Research
Viral Pathogenesis
Many emerging vector-borne flaviviruses have the ability to invade the central nervous system and cause neurological symptoms. Zika Virus, West Nile Virus, and Usutu Virus are emerging flaviviruses of public health importance. During pregnancy, Zika is able to cross the blood-placental barrier and cause serious birth defects in the baby. West Nile Virus and Usutu Virus are both mosquito-borne bird flaviviruses that can cause encephalitis in humans upon crossing the blood-brain barrier. Although all three of these flaviviruses are neuroinvasive, they differ in pathogenesis and epidemiology. We are interested in investigating the innate immune mechanisms underlying the differential pathogenesis of neuroinvasive flaviviruses.
Dengue is a mosquito-borne flavivirus that causes hundreds of millions of infections each year. Dengue virus biology is complicated by the fact that Dengue has four serotypes, each of which are genetically distinct. While primary infection with one serotype generally leads to an asymptomatic or mild symptomatic case, a subsequent infection with a different serotype can cause severe disease, including Dengue Hemorrhagic Fever and Dengue Shock Syndrome. Each year, around 40,000 children die from Dengue. It is thought that antibodies generated during the primary infection facilitate Dengue virus entry into immune cells during a second infection by the binding of the Fc region of the antibody to the Fcγ receptor of immune cells. This phenomenon causes enhanced viral replication and more severe disease and is called antibody-dependent enhancement (ADE). We are interested in investigating mechanisms of ADE of replication and inflammation.
Chikungunya is a mosquito-borne alphavirus that causes hundreds of thousands of infections per year. Chikungunya rose to fame in 2013 when it caused a massive outbreak in the Caribbean and spread to Central and South America, where it is now endemic. Chikungunya infection causes severe acute joint and muscle pain. At least 10% of cases result in chronic arthralgia, which is a debilitating condition that lasts for months or years. The immune mechanisms underlying Chikungunya-associated chronic inflammation and pain is not well understood. We are interested in understanding what happens during and after acute Chikungunya infection that leads to chronic arthralgia.
Vaccinology
As the number of global Dengue cases has been on the rise, there has been an increased interest in the development of Dengue vaccines. In 2015, Dengvaxia, a tetravalent live-attenuated vaccine, was rolled out in the Philippines. Dengaxia at first appeared promising because it has the same backbone as the successful Yellow Fever Virus 17D Vaccine. However, while the 17D vaccine provides long-term, and perhaps life-long, immunity, Dengvaxia provides only temporary immunity, at best, and actually causes disease enhancement, at worst. Since the initial roll-out of Dengvaxia, it has become widely thought that Dengvaxia puts seronegative children — or children who test negative for a prior dengue infection at the time of vaccination — at risk for the development of more severe disease upon subsequent infection. It is widely thought that Dengvaxia-associated antibody-dependent enhancement (ADE) contributes to the poor outcome of seronegative vaccinated children. We are interested in investigating differences between the memory B cells and antibodies generated by the 17D and Dengvaxia vaccines to determine what makes the 17D vaccine so successful and the Dengvaxia vaccine so unsuccessful.
As Dengvaxia may put certain populations at risk for disease severity, we are interested in developing an mRNA-based vaccine approach for dengue virus. Ideally, a dengue vaccine would provide long-lasting, and superior immunity that may avoid features of live-attenuated vaccines or natural infection that increases disease severity in humans.
So far in the 21st century, there have been three significant coronavirus outbreaks. The SARS-CoV outbreak in 2003-2004 caused over 8000 infections and at least 770 deaths. Since 2012, MERS-CoV has caused 2,622 cases and 950 deaths. While SARS-CoV and MERS-CoV were more regionally confined, SARS-CoV-2 caused the COVID-19 pandemic that caused global havoc. Thankfully, within about one year of the pandemic commencing, mRNA vaccines targeting the SARS-CoV-2 spike protein were developed that significantly reduced the risk of severe or fatal disease from COVID-19. However, each year we now need an updated SARS-CoV-2 vaccine due to mutations incurred by the Spike protein and waning antibody titers in vaccinated individuals. We therefore need to develop an mRNA-based vaccine that produces longer lasting immunity towards current and future SARS-CoV-2 variants. As SARS- or MERS-related bat zoonotic coronaviruses will likely continue to cause public health threats, it is important to work towards the development of pan-coronavirus vaccines. We are interested in contributing to these efforts.