Wednesday, May 09, 2018

Ebola In The DRC & Cell Repts. Study On Ebola Makona Mutations


Although details are still filtering in, the big story yesterday (while I was away from my desk) was the announced outbreak of Ebola in the DRC (see Crof's blog New Ebola outbreak in DRC: 21 registered cases, including 17 deaths).
This is the first Ebola outbreak of 2018, although last year the DRC reported an outbreak in Bas Uele Province (see WHO Update: Ebola In the DRC) and last fall Uganda reported a limited outbreak of Marburg (see WHO Update: Marburg Virus In Uganda & Kenya).
As we discussed a week ago in WHO Handbook: Managing Epidemics, and  last March in WHO List Of Blueprint Priority Diseases, Ebola virus disease and the (closely related) Marburg virus are on the short list of pathogens viewed as having the potential to spark major public health emergencies and are in urgent need of accelerated research and the development of effective therapeutics. 
Less than two weeks ago, in mBio: Statins Suppress Ebola Infectivity In Vitro, we looked at one possible avenue of investigation, while last year in Cell: Researchers Identify Broadly Protective Antibodies In Ebola Survivor we looked at another.

Prior to 2014, Ebola outbreaks had historically been fairly small and self limiting. The unprecedented West African epidemic  - which affected more than 30,000 people, killing more than 11,000 - shattered conventional wisdom.

We also saw exported cases turn up in both the United States and in Europe, demonstrating that Ebola has the ability to become more than just a regional threat. Hence the ongoing training of medical workers in the safe handling of highly infectious patients.
HHS National Exercise On Moving Infectious Patients
HHS Launches National Ebola Training & Education Center
Fact Sheet Safe Handling, Treatment, Transport and Disposal of Ebola-Contaminated Waste
CDC Ebola Guidance: Web Based PPE Training
The West African epidemic was notable not only for its size, but for the rapid mutation of the Ebola virus, which sparked fears that might be driving both its virulence and transmissibility (see Nature News Ebola virus mutating rapidly as it spreads).
While many mutations were documented over the summer of 2014, their impact on the behavior and fitness of the virus was far less apparent.
Which brings us to a new study, funded by the N.I.H., which appeared yesterday in Cell Reports, which looks at the effects of these mutations in two animal models (mice and rhesus macaques).

Their major finding is in the title of their paper.  You can follow the link to read the full open-access study, or the link (following the study) to the N.I.H. press release that summarizes their findings.
Recently Identified Mutations in the Ebola Virus-Makona Genome Do Not Alter Pathogenicity in Animal Models
Andrea Marz Spencer Chadinah , Elaine Haddock, Friederike Feldmann, Nicolette Arndt, Cynthia Martellaro, Dana P. Scott, Patrick W. Hanley, Tolbert G. Nyenswah, Samba Sow, Moses Massaquoi, Heinz Feldmann5

Open Access

  • Distinct EBOV-Makona isolates cause severe disease in IFNAR−/− mice and rhesus macaques
  • Recent mutations in the EBOV-Makona genome do not alter pathogenicity in animal models
  • EBOV-Makona isolates show attenuated pathogenicity in animals compared to EBOV-Mayinga
Ebola virus (EBOV), isolate Makona, the causative agent of the West African EBOV epidemic, has been the subject of numerous investigations to determine the genetic diversity and its potential implication for virus biology, pathogenicity, and transmissibility. Despite various mutations that have emerged over time through multiple human-to-human transmission chains, their biological relevance remains questionable. 

Recently, mutations in the glycoprotein GP and polymerase L, which emerged and stabilized early during the outbreak, have been associated with improved viral fitness in cell culture. Here, we infected mice and rhesus macaques with EBOV-Makona isolates carrying or lacking those mutations. Surprisingly, all isolates behaved very similarly independent of the genotype, causing severe or lethal disease in mice and macaques, respectively. Likewise, we could not detect any evidence for differences in virus shedding. 

Thus, no specific biological phenotype could be associated with these EBOV-Makona mutations in two animal models.
        (Continue . . . . )

Despite Mutations in Makona Ebola Virus, Disease Consistent in Mice, Monkeys

May 8, 2018

Early during the recent Ebola epidemic in West Africa, scientists speculated that the genetic diversity of the circulating Makona strain of virus (EBOV-Makona) would result in more severe disease and more transmissibility than prior strains. However, using two different animal models, National Institutes of Health scientists have determined that certain mutations stabilized early during the epidemic and did not alter Ebola disease presentation or outcome. Their work, published in Cell Reports, offers further evidence to support previous findings from molecular sequencing that the diversity of EBOV-Makona did not significantly impact the course of disease.

EBOV-Makona swept through Liberia, Guinea and Sierra Leone from late 2013 to early 2016. Scientists from NIH’s National Institute of Allergy and Infectious Diseases (NIAID) compared EBOV-Makona isolates from early in the outbreak—March 2014—to isolates circulating between five and nine months later, when certain mutations had emerged in the viral surface glycoprotein and elsewhere. They then infected mice and rhesus macaques with these various virus isolates to assess disease progression and viral shedding.

“We were unable to find any significant differences between early and late isolates lacking or carrying those mutations, suggesting that these mutations do not lead to alterations in the disease-causing ability in animal models,” the authors write.

They also compared their results from the EBOV-Makona isolates to findings from macaques infected with the original EBOV-Mayinga strain from 1976. They determined that EBOV-Makona is less virulent than EBOV-Mayinga.

No convincing finding has been published showing that EBOV-Makona bears unusual biological features explaining increased pathogenicity or transmissibility, the authors write. The NIAID group suggests intensifying studies on non-viral factors that may explain increased case numbers and fatalities.

Examples include population mobility, available health care, and virus persistence in survivors—all which may affect outbreak dynamics.

A Marzi et al. Recently identified mutations in the Ebola virus-Makona genome do not alter pathogenicity in animal models. Cell Reports DOI: 10.1016/j.celrep.2018.04.027 (2018).

Heinz Feldmann, M.D., Ph.D., chief of NIAID’s Laboratory of Virology, and Andrea Marzi, Ph.D., staff scientist, are available to comment on this study.

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