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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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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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How Technology Can Help Reboot Ebola-Free Sierra Leone

submitted by George Hurlburt  

             

The new Sensi Technology Innovation Hub hopes to help the country rebuild after its Ebola crisis

cnn.com - by Peter Guest - November 7, 2015

(CNN) - Morris Marah was working in the Sierra Leonean High Commission in London when the devastating Ebola outbreak struck his country last year.

Desperate to help, he went home; first to volunteer in a community health center, then by applying his technology skills to build an SMS-based platform that disseminated weekly information and advice on how to avoid contracting the disease to more than 500,000 people.

"I felt, sitting in London there wasn't much I could do from that far away. I wanted desperately to come out here and see how I could be useful," he says over the phone from the capital, Freetown.

Working on that platform, called Sensi, and on other public health initiatives demonstrated how successfully technology could be leveraged for social good, and inspired him to look for ways to bring the country's small, but talented, tech community together to help restart the country's stalled economy.

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How Much Did Ebola Cost Sierra Leone?

submitted by George Hurlburt

             

(Francisco Leong / Getty News Images)

cnn.com - by Peter Guest - November 12, 2015

. . . Before the outbreak, Sierra Leone was already heavily dependent on aid money. Around 50% of public expenditure programmes were financed by donors, according to UN figures. . . .

. . . Without growth and investment, the country will struggle to create jobs for its young population -- many of whom lack stable employment -- and rebuild public services.

The government's recovery strategy, which is supported by the international community, is about "building back better," says Sudipto Mukerjee, the United Nations Development Program's country director for Sierra Leone. This is particularly relevant to the health sector, which was seriously under-developed before the crisis began, and its weakness undoubtedly contributed to the speed with which the outbreak got out of control.

"When you're talking about the health sector, you're not talking about bringing it back to where you were at the beginning of the outbreak," he says. "That's not good enough. It's also about making sure that you not only build on the investments made so far, but you invest to make it much more resilient in the future."

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How Ebola Spread: Map Could Aid Outbreak Responses

submitted by George Hurlburt

          

CLICK HERE - STUDY - Transmission network of the 2014–2015 Ebola epidemic in Sierra Leone

livescience.com - by Agata Blaszczak-Boxe - November 10, 2015

A new map reveals the path that the Ebola virus took during the outbreak in Sierra Leone, giving a detailed picture of how and where the disease spread, a new study said.

The researchers made the map using a new statistical model, and they say it could be used in the future to improve the way help is delivered to outbreak regions.

"For a future outbreak, this is something that can be readily applied to help identify the regions that need intervention most critically," said study author Jeffrey Shaman, an associate professor of environmental health sciences at Columbia University's Mailman School of Public Health. The model could help authorities figure out where to best deploy people to respond to the outbreak, he said.

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Sierra Leone May Be Ebola-Free But The Virus Still Casts A Shadow

Health workers in Sierra Leone check travelers entering the country from Liberia. Zoom Dosso/AFP/Getty Images

Image: Health workers in Sierra Leone check travelers entering the country from Liberia. Zoom Dosso/AFP/Getty Images

npr.org - November 7th, 2015 - Nahid Bhadelia

Today marks the 42nd day that Sierra Leone has had no new cases of Ebola. That potentially signals the end of the epidemic in that country.

I spent almost three months in Sierra Leone over the last year, both as a clinician in Ebola treatment units and as an infection control educator.

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