UCLA

In arms-race between the human host and viral pathogens, the favor often belongs to the pathogens. I have investigated emerging viruses by using meta-genomic data and system-wide mutagenesis of Zika and Influenza virus.

Initially isolated from the Zika forest at Uganda in 1947. Zika virus (ZIKV) has been spreading in Africa, Asia and Asian-Pacific islands. It is not until late 2015 that Zika virus has emerged as a virus with significant public health impact, with rapidly accumulating evidence of a causal relationship with fetal neurologic birth defects. First reported from Northeast of Brazil in May 2015, followed by Colombia and Suriname in October 2015. Over the next couple of years, the virus has spread over 130 countries and infected tens of millions of people globally. It has been hypothesized that the virus may have recently evolved to become more neurotropic, to exhibit increased replicative capacity, and/or to become more transmissible to humans, but causal support for these possibilities is outstanding. To gain a better understanding of the molecular evolution of the virus, we have developed a novel genetic footprint method, as well as targeted structural modeling, on all known full-length ZIKV available to date. We were able to classify the ZIKV strains into ten groups and trace the spread and evolution of ZIKV in different parts of Brazil and other countries. Our analysis further pointed to the possibility that different groups of ZIKV may trigger different levels of host immune responses and cause distinct levels of pathogenesis.

Vaccination is one of the greatest accomplishments in modern medicine and has effectively eradicated several life-threatening viruses in the past. A vaccine is essentially the injection of an attenuated pathogen, allowing the immune system to recognize and generate protective antibodies, which could serve future protection when re-exposed to the same pathogen. Over the years, the development of vaccine has followed an empirical paradigm, which has been successful for a few viruses, but not others. We began to recognize that viruses have developed their own complex strategies to combat vaccine-induced immune recognition. Viruses like influenza and HIV have developed powerful mutational strategies, that requires rational vaccine-design strategies to reduce or eradicate.

Influenza A virus is a major public health problem, infecting as many as 500 million people a year worldwide. Unfortunately, the current vaccines are highly inefficient in its cross-protection. It is urgent that we uncover new strategies for generating a universal vaccine. Here we combined high-coverage and unbiased transposon mutagenesis of influenza virus with a rapid high-throughput screening for attenuation to generate W7-791, a live attenuated mutant virus strain. W7-791 produced only a transient asymptomatic infection in adult and neonatal mice even at doses 100-fold higher than the LD50 of the parent strain. A single administration of W7-791 conferred full protection to mice against lethal challenge with H1N1, H3N2, and H5N1 strains, and improved viral clearance in ferrets. Furthermore, W7-791-immunized mice conferred heterologous protection, indicating a role for T cell-mediated immunity.