Tuesday, April 15, 2014

Headlines- Ebola outbreak 2014


      Infectious diseases make more headlines than anybody else, especially if there is a outbreak. Be it the SARS epidemic, Influenza pandemic, MERS Coronavirus or the latest Ebola. And if you scare the people enough, media will use it to great potency, and will be the breaking news. No doubt, infections such as Ebola makes a strong statement (BSL-4 category), they are not human race wiping infections. This probably is the right time to talk about it. When i talk of Ebola almost everyone remembers the movie "Outbreak"

Table 1: Key features of Ebola virus.
      Ebola was first recognized near the Ebola River valley (Hence the name) in 1976. The virus is a member of Filovirus family with Negative-sense RNA. Studies identified that there are 5 strains of Ebola- Zaire, Sudan, Ivory coast, Reston, and Bundibugyo. Of these Zaire, Ivory Coast, and Sudan strains have been shown to be associated with human infections. The case fatality ratio of Ebola ranges from 50-90%. It is not known as to what are the actual reservoirs of this virus. Humans and other primates are thought to be accidental hosts. There are strong arguments in current research that indicates "Bats", as the most likely reservoir. The key features of Ebola virus is given in Table 1.

       The Ebola virus life cycle is not completely understood. In 2011, a multidisciplinary research team were able to showed that T-cell Ig and mucin domain 1 (TIM-1) was the receptor for Ebola and a closely related Marburg virus. The virus is proposed to be a macropinocytosis-like process that delivers the virus to early endosomes and subsequently to late endosomes. It is being postulated that the virus attacks immune cells (The dendritic cells, monocytes and macrophages). The virus can modulate the immune response such as meddling with interleukin and immune cell expression molecules. Infection spreads to multiple other cells including liver hepatocytes and vascular epithelial cells. The nature of human to human transmission is believed to be by close contact through broken mucus membrane. The virus kills the epithelial cells. In the vascular lining severe loss of endothelial cells causes vascular damage. The virus has an incubation period of two to 21 days This manifests as a hemorrhage and hence known as Ebola Hemorrhagic Fever (EHF).

Fig 1: Ebola Outbreak map 2014.
Source: CDC;
Last reviewed: March 24, 2014
   As of on April 14, 2014, 200 suspected or confirmed cases with 121 fatality is reported (Reference) for EHF. Outbreak ongoing in the southeastern part of Guinea. It is not published as to what is the strain type involved or what is the case zero. The previous outbreak was in Uganda (Luwero District; November 2012-January 2013), caused by Sudan strain. In that outbreak a 50% case fatality ratio was published.

      Currently there is a large effort in trying to contain the virus from spreading by actively diagnosing the cases. However, very little can be done in terms of treatment. There is no established antivirals. Currently researchers are trying to develop drugs against multiple viral components especially the Filoviral polymerase.

    The EHF causes bleeding from multiple body sites patients usually die due to extensive blood and fluid loss. Dr. Anthony Fauci, Director of NIAID says "If you have a medical facility to give you blood or plasma or fluid, you're not specifically attacking the Ebola, but you're giving the patient a better chance of surviving, Some people who have the best medical care still die, and there are some people with no care who survive. But you have the best chance if you have medical care." Source

   Vaccines, are also in research phase. There are no commercially available vaccines. It is possible that antibodies against the viral receptors to TIM-1 can induce significant protection. A study has been published in 2013, where a replication-competent rabies virus vaccine was engineered to expressing Ebola glycoprotein. In a primate model, after 42 days there was 100% protection. In contrast replication-deficient and inactivated vaccines afforded 50 percent protection. The vaccine hasn't yet been tested on human volunteers and hence not available in the current outbreak. There are reports of use of siRNA (to be administered within minutes of exposure), monoclonal antibodies etc are published they are not yet ready for mass public use.

    So what are we looking at? A BSL-4 virus, high case fatality, No antivirals, No vaccine. But there is a good news also. Ebola doesn't seem to be a human pathogen. They are accidentally transferred to humans and hence will subside to spread if enough preventive measures are taken. The best procedure is to quarantine the suspected case.

Kondratowicz AS, Lennemann NJ, Sinn PL, Davey RA, Hunt CL, Moller-Tank S, Meyerholz DK, Rennert P, Mullins RF, Brindley M, Sandersfeld LM, Quinn K, Weller M, McCray PB Jr, Chiorini J, & Maury W (2011). T-cell immunoglobulin and mucin domain 1 (TIM-1) is a receptor for Zaire Ebolavirus and Lake Victoria Marburgvirus. PNAS, 108 (20), 8426-31 PMID: 21536871

Saeed MF, Kolokoltsov AA, Albrecht T, & Davey RA (2010). Cellular entry of ebola virus involves uptake by a macropinocytosis-like mechanism and subsequent trafficking through early and late endosomes. PLoS pathogens, 6 (9) PMID: 20862315

Albariño CG, Shoemaker T, Khristova ML, Wamala JF, Muyembe JJ, Balinandi S, Tumusiime A, Campbell S, Cannon D, Gibbons A, Bergeron E, Bird B, Dodd K, Spiropoulou C, Erickson BR, Guerrero L, Knust B, Nichol ST, Rollin PE, & Ströher U (2013). Genomic analysis of filoviruses associated with four viral hemorrhagic fever outbreaks in Uganda and the Democratic Republic of the Congo in 2012. Virology, 442 (2), 97-100 PMID: 23711383

Blaney JE et al. (epub May 30, 2013). Antibody quality and protection from lethal ebola virus challenge in nonhuman primates immunized with rabies virus based bivalent vaccine. PLoS Pathogens. DOI: 10.1371/journal.ppat.1003389. PMC: 3667758

Qiu X, Wong G, Fernando L, Audet J, Bello A, Strong J, Alimonti JB, & Kobinger GP (2013). mAbs and Ad-Vectored IFN-α therapy rescue ebola-infected nonhuman primates when administered after the detection of viremia and symptoms. Science translational medicine, 5 (207) PMID: 24132638

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