Yellow fever is a disease that can result in symptoms ranging from fever to severe liver damage. Found in South America and sub-Saharan Africa, each year the disease results in 200,000 new cases and kills 30,000 people. About 900 million people are at risk of contracting the disease.
Now a research team led by a biomedical scientist at the University of California, Riverside has determined that the yellow fever virus, a hemorrhagic fever virus, replicates primarily in the liver. Therefore, other organ failures that often follow in people with the disease are due to secondary effects.
When the virus targets the liver, it replicates rapidly causing significant damage to liver cells. In the process, inflammatory cytokines – proteins secreted by cells especially of the immune system – are made in massive amounts, which soon gain access to the blood stream. These cytokines are most likely responsible for the damage to distant organs, the research team’s findings suggest. The research team also identified a clinical parameter that could greatly help in managing yellow fever cases.
“Yellow fever causes severe loss of lymphocytes,” said Ilhem Messaoudi, an associate professor of biomedical sciences in the UC Riverside School of Medicine, who led the research project. “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.”
Study results appear in PLOS Neglected Tropical Diseases.
The research, performed on rhesus macaques (currently, the best model for studying human yellow fever infection) at Oregon National Primate Research Center, is the first study on yellow fever in non-human primates in more than 20 years.
“Yellow fever is truly a neglected tropical disease,” Messaoudi said. “Even though it continues to cause fatality, it remains understudied. 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.”
According to Messaoudi, a good understanding of the pathophysiology of yellow fever in a robust animal model gives researchers also a preclinical animal model for testing new inactivated vaccines, which would be much safer for infants and the elderly.
She explained that yellow fever is characterized by two phases. During the acute phase, the patient has fever and myalgia – not exactly disease-specific symptoms. These symptoms last about 48 hours. While most people are able to resolve them, some enter remission in which the fever disappears for about 24 hours only to be followed by the toxic phase in which viral loads greatly increase. Yellowing of the skin and the whites of the eyes (which is what gives the disease its name) is a consequence of liver failure.
Pathophysiologic and Transcriptomic Analyses of Viscerotropic Yellow Fever in a Rhesus Macaque Model, Engelmann F, Josset L, Girke T, Park B, Barron A, et al., PLoS Negl Trop Dis, doi:10.1371/journal.pntd.0003295, published 20 November 2014.
This work was supported by the National Institutes of Health www.nih.gov U54 AI081680 (MKS IM), R44 AI079898 (MKS), and 8P51 OD011092-53 (MKS IM). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Oregon Health and Science University, MKS, and EH declare a financial interest based on shares in Najít Technologies, Inc., a company that may have a commercial interest in the results of this research and technology. This potential individual and institutional conflict of interest has been reviewed and managed by Oregon Health and Science University. This does not alter our adherence to all PLOS policies on sharing data and materials.