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.