Overview

Flaviviruses are transmitted to humans by mosquitoes or ticks and can cause a range of symptoms from a mild fever to severe hemorrhagic or neuroinvasive disease. Increased global trade and connectivity have fueled the geographical expansion of the mosquito vector for flaviviruses such as dengue virus (DENV) and Zika virus, and climate change threatens further spread, highlighting the need for effective clinical interventions to protect against these viruses.

Designing an effective vaccine against DENV has been hampered by the complexity of the antibody response to the four circulating viral serotypes (DENV1-4). Although antibodies play a critical role in flavivirus immunity, pre-existing antibodies from a primary DENV infection with one serotype are associated with severe disease following subsequent infection with a different DENV serotype.

Our research program aims to identify the viral and host determinants of protective and pathogenic functions of antibodies against flaviviruses. Our overall goal is to inform vaccine design and discover drug targets.

The Role of Antibodies in Dengue Virus Pathogenesis

Despite a well-established epidemiological link, little is known about the mechanisms by which antibodies contribute to severe dengue disease following secondary infection with a different serotype. This phenomenon is partly attributed to the prevalence of cross-reactive antibodies from primary infection that can bind, but not neutralize the secondary virus. Instead, these antibodies have the potential to facilitate viral uptake into target cells in a process known as antibody-dependent enhancement (ADE).

We use genome-wide knockout screens and single-cell transcriptomics to define host factors and pathways that distinguish direct DENV infection from indirect infection via ADE to gain insight into how the latter contributes to pathogenesis.

The Role of Antibodies in Flavivirus Immunity

The development of neutralizing antibodies is an important component of most successful vaccines, including those against flaviviruses such as Yellow Fever virus and Japanese encephalitis virus.  For DENV, a safe and effective vaccine should elicit durable and potent neutralizing antibodies against all four serotypes simultaneously to minimize the risk of ADE. Moreover, given the co-circulation of related flaviviruses in many geographical regions, antibodies that can potently neutralize multiple flaviviruses are desirable. The viral and host determinants leading to the development of such broadly neutralizing antibodies are poorly understood.

We analyze single B cells from flavivirus-immune individuals to isolate highly functional antibodies and map their targets on the virus surface envelope protein. In parallel, we use next-generation sequencing and analysis of the B cell repertoire to understand how these antibodies evolve. Finally, we want to understand how the complex interplay among antibodies of different specificities and functions present following infection or vaccination impacts overall immunity. These studies will inform the design of improved vaccines and therapeutic antibodies.