Ebola Virus Part II: Infection And The Immune Response

Instead of hiding from your immune system Ebola Virus (EBOV) infects cells of your immune system first. A number of other viruses also do this, including Measles Virus (MV), and of course HIV. With EBOV, lymphocytes are NOT infected, but the infection eventually leads to their depletion.

Once the virus infects your immune cells and begins to replicate, it evolves to have an affinity for other cell types, especially liver cells. Many different cell surface proteins, found on many different types of cells, can act as receptors for the virus making it possible to infect many other cell types.

The incubation period for EBOV infection can be anywhere from 2-21 days

Pathogenic Mechanisms

EBOV has two main, and complementary, pathogenic mechanisms that make it so deadly:

  1. It turns on the inflammatory response full-blast. This results in increased vascular permeability, hemorrhage, shock, and ultimately, death.
  2. It turns off the activation of virus-specific immune responses so you get little-to-no anti-viral immunity to control the replication of the virus inside your body.

Ebola also has a liking for liver cells and causes liver failure. And guess what?! Most of the blood clotting factors are made in the liver. Bad news.

The infection process goes something like this:

  1. EBOV infects Dendritic Cells (DCs), monocytes, and macrophages (MO), and also activates neutrophils. These are all cells belonging to your early or “innate” immune system, which is your front-line defense against foreign invaders.
  2. These events cause the release of massive amounts of pro-inflammatory cytokines such as TNFa, which increase vascular permeability, fluid leakage, and shock. This effect is known as “cytokine storm”. Tissue Factor (TF) is also produced, which disrupts normal blood clotting and contributes to hemorrhaging.
  3. Virus replication escalates in the infected cells
  4. In the infected cells, the production of interferon-gamma (IFNg) is turned off. Downstream interactions of DCs and MO with lymphocytes (T cells and B cells) to initiate an anti-viral immune response, which are dependent on IFNg, are disrupted.
  5. The maturation of DCs into functional antigen-presenting cells is inhibited, which, along with the decrease in IFNg, blocks activation of T cells and B cells preventing development of virus-specific immunity.
  6. Virus replication is rampant in infected cells resulting in rapid spread internally, high viral loads, and nothing to keep the virus in check.
  7. The virus spreads to other cell types, in particular liver cells, eventually leading to liver failure, increasing the potential for hemorrhaging.
  8. Once symptoms appear, death typically occurs within 7-14 days. If the patient survives, recovery can be a very long and difficult process.

Ebola Infection Domino Effect

What About A Vaccine?

A wide variety of vaccine candidates and approaches have been tested or are currently being tested. These include killed viruses, live attenuated viruses, subunit vaccines, DNA vaccines, recombinant vaccines using other viruses as vectors. The approaches to create an Ebola vaccine are the same as those taken to produce a vaccine for other organisms, and the difficulties and pitfalls are also the same.  The primary issue is finding the balance between potency/efficacy and safety, especially in the case of live or recombinant vaccines. It is also clear that a durable and potent vaccine needs to generate both cellular (T cell-mediated) and humoral (antibody-mediated) immunity. Furthermore, variation and changes in the viral envelope protein (GP) make it difficult to neutralize with antibodies from either natural immunity or a vaccine. Work remains in progress.

Reference

Mansour Mohamadzadeh M, Chen L, and Schmaljohn AL. 2007. How Ebola and Marburg viruses battle the immune system. Nature Reviews Immunology 7: 556-567.

Author: Steve Anderson, Ph.D.

Steve Anderson has a Ph.D. in Immunology with over 25 years experience in biomedical research. His scientific expertise includes immunology, immunological diseases, tumor immunology, virology, and HIV pathogenesis.