Small animal models for testing therapeutics to combat COVID-19
With support from the UC Davis Office of Research, UC Davis School of Medicine, and UC Davis School of Veterinary Medicine, we are performing studies with SARS-CoV-2 in hamsters and humanized ACE2-receptor expressing mice with a goal of finding therapies that reduce disease. We identified a compound that shows efficacy in reducing lethal disease in SARS-CoV-2 infected mice.
In collaboration with Kent Lloyd of the Mouse Biology Program, we are testing new polygenic humanized mouse models of COVID-19. This project uses newly acquired equipment in our animal biosafety level-3 facility, funded via NIH, and includes a microCT for whole animal imaging.
Safer arbovirus vaccines
In a project funded by the National Institutes of Health NIAID, we are developing safer live attenuated vaccines for chikungunya and Venezuelan equine encephalitis viruses using virus variants that mutate less frequently and therefore develop fewer mutations that confer virulence. We generated fidelity variant live attenuated vaccines that are safe and efficacious in mice.
Together with the California National Primate Research Center and Emergent, Biosolutions Inc., we are assessing safety and correlates of protection for a candidate chikungunya virus-like particle vaccine in non-human primates.
Emerging and re-emerging viruses in California
We are genetically characterizing contemporary St. Louis encephalitis virus circulating in mosquitoes in California and performing experimental studies to evaluate viral, host, and environmental factors that promoted the re-emergence and establishment of St. Louis encephalitis virus in California since 2015. This work is funded by the CDC Center of Excellence in Vector Borne Diseases for the Pacific Region of the United States. Our genetic tracing identified three routes of St. Louis encephalitis virus dispersal into the Western United States since 2015, probably introduced by avian reservoirs.
We are studying how microbes acquired throughout the life of a mosquito conditions resistance to arbovirus transmission. By rearing mosquitoes in laboratory tap water or water with microbes collected from cemeteries, we determined that the presence of microbes in larval water enhances Aedes aegypti development but reduces transmissibility of Zika virus. Next, by selectively reducing microbes via antibiotic treatment, we found that exposure to microbes throughout the life (pupae, larvae and adults) of Aedes aegypti restricts ZIKV dissemination by facilitating blood digestion and limiting midgut cell infection.
Responding to emerging infectious diseases
Together with partners in the One Health Institute, we are part of the NIH funded Centers for Research in Emerging Infectious Diseases (CREID) network. Our EpiCenter for Emerging Infectious Disease Intelligence (EEIDI) is focused on advancing understanding of viral emergence from wildlife in urbanizing environments in Peru and Uganda.
Infectious disease epidemiology
With the Epicenter for Disease Dynamics we are studying the impacts of environmental change on the epidemiology, ecology, and evolution of zoonotic diseases in Southeast Asia via an Ecology and Evolution of Infectious Diseases project funded by the National Science Foundation.
Intrahost genetic diversity and arboviral disease
We are studying how genetically diverse viral populations of chikungunya virus generated by error-prone viral replication influence mosquito-borne virus transmission and disease.
Alphavirus mutation rates
We are performing studies to measure the mutation rate of three alphaviruses using a novel PCR-independent assay that captures lethal mutations. We will use mutation rate measurements to understand alphavirus molecular evolution by defining constancy of and environmental factors that affect it, which can inform the potential for viral escape from countermeasures like drug treatment.
Enhanced arbovirus surveillance
We are developing novel cost-effective approaches to detect arbovirus circulation in mosquitoes in California based on deposition of arbovirus RNA by wild mosquitoes during sugar feeding. Scented sugar baits deployed in California detect early West Nile virus and St. Louis encephalitis virus transmission by mosquitoes, representing an improvement to conventional arbovirus surveillance that relies heavily on infection rates in mosquito pools, and is more economical.
Recent Past Projects
Influenza virus surveillance
As part of a NIH NIAID Centers for Excellence in Influenza Research and Surveillance (CEIRS) project, we perform surveillance for influenza virus in birds and marine mammals in California.
- To understand susceptibility of wild California sea lions and Northern elephant seals to influenza A virus, we developed an ex vivo respiratory explant model and used it to compare infection kinetics for multiple IAV subtypes.
- We also identified human H1N1 influenza A virus circulating in marine mammals on the California Coast in 2019.
Non human primate model of Zika virus
Together with the California National Primate Research Center including Koen Van Rompay, we generated a pregnant macaque model of human Zika virus disease. In addition to using the model to understand human ZIKV infection dynamics and disease with potential effects on fetal development and transfusion transmission, we are testing candidate vaccines and therapies.
- We partnered with the Food and Drug Administration to investigate which tissues Zika virus targets in non-human primates to inform FDA policies on the risk of Zika virus transmission through infected tissue products.
- We partnered with the National Institutes of Health Vaccine Research Center to evaluate efficacy of a Zika virus DNA vaccine in the rhesus macaque model of congenital Zika virus infection. Vaccination before conception protected Zika virus exposed pregnant macaques against prolonged viremias and improved fetal outcomes.
- Together with Vitalant Research Institute (formerly Blood Systems Research Institute)/University of California San Francisco, we characterized blood transfusion-transmission of Zika virus in macaques to establish minimal requirements for Zika virus blood or organ transfusion-transmission and to characterize pathogen reduction approaches to interrupt transfusion or organ transmission.
- We sequenced Zika virus evolved intrahost in pregnant rhesus macaques to determine whether mutations developed in pregnancy are responsible for fetal neurologic disease and death. Defining the viral determinants of clinical Zika virus outcome in macaques could be translated to candidate vaccines or therapies to protect mothers and their infants against the most severe forms of Zika virus disease. We identified a mutation evolved in pregnant macaques that shows increased viral fitness in pregnant mice, but is more poorly transmitted by Aedes aegypti vectors. These data show that intrahost ZIKV mutations capable of augmenting fitness in pregnant vertebrates may not necessarily spread efficiently via mosquitoes during epidemics.