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. Individuals infected with an arthritogenic alphavirus, which includes chikungunya (CHIKV), Ross River (RRV), and Mayaro (MAYV) viruses, develop fever, malaise, myalgia, rash, and debilitating polyarthritis and polyarthralgia. While infection with encephalitic alphaviruses, including Venezuelan equine encephalitis (VEEV), eastern equine encephalitis (EEEV), and western equine encephalitis (WEEV) viruses, can result in fever, headache, and encephalitis. For a subset of individuals, severe joint pain or neurological sequalae can persist for months to years. While CHIKV is globally distributed, the other viruses are more geographically isolated (e.g., MAYV is primarily found in South America, RRV in Australia and Pacific Islands, VEEV, EEEV, and WEEV are found in the Americas) but pose a significant risk of spreading into other regions. There are currently no approved vaccines or therapeutics to prevent or treat the acute or chronic stages of disease. Alphavirus-infected individuals develop innate and adaptive immune responses which 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, antibodies are the main correlate of protection for vaccine approaches. 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.