Arthropod-borne pathogens account for millions of death each year. Understanding the genetic basis of vector susceptibility to pathogens is pivotal to novel disease control strategies. The hypothesis that induction of apoptosis is a fundamental innate immune response has been supported by virology studies, which demonstrated that the anti- apoptotic activities of many viral genes are essential for their infectivity and/or virulence. However, the cellular mechanism mediating the induction of apoptosis following virus infection remained enigmatic. In addition, studies with cultured insect cells showed that either there is a lack of apoptosis, or the pro-apoptotic response happens relatively late, casting doubt on the functional significance of apoptosis as an innate immunity. Using in vivo mosquito models mimicking native routes of viral infection, we found that there is a rapid induction of pro-apoptotic genes (RIPAG) within a few hours following exposure to DNA/RNA viruses. More importantly, using genetic tools in Drosophila, we showed that the RIPAG, and the ensuing apoptosis, is responsible for denying the expression of viral genes and blocking/limiting the infection. Animals with compromised RIAPG are much more susceptible to viral infection than wild type. In this proposal, we seek to unravel the transcriptional mechanisms and the regulatory pathway(s) controlling RIPAG using a combination of Drosophila genetics and comparative genomics. In addition, utilizing the information obtained through the mechanistic analysis, we will test the hypothesis that increased innate immunity against viral infection may be achieved by enhancing the RIPAG response to viral infection. Finally, we assess the fitness of the antiviral constructs we create in Drosophila, then translate the most powerful and most fit constructs to two mosquito vectors and perform preliminary evaluations of transgene effectiveness against Dengue.
Arthropod-borne pathogens account for millions of death each year. Understanding the genetic basis controlling vector susceptibility to intracellular pathogens is pivotal to novel disease control strategies. The knowledge gained from this study should have significant impact for combating arthropod-born diseases.
|Sundaresan, Varsha; Lin, Victor T; Liang, Faming et al. (2017) Significantly mutated genes and regulatory pathways in SCLC-a meta-analysis. Cancer Genet 216-217:20-28|
|Piontkivska, Helen; Frederick, Madeline; Miyamoto, Michael M et al. (2017) RNA editing by the host ADAR system affects the molecular evolution of the Zika virus. Ecol Evol 7:4475-4485|
|Deng, Changwang; Li, Ying; Zhou, Lei et al. (2016) HoxBlinc RNA Recruits Set1/MLL Complexes to Activate Hox Gene Expression Patterns and Mesoderm Lineage Development. Cell Rep 14:103-114|
|Kim, Sebo; Sundaresan, Varsha; Zhou, Lei et al. (2016) Integrating Domain Specific Knowledge and Network Analysis to Predict Drug Sensitivity of Cancer Cell Lines. PLoS One 11:e0162173|
|Li, Ying; Schulz, Vincent P; Deng, Changwang et al. (2016) Setd1a and NURF mediate chromatin dynamics and gene regulation during erythroid lineage commitment and differentiation. Nucleic Acids Res 44:7173-88|
|Chakraborty, Riddhita; Li, Ying; Zhou, Lei et al. (2015) Corp Regulates P53 in Drosophila melanogaster via a Negative Feedback Loop. PLoS Genet 11:e1005400|
|Nirmala, Xavier; Schetelig, Marc F; Zimowska, Grazyna J et al. (2015) Pro-apoptotic gene regulation and its activation by gamma-irradiation in the Caribbean fruit fly, Anastrepha suspensa. Apoptosis 20:1-9|
|Zhang, C; Casas-Tintó, S; Li, G et al. (2015) An intergenic regulatory region mediates Drosophila Myc-induced apoptosis and blocks tissue hyperplasia. Oncogene 34:2385-97|
|Salz, Tal; Li, Guangyao; Kaye, Frederic et al. (2014) hSETD1A regulates Wnt target genes and controls tumor growth of colorectal cancer cells. Cancer Res 74:775-86|
|Zhang, Can; Liu, Bo; Li, Guangyao et al. (2011) Extra sex combs, chromatin, and cancer: exploring epigenetic regulation and tumorigenesis in Drosophila. J Genet Genomics 38:453-60|