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The Science Behind the Hot Zone

Ebola is a disease of humans and non-human primates caused by Ebola virus, a member of the Filoviridae family. It contains a single-stranded non-infectious RNA genome of about 19kb in length encoding seven proteins including Ebola virus structural glycoprotein responsible for binding and infecting target cells. Five different strains of Ebola virus have been described since its discovery in Zaire (now the Democratic Republic of Congo) in 1976 but only four of them are known to cause Ebola hemorrhagic fever in humans. Zaire Ebola virus is accountable for the current outbreak in West Africa with the most deaths (i.e. at least 5400 according to the World Health Organization). African fruit bats are thought to be the normal carrier in nature and able to spread the virus by contact with humans or other animals without being affected by it. It spreads by direct contact of mucous membranes with blood or other body fluids of an infected human or other animal. First symptoms are high fever, muscle pain, headache and sore throat. It is then accompanied by vomiting, diarrhea, impaired kidney and liver function and in some of the most extreme cases, internal and external bleeding followed by death.


Despite extensive research and a good understanding of how the virus spreads throughout the body, very little is known about the mechanism of infection of endothelial and immune cells by Ebola virus. Back in 2011, Dr. Kondratowicz and colleagues from the University of Iowa identified for the first time a cellular receptor for Ebola virus. Using a bioinformatics approach, they directly correlated the transduction efficiency of Ebola virus with the expression of T cell immunoglobulin and mucin domain 1 (TIM-1), also referred to as kidney injury molecule 1 (KIM-1). By silencing TIM-1 in a TIM-1-positive monkey kidney cell line (Vero), they showed a direct interaction between TIM-1 and the receptor binding domain of Ebola virus glycoprotein and that expression of cell surface TIM-1 greatly enhanced entry of Ebola virus into the cells. TIM-1 was found to be abundantly expressed on human airway and eye mucosal epithelium, which explains why one of the established routes of infection is the inhalation of aerosolized particles. It is also expressed in Th2 cells and a variety of epithelial cells in vitro. Interestingly, Ebola virus was also found in cells known to have low levels of TIM-1 such as macrophages and dendritic cells indicating that Ebola virus entry might be mediated by other cell surface receptors than TIM-1. Finally, blockade of the latter with a monoclonal antibody called ARD5 successfully inhibited binding of Ebola virus glycoprotein and infectious Ebola virus replication in Vero cells. Altogether, these results lifted up a major roadblock to understanding the pathogenesis of Ebola virus and to building up novel therapies.

Several research articles have since then described potential new therapeutic targets and the accepted opinion is that monoclonal antibody-based therapies are the most effective at stopping Ebola virus infection in non-human primate models, which reproduce human disease with high resemblance. There is currently no FDA-approved treatment or vaccine for Ebola. There is, however, a buzz at the moment surrounding one treatment called ZMapp from Mapp Pharmaceuticals. The latter is an optimized cocktail of three monoclonal antibodies against Ebola virus produced by a genetically engineered virus injected into a tobacco plant. Upon administration of ZMapp, Dr. Qiu and collaborators from the Public Health Agency of Canada demonstrated the reversal of high fever, viraemia, abnormal blood count and blood chemistry as well as symptoms associated with advanced disease in rhesus monkeys. 100% of rhesus monkeys were rescued when treatment with ZMapp was initiated up to five days post-challenge. More recently, it was successfully used to save the lives of two Americans. Unfortunately, there is still no sufficient proof that ZMapp is capable of efficiently treating Ebola in humans but these preliminary results are a testament that with further research, it holds a strong potential for clinical use.

Enzo Life Sciences recently launched a monoclonal antibody capable of specifically recognizing Ebola virus in human samples. In addition, Enzo offers virologists several tools for the study of viruses including antibodies, probes, native and recombinant proteins as well as high sensitivity ELISA kits (e.g. KIM-1 ELISA kit), some of which are listed below:

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References:

  1. A.S. Kondratowicz, et al. T-cell immunoglobulin and mucin domain 1 (TIM-1) is a receptor for Zaire Ebolavirus and Lake Victoria Marburgvirus. Proc. Natl. Acad. Sci. U.S.A. (2011) 108, 8426.
  2. X. Qiu, et al. Reversion of advanced Ebola virus disease in nonhuman primates with ZMapp. Nature (2014) 514, 47.

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