Virus relies on its infected host cell to replicate, while the host has developed various means against invader. What mechanisms a host cell can use to protect itself? How a virus replicates in a hostile environment? What is the relationship between a virus and its infected host cell during an infection? Study of these questions provides not only knowledge to viral replication, but also fundamental life processes of the host cells, ultimately leading to the development of strategies to treat and prevent viral diseases.
The long-term goal of my laboratory is to understand the viral and host cell survival strategies during an infection. A parallel goal is to inspire and train the next generation of researchers and scientists. The current focus is the host and viral gene expression in the context of dynamic host-virus interactions during a viral infection. The research comprises three levels: analysis of host and viral gene expression, the underlying cellular and viral mechanisms, and the subsequent biological impacts on the host and virus. At present, my laboratory combines molecular biology, genetic engineering, genomic, proteomic and bioinformatics approaches to investigate the following research areas.
1. Host response induction and shutoff during poxvirus infection
Poxviruses comprise a large family of viruses. The most notorious member of Poxviridae and causative agent of smallpox, variola virus, was eradicated three decades ago. However, poxviruses, including monkeypox, cowpox and molluscum contagiosum, are still of significant interest due to their potential for causing morbidity and mortality in humans and economically important animals, their potential for use as biological weapons, and their considerable utility as gene delivery or vaccine vectors. Vaccinia virus, which was used as the vaccine to eradicate smallpox, is the most extensively studied and prototype poxvirus
Our previous work by simultaneous profiling of the transcriptomes of and its infected cells revealed that the expression of a small group of cellular mRNAs was increased during the early stage of viral infection before viral DNA replication, suggesting a specific host response to the virus. Many of the upregulated mRNAs are involved in the innate immune response. However, during the post DNA replication stage of viral infection, vaccinia virus induced a global downregulation of host mRNAs, termed host shutoff, including those genes that were upregulated at the early stage (Yang et al., 2010, PNAS). We study several important aspects of gene expression during this dynamic process, with a focus on the innate immune response genes.
2. Pervasive gene expression of poxvirus
Our work on global gene expression of poxvirus using high throughput RNA-seq, 5’ and 3’ ends RNA analysis and ribosome-profiling uncovered surprising complexity of transcription, translation of poxvirus genome, including the expression of numerous unexpected gene products (Yang et al, 2011, 2012, J Virol). We study the basis, role and significance of the genomic complexity of poxvirus.
3. Translation during the host shutoff in virally infected cells
Many viruses, including vaccinia virus, influenza and herpesvirus, can cause global host shutoff. One of the hallmarks of the host shutoff is that the cellular gene expression, including protein synthesis, is suppressed. Though the host shutoff may be beneficial for virus by providing host resources for viral production, it also poses challenges to the virus. One is how the virus can ensure the host cell maintaining the capability to express viral genes and host genes important for viral production. We study the molecular events of translation in virus-induced host shutoff using various genomic, proteomic and molecular biology approaches. We anticipate identifying critical cellular processes, pathways and factors for viral replication through studying this process.
Yang Z, Maruri-Avidal L, Jerry Sisler J, Carey A. Stuart CA, Bernard Moss B. Cascade Regulation of Vaccinia Virus Gene Expression Is Modulated by Multistage Promoters. Virology. 447 (1-2): 213–220, 2013. Highlighted paper. To be featured in Virology Highlights blog (http://www.virologyhighlights.com/)
Yang Z, Martens CA, Bruno DP, Porcella SF, Moss B. Pervasive Initiation and 3’ End Formation of Poxvirus Post-Replicative RNAs. J Biol Chem. 287 (37): 31050-31060, 2012.
Yang Z, Reynolds SE, Martens CA, Bruno DP, Porcella SF, Moss B. Expression Profiling of the Intermediate and Late Stages of Poxvirus Replication. J Virol. 85 (19): 9899-9908, 2011.
Yang Z, Bruno DP, Martens CA, Porcella SF, Moss B. Genome-wide analysis of the 5' and 3' ends of vaccinia virus early mRNAs delineates regulatory sequences of annotated and anomalous transcripts. J Virol. 85(12):5897-909, 2011.
Bengali Z, Satheshkumar PS, Yang Z, Weisberg AS, Paran N, Moss B. Drosophila S2 cells are non-permissive for vaccinia virus DNA replication following entry via low pH-dependent endocytosis and early transcription. PLoS One. 6(2):e17248, 2011.
Yang Z, Bruno DP, Martens CA, Porcella SF, Moss B. Simultaneous high-resolution analysis of vaccinia virus and host cell transcriptomes by deep RNA sequencing. Proc Natl Acad Sci U S A. 107(25):11513-8, 2010.
Yang Z & Wood C. The replication and transcription activator (RTA) of Kaposi's sarcoma-associated herpesvirus/human herpesvirus-8. Front. Biol. 5(2), 105-115, 2010. Highlighted paper.
Wen HJ, Yang Z, Zhou Y, Wood C. Enhancement of autophagy during lytic replication by the Kaposi's sarcoma-associated herpesvirus replication and transcription activator. J Virol. 84(15): 7448-58, 2010.
Yang Z, Moss B. Interaction of the vaccinia virus RNA polymerase-associated 94-kilodalton protein with the early transcription factor. J Virol. 83(23):12018-26, 2009.
Yang Z, Wen HJ, Minhas V, Wood C. The zinc finger DNA-binding domain of K-RBP plays an important role in regulating Kaposi's sarcoma-associated herpesvirus RTA-mediated gene expression. Virology. 391(2): 221-31, 2009.
Yang Z, Yan Z, Wood C. Kaposi's sarcoma-associated herpesvirus transactivator RTA promotes degradation of the repressors to regulate viral lytic replication. J Virol. 82(7): 3590-603, 2008.
Yang Z, Wood C. The transcriptional repressor K-RBP modulates RTA-mediated transactivation and lytic replication of Kaposi's sarcoma-associated herpesvirus. J Virol. 81(12): 6294-306, 2007.