Yellow fever research breakthrough could lead to better treatment

Yellow fever is an infectious tropical virus disease that can be caught from the bite of an infected mosquito and has symptoms ranging from self-limiting fever to severe liver damage with bleeding. 

Although it is an important and potentially deadly human disease, the basis of its severity is not well understood. Now, a new study has found changes in white blood cells that could signal an early sign of fatal yellow fever and may lead to better diagnosis and treatment.

Researchers have found changes in white blood cells that could signal an early sign of fatal yellow fever - a mosquito-borne disease that infects 200,000 people a year.

Results of the study, led by the University of California (UC)-Riverside, appear in the journal PLOS Neglected Tropical Diseases.

About 900 million people are at risk of contracting yellow fever, a hemorrhagic fever virus that infects around 200,000 and kills 30,000 people a year in South America and sub-Saharan Africa.

While many people who contract yellow fever do not experience symptoms, the disease can cause cardiovascular shock and multiple organ failure.

Because of the sporadic nature and remote locations of yellow fever outbreaks, few studies have examined the changes in the body that occur during infection and what happens in severe infection.

Yellow fever is a 'truly neglected tropical disease'

For their study, the team examined the effects of yellow fever virus in rhesus macaques at Oregon National Primate Research Center. Their project is the first study of yellow fever in non-human primates in more than 20 years.

Researchers at UC-Riverside's School of Medicine, describes yellow fever as a "truly neglected tropical disease," and say:

"While it is true there is a highly effective vaccine, it remains extremely challenging to get comprehensive vaccine coverage in sub-Saharan Africa and Latin America. Moreover, the vaccine works well if you are between one and 55 years old. It is not safe for babies or the elderly, who could develop yellow fever from the vaccine."

The researchers have discovered that the yellow fever virus replicates primarily in the liver, indicating that other organ failures that often follow in people with the disease are due to knock-on effects.

Yellow fever causes loss of white blood cells and huge change in genes

Once it gets into the liver, the yellow fever virus damages the liver cells and causes them and immune cells to release large amounts of cytokines into the bloodstream. The researchers suggest these inflammatory proteins are most likely what cause the damage to other organs.

The team also found these events in the liver are preceded by severe loss of lymphocytes, a type of white blood cell.

The research team explains how spotting loss of lymphocytes could be useful for managing yellow fever cases:

"This process, called lymphopenia, occurs before any measurable changes in liver enzymes can be detected - that is, about a day or so before we see changes in the liver. It could provide an earlier clinical outcome measure of subsequent disease severity, giving doctors a good prognostic tool for offering more aggressive supportive care for these patients."

The team also studied changes in gene expression in white blood cells during the early stages of yellow fever infection - before clinical symptoms emerge and before the monkeys showed any signs of being sick.

They found that 3 days after infection, the virus had changed the expression of over 700 genes - many of which suppress immunity and cause cell death.

The researchers describe the large change in gene expression:

"In just 72 hours after infection, half of the genes were up-regulated, or turned on, while the rest were down-regulated. Also, about two thirds of genes related to some function of the immune system were suppressed by the infection. Those that were up-regulated were highly pro-inflammatory cytokines, which likely cause organ damage."

On the other hand, the researchers found that yellow fever vaccine induced expression of many genes for antiviral immunity - genes that are good for making antibodies that fight the infection when it occurs.

Findings may lead to faster diagnosis of yellow fever severity

The findings lead researchers to wonder if gene expression could be used as a clinical diagnosis tool for yellow fever:

Could  they run a quick analysis on patients' white blood cells and determine which infected person is at high or low risk? Supportive care would follow for all patients, but it would change the dynamics of how aggressive the treatment needs to be.

Yellow fever kills up to 50% of people who do not receive the vaccine. In 32 African countries and 13 South American countries, the virus is either endemic or causes intermittent outbreaks. The Centers for Disease Control and Prevention (CDC) say yellow fever is a rare cause of illness for US travelers.

There is no specific treatment for yellow fever, note the CDC - care is based on symptoms. Prevention measures include getting vaccinated, using insect repellent and wearing protective clothing.

The team now plans to study what happens to the genes of animals that survive yellow fever infection, and they also want to find out which viral proteins block the immune system, as this could lead to new antiviral drugs.

Funds for the study came from the National Institute of Allergy and Infectious Diseases, which is one of the National Institutes of Health.

References:

Pathophysiologic and Transcriptomic Analyses of Viscerotropic Yellow Fever in a Rhesus Macaque Model, Flora Engelmann, PLoS Negl Trop Dis, doi:10.1371/journal.pntd.0003295, published online 20 November 2014.
University of California-Riverside news release, accessed 24 November 2014.