Research & Scholarship
My current research interests focus on the intersection between the fields of virology and immunology: the complex interactions between a virus and the infected host. I am particularly interested in the intracellular innate immune response and its ability to interfere with viral infection and/or reduce disease severity. During immune-stimulating viral infections, hundreds of genes are up-regulated, yet the functional significance of many of them remains unclear.
A common trigger of immune responses during viral infection are defective viral genomes (DVGs) which are produced by error-prone viral polymerases. DVGs are found in many types of viral infections including RNA viruses, such as influenza and Dengue Virus, as well as the DNA virus, Hepatitis B. These infections can range from acute to chronic, with the potential for life-long complications, and it is unclear what role the intracellular response may have in these outcomes. The early immune response to an infection, specifically within the very first cells to be infected, can be pivotal in shaping the course of infection for these and many other viruses. An in-depth understanding of these early responses could be used to prevent disease complications or the establishment of chronic infections.
Within the model of viral-mediated immunostimulation, my research is focused on identifying ISGs that contribute to the antiviral response and characterizing their mechanistic functions. Alternately, we are also interested in identifying any ISGs that may actually be beneficial to the virus. We are primarily looking within the infected cells themselves in order to understand the pieces in play during the earliest stages of a viral infection. We hope to identify proteins and pathways that are protective for the host following viral infection to serve as targets for new therapeutic approaches or correlates of protection for novel vaccination strategies.
There are many possible research avenues for students in my lab; with hundreds of possible genes to choose from and both host and viral effects to consider. As a general framework, potential antiviral genes can be identified from literature searches or bioinformatics analysis of publically available data sets. The candidate genes will be mutated in biologically relevant cell lines using the CRISPR-Cas9 system, followed by treatment with immunostimulatory molecules or viral infection. Using molecular biology techniques, such as RT-PCR, Western blotting, and fluorescence microscopy, students will assess their candidate genes for effects on the virus and the overall host immune response. Students can chose to work on a gene by themselves, or in groups to study different aspects of the gene during infection, which can then be assembled into a bigger picture.
Philip NH, DeLaney A, Peterson LW, Santos-Marrero M, Grier JT, Sun Y, Wynosky-Dolfi, MA, Zwack EE, Hu B, Olson TM, Rongvaux A, Pope SD, López CB, Oberst A, Beiting DP, Henao-Mejia J, Brodsky IE. Activity of uncleaved caspase-8 controls anti-bacterial immune defense and TLR-induced cytokine production independent of cell death. PLOS Pathogens. 2016.
Xu J, López X, Grier JT, Chun L, Irvine E, Toro Y, Hur S, Gale M, Raj A, López CB. Identification of a Natural Viral RNA Motif that Optimizes Sensing of Viral RNA by RIG-I. mBio. 2015
Grier JT, Forbes LR, Monaco-Shawver L, Oshinsky J, Atkinson TP, Moody C, Pandey R, Campbell KS, Orange JS. Human immunodeficiency-causing mutation defines CD16 in spontaneous NK cell cytotoxicity. 2012. J Clin Invest. 122(10):3769-8
Heyward CY, Patel R, Mace EM, Grier JT, Guan H, Makrigiannis AP, Orange JS, Riccardi RP. Tumorigenic adenovirus 12 cells evade NK cell lysis by reducing the expression of NKG2D ligands. 2012. Immunol Lett. 144:16-23.