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- All Subjects: Dengue
- Creators: Angilletta, Michael J
Description
Flavivirus infections are emerging as significant threats to human health around the globe. Among them West Nile(WNV) and Dengue Virus (DV) are the most prevalent in causing human disease with WNV outbreaks occurring in all areas around the world and DV epidemics in more than 100 countries. WNV is a neurotropic virus capable of causing meningitis and encephalitis in humans. Currently, there are no therapeutic treatments or vaccines available. The expanding epidemic of WNV demands studies that develop efficacious therapeutics and vaccines and produce them rapidly and inexpensively. In response, our lab developed a plant-derived monoclonal antibody (mAb) (pHu-E16) against DIII (WNV antigen) that is able to neutralize and prevent mice from lethal infection. However, this drug has a short window of efficacy due to pHu-E16's inability to cross the Blood Brain Barrier (BBB) and enter the brain. Here, we constructed a bifunctional diabody, which couples the neutralizing activity of E16 and BBB penetrating activity of 8D3 mAb. We also produced a plant-derived E16 scFv-CH1-3 variant with equivalent specific binding as the full pHu-E16 mAb, but only requiring one gene construct for production. Furthermore, a WNV vaccine based on plant-derived DIII was developed showing proper folding and potentially protective immune response in mice. DV causes severe hemorrhaging diseases especially in people exposed to secondary DV infection from a heterotypic strain. It is hypothesized that sub-neutralizing cross-reactive antibodies from the first exposure aid the second infection in a process called antibody-dependent enhancement (ADE). ADE depends on the ability of mAb to bind Fc receptors (FcγRs), and has become a major roadblock for developing mAb-based therapeutics against DV. We aim to produce an anti-Dengue mAb (E60) in different glycoengineered plant lines that exhibit reduced/differential binding to FcγRs, therefore, reducing or eliminating ADE. We have successfully cloned the molecular constructs of E60, and expressed it in two plant lines with different glycosylation patterns. We demonstrated that both plant-derived E60 mAb glycoforms retained specific recognition and neutralization activity against DV. Overall, our study demonstrates great strives to develop efficacious therapeutics and potent vaccine candidates against Flaviviruses in plant expression systems.
ContributorsHurtado, Jonathan (Author) / Chen, Qiang (Thesis advisor) / Huffman, Holly A (Committee member) / Steele, Kelly P (Committee member) / Arizona State University (Publisher)
Created2014
Description
The global spread of the Aedes aegypti mosquito, a competent disease vector, is occurring at an alarming pace. These invasive mosquitos have spread to latitudes once thought inaccessible due to thermal and hydric limitations, including Maricopa County, AZ, where strong increases in population size has occurred over the last decade. The Aedes aegypti in Maricopa County follow a highly seasonal pattern with populations all but disappearing each winter, only to return and build exponentially though the summer and fall. Maricopa County’s winters are relatively mild, which raises the question of whether further global climate change will warm conditions enough to create a broadened seasonal breeding period, or worse yet, year-round mosquito activity within desert southwest cities. This dissertation focuses on exploring the possible seasonal constraints on the egg, larva, and adult life stages of the Aedes aegypti mosquito within a suburban desert ecosystem. I explored whether climatic warming would raise temperatures enough to enable survival and development of these animals during the winter offseason. I determined that larval growth and adult flight are constrained by ambient winter temperatures in Maricopa County, explaining the currently observed winter crash in populations. However, warming by only a few degrees Centigrade could enable successful larval growth and development, as well as adult flight, even during the coldest desert months. I found that load and temperature interact to determine the flight cost of mosquitos, which can very up to six-fold, with higher temperatures likely increasing their flight performance but decreasing their distance capacities and increasing their need for fuel.
Aedes aegypti likely primarily overwinters as eggs. However, I showed that the vast majority of Aedes aegypti eggs die overwinter in Maricopa County. By manipulating humidity in eggs exposed to ambient air temperatures, I showed that desiccation, not cold temperatures, is the limiting factor in long-term survival of Aedes aegypti eggs. Together, my data suggests that humid, urban microhabitats may be essential for enabling overwinter egg survival in Maricopa County, providing a potential important pathway toward control of this disease vector.
ContributorsFox, Trevor (Author) / Harrison, Jon F (Thesis advisor) / Angilletta, Michael J (Committee member) / Benoit, Joshua B (Committee member) / Smith, Kirk (Committee member) / Arizona State University (Publisher)
Created2021