Mechanisms of immune-mediated protection and pathogenesis during viral infections

National Institute Of Allergy And Infectious Diseases

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Abstract

Alphaviruses are emerging and re-emerging RNA viruses that are primarily transmitted by mosquitoes and have caused outbreaks worldwide. Alphaviruses can be further divided into arthritogenic and encephalitic based on the disease manifestations observed in infected individuals. Individuals infected with an arthritogenic alphavirus, including chikungunya (CHIKV), Ross River (RRV), and Mayaro (MAYV) viruses, develop fever, malaise, myalgia, rash, and debilitating polyarthritis and polyarthralgia. Infection with an encephalitic alphavirus, including Venezuelan equine encephalitis virus (VEEV), can result in fever, headache, and encephalitis. Infected individuals can develop a chronic disease characterized by severe joint pain or neurological sequelae that persist for months to years following infection. With the global movement of humans and the expanding range of mosquitoes, there remains a serious threat of alphavirus outbreaks and spread to other regions. There are currently no approved alphavirus-specific therapeutics to treat the acute or chronic stages of disease. The increasing geographical overlap of alphavirus endemic regions highlights the need for broadly effective therapeutics that can provide pan-alphavirus protection. Alphavirus-infected individuals develop innate and adaptive immune responses that are essential to prevent mortality and clear infectious virus. Specifically, monoclonal antibodies (mAbs) have been shown to prevent and reduce alphavirus disease through neutralization and Fc-Fc gamma receptor (FcγR) interaction. Characterization of broadly neutralizing anti-alphavirus antibodies and understanding of the required features for optimal antibody-mediated protection could provide treatment possibilities across multiple alphaviruses and inform the design of pan-alphavirus therapeutics. By investigating alphavirus immunity and antibody-based therapies, our laboratory aims to define mechanisms of protection, pathogenesis, and heterologous immunity to develop novel therapies to treat acute and chronic disease. In FY25, our studies for this project characterized anti-alphavirus mAbs and the endogenous antibody response following alphavirus infection, with a focus on Fc effector functions. We evaluated the mechanisms of protection for broadly reactive anti-alphavirus mAbs during VEEV infection using mouse models with prophylactic and therapeutic mAb administration. We employed in vitro assays to assess mAb functionality, then linked these functional attributes back to in vivo protection. From this work, we confirmed an anti-alphavirus mAb as a promising candidate for intervention against multiple alphaviruses and established in vitro assays that could be used to identify protective anti-alphavirus mAbs. We also determined the necessity of activating FcγRs for alphavirus disease resolution in mice, with a focus on the emerging alphavirus, MAYV. This work determined that the interaction of activating FcγRs with the endogenous antibody response is necessary to prevent prolonged MAYV infection and to suppress a pro-viral response in monocytes. Finally, we confirmed the neutralization efficacy of anti-CHIKV mAbs generated in tobacco plants, which offers a more affordable method to manufacture recombinant anti-viral antibodies. In sum, this project identified correlates of antibody-mediated protection that will facilitate the development of enhanced mAb-based therapeutics for alphaviruses.