell proliferation
• Viral replication in DCs without alerting immune
  system

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Assembly and release of virions through lipid raft

• Cholesterol-enriched domains necessary for
  cellular communication, signal transduction
• Virus disorganizes raft, impairing DC ability to
  present and process Ag

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Virus growth in DCs
48 hrs infection
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Septic Shock

• Body

(drama queen)
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Septic shock

• Similar to that induced by endotoxin
• Inappropriate and maladaptive immune response
• seeing a spider and jumping off a cliff
• Virus induced mononuclear phagocytic cells
  release proinflammatory cytokines (ie TNF-a)

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Septic shock

• Dysregulates coagulation cascadeDIC
• Lymphocyte apoptosis

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Differences in septic shock

• Common septic shock trauma or impaired immune
  function, worsens as infection progresses
• EHF septic shock develops in healthy,
  immunocompetent hosts. Few virions needed.

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DIC

• Syndrome brought on by septic shock
• Coagulation cascade activated
• Locally or entire vasculature
• Microthrombi hampers sufficient blood supply
  resulting in multiple organ dysfunction and high
  mortality
• Fibrin encases cells

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Coagulation cascade
TF observed only in macrophages with evidence of
EBOV replication.
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DIC

• Strong link to virus-infected cells
• TEM of infected macaque tissue
• Fibrin deposits only found around EBOV infected
  cells (lymphoid monocytes/macrophages, Kupferr
  cells, DCs)
• Polymorphonuclear cells do not support virus
  replication and were not encased in fibrin.

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Apoptosis

• Results in death of 30-40 CD4 and CD8 T cells
• CD4 required for IgM ? IgG cell death results in
  little to no Ab response
• High levels of cytokines (ie TNF-a, MCP-1, MIP1-
  a) may recruit macrophages and T cells to
  infection site, contributing to death.

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Apoptosis

• By-product of EBOV replication rather than direct
  result
• Cell death not directly linked to viral
  replication
• ?? Link to secreted glycoprotein or soluble GP1

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Apoptosis

• Hosts own response harms self
• Extensive destruction of immune cells harmful
• Exaggerated release of IFN-?, TNF- a, FasL, O2
  radicals

Liver disorders, coagulation failure, endothelium
permeabilization
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The Role of Glycoprotein in Pathogenesis

• Found on surface of mature virus particles
• Facilitate receptor binding and fusion with
  target cells
• Presence of circulating glycoprotein found in
  acute phase infection in humans and
  nonhumansshares 300 amino acids with viral GP
  produced through transcriptional editing of the
  same gene
• May serve as immunological decoy to prevent
  effective immune response

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Glycoprotein functions continued

• Mediates loss of cell adherence by altering
  surface expression or activation of cell adhesion
  molecules
• Important because firm cell to cell contact is
  essential for many aspects of immune system
• ZEBOV has been observed to cause cell detachment
  from culture dishes
• Loss of functional ligands (ie integrins) to
  extracellular matrix component

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Loss of cell adhesion

• Integrin-mediated adhesion serves many roles in
  cell adhesion, signaling, and immune regulation
• Ie trafficking of leukocytes through endothelium
  to sites of infection
• Loss of MHC I cell to cell adhesion molecules
  negatively impacts stimulation of CD8 T cells and
  ability of T cells to kill infected cells
• GP also contributes to cell rounding

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Table of cytokine data
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Conclusions

• Ebola is able to have such high lethality
  because
• It is resistant to the immune system
• Turns the immune system on the body
• Runs course of disease so quickly, epidemics
  sporadic, 3rd world setting, not conducive to
  field research, dangerous to workers
• Continued studies of immune system in
  pathogenesis necessary to one day overcome disease