Mechanisms of immune-mediated protection and pathogenesis during viral infections

National Institute Of Allergy And Infectious Diseases

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Abstract

Viruses have caused the majority of epidemics and pandemics over the last century. Rapid development of small animal models and understanding of the mechanisms that promote long-term protection to viral infections are critical for the development of vaccines and therapeutics. Alphaviruses are emerging and re-emerging RNA viruses that are primarily transmitted by mosquitoes and have caused outbreaks worldwide. These viruses can be further divided into the arthritogenic or encephalitic alphaviruses based on the disease manifestation observed in infected individuals. The EVIU primarily studies the arthritogenic alphaviruses, which includes chikungunya (CHIKV), Ross River (RRV), and Mayaro (MAYV) viruses. Since first bring identified in 1952 in Tanzania, CHIKV has rapidly expanded its geographical distribution to include India, Southeast Asia, and Polynesia. In 2013, CHIKV emerged in the Caribbean and caused explosive outbreaks in Central and South America. Other alphaviruses have remained more geographically isolated (e.g., MAYV is primarily found in South America and RRV in Australia and Pacific Islands) but pose a significant threat to emerge in other regions. With the global spread of CHIKV, there is increasing overlap in the endemic regions of these related viruses. Individuals infected with an arthritogenic alphavirus develop fever, malaise, myalgia, rash, and debilitating polyarthritis and polyarthralgia. For a subset of individuals, severe joint pain can persist for months to years, depending on the virus. There currently are no approved vaccines or therapeutics to prevent or treat the acute or chronic stages of disease. Innate and adaptive immune responses are essential to prevent mortality and clear infectious virus. Specifically, antibodies have been shown to prevent and reduce alphavirus disease through neutralization and Fc-Fc gamma receptor interaction. Importantly, antibody development is the primary goal of vaccine efforts. Characterization of broadly neutralizing anti-alphavirus antibodies and understanding of the required features for optimal antibody-mediated protection could provide treatment possibilities across multiple alphavirus and inform design of pan-alphavirus treatments. By interrogating alphavirus immunity and antibody-based therapies, our laboratory aims to define mechanisms of protection, pathogenesis, and heterologous immunity to development novel vaccines and therapies.