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 outbreaks 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 therapeutic treatments. 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) and Mayaro (MAYV) viruses. CHIKV was first identified in Tanzania in 1952, but has since spread into India, Southeast Asia, and Polynesia. In 2013, CHIKV emerged in the Caribbean and caused explosive outbreaks in Central and South America. Previously, alphaviruses were predominantly geographically isolated; however, with the global spread of CHIKV, there is potential for overlap and cross-protection. 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 is no approved vaccines or therapeutics to prevent disease 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 (FcR) interaction. Importantly, antibody development is the primary goal of vaccine efforts. Identification and characterization of broadly neutralizing anti-alphavirus antibodies 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.