immuno - pathogenesis of ebola virus disease
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Immuno - pathogenesis of Ebola virus disease. DR. MD. MAMUNUR RASHID Assistant Professor Clinical Tropical Medicine Department BITID, Fouzderhat , Ctg. PATHOGENESIS . - PowerPoint PPT PresentationTRANSCRIPT
IMMUNO- PATHOGENESIS OF EBOLA VIRUS DISEASE
DR. MD. MAMUNUR RASHIDAssistant ProfessorClinical Tropical Medicine DepartmentBITID, Fouzderhat, Ctg.
PATHOGENESIS
Due to the difficulty of performing clinical studies under outbreak
conditions, almost all data on the pathogenesis of Ebola virus diseases
have been obtained from laboratory experiments employing on mice,
guinea pigs, and a variety of nonhuman primates.
Whatever the point of entry into the body -
The first line cells to be affected are- macrophages & dendritic cells.
Other cells to be affected are- monocytes, endothelial cells,
fibroblasts, hepatocytes, adrenal cortical cells & epithelial cells.
VIRAL ENTRY
Figure-1. Macropinocytosis.
Upon membrane fusion, the capsid moves into the cell
cytoplasm at a site where replication proceeds optimally.
The Ebola virus glycoprotein (GP) is synthesized in a
secreted (sGP) or full- length transmembrane form & each
gene product has distinct biochemical & biological
properties.
Replication of Ebola virusViral RNA polymerase, encoded by the L gene Promoter Transcription
Synthesis of mRNA
Translation
Synthesis of newer protein
New virus formation
Viral Budding
Figure-2. Budding of newly assembled Ebolavirus virions is mediated by VP40.
Spread of virus to regional lymph nodes from ECF Further rounds of replication
Dissemination of virus to dendritic cells and fixed and mobile macrophages in the liver, spleen, thymus, and other
lymphoid tissues. Aided by virus-induced
suppression of type I interferon
Rapid systemic spread
Systemic spread
Progression of the disease
Infection spread to hepatocytes, adrenal cortical cells , fibroblasts & many other cells
Extensive tissue damage
Induction of systemic inflammatory syndrome by
releasing cytokines like TNF-α, IL-6, IL-8, NO, MCP-1
Fever, inflammation & loss of vuscular integrity
Loss of vascular integrity causes further synthesis of
viral GP
Reduces specific integrins responsible for cell adhesion to the inter cellular structures
Damage of different organs of body causing coagulopathy, hypotension, vasodilation, increased
vascular permeability, shock etc.
Pathophysiology
Figure-3.Pathogenesis schematic
Coagulation defects Ebola virus-infected macrophages synthesize cell-surface
tissue factor (TF) Cytokine induced macrophages TF + Cytokines
Triggering the extrinsic coagulation pathway
Extensive consumptive coagulopathy leading to DIC like
features .The simultaneous occurrence of these two stimuli helps to
explain the early appearance, rapid development, and ultimate severity of the coagulopathy in ebola virus infection causing
bleeding.
Blood samples from Ebola-infected monkeys contain D-
dimers within 24 hours after virus challenge, and D-dimers
are also present in the plasma of humans with Ebola
hemorrhagic fever . In macaques, activated protein C is
decreased on day two, but the platelet count does not begin
to fall until days three or four, suggesting that activated
platelets are adhering to endothelial cells. As the disease
progresses, hepatic injury may also cause a decline in
plasma levels of certain coagulation factors which also
induces bleeding.
EBOLA VIRUS CAUSES DESTABILIZATION OF THE VASCULAR ENDOTHELIUM LEADING TO HEMORRHAGE.
Figure-4
IMMUNE RESPONSE TO EBOLA VIRUS INFECTION
Ebola virus act both directly and indirectly
to disable antigen-specific immune
responses. Dendritic cells, which have
primary responsibility for the initiation of
adaptive immune responses, are a major
site of filoviral replication.
Ebola virus Infection to immune related cells
Apoptotic death of
Dendritic cell Lymphocytes
Loss of Innate Failure of initiation of immunity adaptive immune response
Antibody Dependent Enhancement of Ebolavirus Infection. (A) Human kidney cells infected with Zaire virus in the presence or absence of purified mouse antibodies (B) Human kidney cells were infected with the Zaire virus or VSV pseudotyped with the Zaire GP following incubation with convalescent human plasma or serum (Takada et al. 2003).
Figure-5
C1q-mediated Antibody Dependent Enhancement of Ebolavirus Infection (Model). Ebola virus initiates infection by binding to its specific receptors (top panel). C1q enables binding between the virus-antibody complex and C1q ligands on the cell surface, promoting interaction between the virus and its receptor (bottom panel). Binding of the virus via the C1q molecule increases the likelihood of viral attachment to the cell surface. (Takada et al. 2003).
Figure-6
Therefore, while antibodies normally protect the body, this
virus is able to use them for faster and easier attachment to
target cells. In addition being an essential cofactor for the
viral RNA polymerase complex, VP35 produced in response
to viral infection has been identified as an inhibitor of
multiple components of the interferon (IFN) pathways, which
exerts anti viral, cell growth inhibitory & immunoregulatory
activities.
In summary, an understanding of the mechanisms underlying
Ebola virus-induced cytopathic effects has facilitated the process
of vaccine and antiviral therapy development, which has in turn
provided new information about pathogenesis and the immune
response. Ebola virus does not exhibit the high degree of
variability that other enveloped viruses may employ to evade host
immunity, but Ebola virus GP alters target-cell function and
exemplifies a novel strategy for immune evasion that may have
arisen through the evolution of Ebola virus with its natural host.
The cytotoxic effects of GP on macrophage and endothelial cell
disrupt inflammatory cell function and the integrity of the
vasculature.
In addition, by altering the cell surface expression of
adhesion proteins and immune recognition molecules,
Ebola virus may disrupt processes critical to immune
activation and cytotoxic-T-cell function. These
phenomena likely account for the dysregulation of the
inflammatory response and the vascular dysfunction
characteristic of lethal Ebola virus infection, providing a
rationale for focusing on GP as a target for a
preventative vaccine and other clinical interventions.
Another target focus may be the viral entry pathway to
stop replication.