Alphaviruses are members of the Togaviridae family and include human pathogens known to cause fever, rash, arthritis (Sindbis, Chikungunya, O??nyong-nyong, and Ross River virus) and encephalitis (Eastern equine encephalitis, Venezuelan equine encephalitis, and Western equine encephalitis virus) in many parts of the world. These viruses are a major health concern due to their ability to emerge and cause major epidemics (due either to intentional release during a bioterrorism attack or to widespread natural emergence). The latter has been seen with the recent epidemic of Chikungunya virus in La R??union Island and India, highlighting our need for a better understanding of the host response to this family of viruses. Type I IFNs, which are composed of up to 13 IFN alphas and a single IFN-beta, -kappa, -epsilon, and - omega, are known to play a central role in the innate immune response mounted against alphaviruses, since deletion of the type I receptor results in dissemination of the virus to multiple organs and early lethality in both neonates and adults infected with CHIKV. However, little is known about the function of the individual subtypes of IFN and how they contribute to the host response to viral infection. We have begun to analyze the role of IFN?? and IFN?? during CHIKV infection by utilizing subtype specific knockout mice and have made the following new observations. First, mice lacking IFN-?? are more susceptible to CHIKV induced lethality, although not to the same degree as IFNAR1-/- mice, indicating other subtypes also have antiviral activity. Second, mice lacking IFN-?? are resistant to CHIKV induced lethality. This proposal will explore the host response to CHIKV infection in the absence of IFN-kappa and begin to analyze differences in receptor activation and signaling between IFN-B and IFN-k. The results obtained from these studies will provide important insight into the mechanism of action of IFN-kappa and provide a potential new therapeutic target in the fight against alphavirus infections.

Public Health Relevance

Type I interferons play a role in the host response against several human pathogens, including the reemerging alphavirus, Chikungunya virus. This proposal will explore the mechanism by which IFN-kappa regulates Chikungunya virus pathogenesis and its ability to cause disease. These studies may provide insight into new therapeutic targets in the fight against viral infection.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Specialized Center--Cooperative Agreements (U54)
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Special Emphasis Panel (ZAI1-DDS-M)
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Washington University
Saint Louis
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