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Identification of NPC1 as the Target of U18666A, an Inhibitor of Lysosomal Cholesterol Export and Ebola Infection

eLife 2015;10.7554/eLife.12177 - DECEMBER 8, 2015
DOI: http://dx.doi.org/10.7554/eLife.12177

Abstract

Niemann-Pick C1 (NPC1) is a lysosomal membrane protein that exports cholesterol derived from receptor-mediated uptake of LDL, and it also mediates cellular entry of Ebola virus. Cholesterol export is inhibited by nanomolar concentrations of U18666A, a cationic sterol. To identify the target of U18666A, we synthesized U-X, a U18666A derivative with a benzophenone that permits ultraviolet-induced crosslinking. When added to CHO cells, U-X crosslinked to NPC1. Crosslinking was blocked by U18666A derivatives that block cholesterol export, but not derivatives lacking blocking activity. Crosslinking was prevented by point mutation in the sterol-sensing domain (SSD) of NPC1, but not by point mutation in the N-terminal domain (NTD). These data suggest that the SSD contains a U18666A-inhibitable site required for cholesterol export distinct from the cholesterol-binding site in the NTD. Inasmuch as inhibition of Ebola requires 100-fold higher concentrations of U18666A, the high affinity U16888A-binding site is likely not required for virus entry. 

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WADPI Aims to Exploit Lessons From Ebola Epidemic

observer.gm - by Saffiatou Colley  - December 3, 2015

The Executive Director of the National Disaster Management Agency (NDMA) has disclosed that the West Africa Disaster Preparedness Initiative’s (WADPI) main objective is to utilise the lessons learned from the Ebola epidemic as well as strengthen national capacities among the 16 West African countries to implement an all-hazards approach to disaster response and management.

Lt. Col. Alhagie Sanneh was speaking on Tuesday at the ongoing high-level discussion on the ‘Development of a strategic work plan and to conduct a post-course assessment’, at a local hotel in Brufut.

He indicated that the training is part of the requirements of the recent West Africa Disaster Preparedness Initiative training held in Ghana, where Gambia participated.

“The WADPI programme would develop and promote inter-regional integration through ensuring continuous collaboration, communication and coordination to explore preparedness strategies that can strengthen ECOWAS member states to manage and recover from disaster events,” he said.

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WADPI Ends Disaster Management Training

thenewdawnliberia.com - by Lewis S. Teh - edited by Jonathan Browne - December 1, 2015

The West Africa Disaster Preparedness Initiative or (WADPI) has ended a two weeks intensive training on disaster management in Monrovia.

The training, which began last week at the Golden Gate Hotel in Paynesville outside Monrovia, brought together officials of government line ministries and agencies, and commissions with 30 participants from five counties includingMontserrado, Gbarpolu, Bomi, Grand Cape Mount, and Margibi, respectively.

The exercise was conducted under the auspices of the West Africa Disaster Preparedness Initiative or WADPI in collaboration with the Kofi Annan International Peacekeeping Training Centre (KAIPTC) based in Ghana.

It was specifically meant to build capacities of ECOWAS countries to improve responses to disasters such as Ebola at the national and international levels, and other disasters that may occur.

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Liberia: 'Blood Transfusion' - Responsible For New Ebola Outbreak

allafrica.com - November 27, 2015

Investigation conducted by this paper has established that unsafe blood transfusion is probably responsible for the new Ebola outbreak in Liberia.

A 15-year-old-boy was last weekend tested positive for Ebola and later pronounced dead on Tuesday. Dr. Francis Kateh, Chief Medical Officer of Liberia, said the boy's parents have also been tested positive for the virus and were undergoing observation.

The Ministry of Health and its partners are yet to disclose the source of the new outbreak, but a weeklong investigation conducted by this paper has established that blood recently transfused into the boy's mother at the Benson Hospital in Paynesville is the probable cause of the new Ebola infection.

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Another American Ebola Survivor Had Eye Problems

Ebola survivor Dr. Richard Sacra experienced eye problems, including vision loss, pain and redness, shortly after he recovered from the disease.

Credit: Chancellor JR, Padmanabhan SP, Greenough TC, Sacra R, Ellison RT III, Madoff LC, et al. Uveitis and systemic inflammatory markers in convalescent phase of Ebola virusdisease. Emerg Infect Dis. 2016 Feb

CLICK HERE - STUDY - CDC - Uveitis and Systemic Inflammatory Markers in Convalescent Phase of Ebola Virus Disease

livescience.com - by Rachael Rettner - November 25, 2015

Ebola survivor Dr. Ian Crozier wasn't the only American to experience eye problems following the disease — a new report describes eye problems in another American doctor who lived through the disease.

Dr. Richard Sacra, who works for the Christian mission organization SIM USA, contracted Ebola last year while caring for pregnant women in Liberia during the rise of the Ebola outbreak there. He was evacuated to the United States for treatment in early September 2014, and was declared Ebola-free after spending about a month in the hospital.

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Panels Advise Bolstering W.H.O. for Crises Like Ebola

nytimes.com - by Sheri Fink - November 22, 2015

In recent months, numerous groups of health experts have gathered to debate how to prevent another crisis like the Ebola epidemic in West Africa, which jumped borders, spread fear across the globe, and directly killed more than 11,000 people. Many more died as hospitals and clinics closed for months.

Now two of those groups — one independent and the other convened by the World Health Organization — have released specific recommendations and called for urgent action. Both concluded that the W.H.O.’s outbreak and emergency response capacities should be strengthened and consolidated, protected from political meddling and independently overseen. The health organization is a United Nations agency.

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CLICK HERE - WHO - Advisory Group on Reform of WHO’s Work in Outbreaks and Emergencies with Health and Humanitarian Consequences

CLICK HERE - WHO - First report of the Advisory Group on Reform of WHO’s work in outbreaks and emergencies (20 page .PDF report)

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Interferon-γ Inhibits Ebola Virus Infection

submitted by George Hurlburt

                                                         

CLICK HERE - STUDY - Interferon-γ Inhibits Ebola Virus Infection

scicasts.com - November 19, 2015

The recent Ebola outbreak in West Africa has claimed more than 11,300 lives and starkly revealed the lack of effective options for treating or preventing the disease. Progress has been made on developing vaccines, but there is still a need for antiviral therapies to protect health care workers and local populations in the event of future outbreaks.

A new study led by University of Iowa virologist Dr. Wendy Maury, suggests that gamma interferon, which is an FDA-approved drug, may have potential as an antiviral therapy to prevent Ebola infection when given either before or after exposure to the virus.

The study, published in the journal PLOS Pathogens, found that gamma interferon, given up to 24 hours after exposure, can inhibit Ebola infection in mice and completely protect the animals from death.

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CDC - Ebola Virus RNA Stability in Human Blood and Urine in West Africa’s Environmental Conditions

cdc.gov

Janvier F, Delaune D, Poyot T, Valade E, Mérens A, Rollin PE, et al.

CLICK HERE - Ebola virus RNA stability in human blood and urine in West Africa’s environmental conditions
Emerg Infect Dis. 2016 Feb. http://dx.doi.org/10.3201/eid2202.151395

DOI: 10.3201/eid2202.151395

Abstract

We evaluated RNA stability of Ebola virus in EDTA blood and urine samples collected from infected patients and stored in West Africa’s environmental conditions. In blood, RNA was stable for at least 18 days when initial cycle threshold values were <30, but in urine, RNA degradation occurred more quickly.

 

 

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Ebolavirus Evolution: Past and Present

PLOS PATHOGENS  by Marc-Antoine de La Vega,  Derek Stein, and GaryKopinger, University of Manitoba, Canada , Nov. 12, 2015    

Winnipeg, Manitoba, Canada The past year has marked the most devastating Ebola outbreak the world has ever witnessed, with over 28,000 cases and over 11,000 deaths. Ebola virus (EBOV) has now been around for almost 50 years. In this review, we discuss past and present outbreaks of EBOV and how those variants evolved over time. We explore and discuss selective pressures that drive the evolution of different Ebola variants, and how they may modify the efficacy of therapeutic treatments and vaccines currently being developed. Finally, given the unprecedented size and spread of the outbreak, as well as the extended period of replication in human hosts, specific attention is given to the 2014–2015 West African outbreak variant (Makona).

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http://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1005221

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