In this study, we aim to functionally Interrogate host-pathogen relationships using three different enteroviruses (poliovirus, EV71 and coxsackievirus). To this end, we will use a variety of methods to systematically generate viral-host protein-protein and genetic interaction maps. The data generated using these initial, unbiased approaches will fuel more targeted, hypothesis-driven research in the subsequent projects. Although we intend to follow up on the most Interesting, unanticipated connections we uncover, we will be closely monitoring for links to host factors involved in quality control processes, including chaperone function, protein ubiquitination and protein degradation, which will link this work to the work described in Projects 2 and 3. In collaboration with Sumit Chanda (Burnham Institute) and John Young (Salk Institute), we will utilize RNAI methodology to globally assess the genetic dependencies, both positive and negative, of host factors to the pathogenesis of the three enteroviruses (Aim 1). Next, to characterize the enterovlrus-human protein-protein interactions, we intend to collaborate with Al Burlingame (UCSF) to employ a systematic affinity tag/purlflcation-mass spectrometry approach to Identify the viral-host protein complexes (Aim 2). We also Intend to globally ascertain the effects of protein post-translational modifications upon infection using mass spectrometry (Aim 3). Finally, In Aim 4, we will utilize a suite of bioinformatic and visualization tools to integrate the data sets in a meaningful fashion so that specific hypotheses regarding quality control processes can be generated and tested in collaboration with Judith Frydman (Project 2) and Raul Andino (Project 3). This integrated approach will leverage the expertise from multiple groups, including Pis of the Technology Core (Andrej Sali and Joe Derisi), so that novel host pathways that are hijacked during Infection can be Identified and characterized. This information will hopefully lead to breakthroughs with anti-viral drugs and vaccines.
Human enteroviruses Infect millions of people worldwide each year, resulting in a wide range of clinical outcomes ranging from respiratory illness to meningitis. To gain insight Into the pathogenesis of these viruses, we aim to analyze the functional, genetic and biochemical relationships between several members of this class of virus and host cells, which will reveal key human pathways that are being hijacked during infection. This information can ultimately be used to generate novel anti-viral drugs and vaccines.
|Davis, Zoe H; Verschueren, Erik; Jang, Gwendolyn M et al. (2015) Global mapping of herpesvirus-host protein complexes reveals a transcription strategy for late genes. Mol Cell 57:349-60|
|Stern, Adi; Bianco, Simone; Yeh, Ming Te et al. (2014) Costs and benefits of mutational robustness in RNA viruses. Cell Rep 8:1026-36|
|Acevedo, Ashley; Andino, Raul (2014) Library preparation for highly accurate population sequencing of RNA viruses. Nat Protoc 9:1760-9|
|Morris, John H; Knudsen, Giselle M; Verschueren, Erik et al. (2014) Affinity purification-mass spectrometry and network analysis to understand protein-protein interactions. Nat Protoc 9:2539-54|
|Acevedo, Ashley; Brodsky, Leonid; Andino, Raul (2014) Mutational and fitness landscapes of an RNA virus revealed through population sequencing. Nature 505:686-90|
|Hagai, Tzachi; Azia, Ariel; Babu, M Madan et al. (2014) Use of host-like peptide motifs in viral proteins is a prevalent strategy in host-virus interactions. Cell Rep 7:1729-39|
|Pechmann, Sebastian; Frydman, Judith (2014) Interplay between chaperones and protein disorder promotes the evolution of protein networks. PLoS Comput Biol 10:e1003674|
|Fraser, James S; Gross, John D; Krogan, Nevan J (2013) From systems to structure: bridging networks and mechanism. Mol Cell 49:222-31|
|Geller, Ron; Andino, Raul; Frydman, Judith (2013) Hsp90 inhibitors exhibit resistance-free antiviral activity against respiratory syncytial virus. PLoS One 8:e56762|
|Roguev, Assen; Talbot, Dale; Negri, Gian Luca et al. (2013) Quantitative genetic-interaction mapping in mammalian cells. Nat Methods 10:432-7|
Showing the most recent 10 out of 17 publications