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PhD candidate Matthew Grunewald successfully defends thesis

Matt Grunewald and Stanley Perlman

On May 9, 2019 Matthew Grunewald successfully defended his thesis titled, "ADP-ribosylation During Coronavirus Infection: Connections to Viral Protein Modification, Immunity, and the Toxin Response”.   He is pictured with his mentor Dr. Stanley Perlman.


Research

Coronaviruses (CoVs) are responsible for several economically and medically relevant diseases of outbreak potential such as Severe Acute and Middle East Respiratory Syndromes (SARS and MERS). Understanding the cellular processes directing the host response to CoV infection is vital to developing antiviral strategies. One of these processes, ADP-ribosylation, is the post-translational addition of ADP-ribose (ADPr) to proteins to regulate their function. This addition is catalyzed by poly-ADPr polymerases (PARPs), which have been implicated in regulating antiviral host defenses. Because all CoVs encode a viral macrodomain that removes ADPr from proteins, we hypothesized that ADP-ribosylation was integral to CoV replication or to the host immune response.

During a screen for ADP-ribosylated proteins, we found that viral nucleocapsid (N) protein, which stabilizes the viral genome, was ADP-ribosylated during infection by multiple CoVs, including mouse hepatitis virus (MHV), SARS-CoV, and MERS-CoV. Interestingly, this modification only occurred during infection conditions, implying that it may function as a critical regulator of the CoV nucleocapsid.

Because the CoV macrodomain counters host PARPs, we next investigated how deficiency of the macrodomain affects infection. We found that catalytic inactivation of the macrodomain reduced MHV replication and increased interferon production in infected macrophages in an ADP-ribosylation-dependent manner. Individual knockdown of PARPs that were highly expressed during infection showed that PARP12 and PARP14 were responsible for the restriction of viral replication in the absence of macrodomain activity. Furthermore, we discovered that PARP14 facilitates IFN production in MHV-infected macrophages and in cell lines stimulated with poly(I:C). Taken together, we identified two antiviral proteins that are countered by the activity of the MHV macrodomain and conclude that modulation of ADP-ribosylation or PARPs may be a potential therapeutic avenue for viral infections.

 

Biographical Sketch

Matt was born in Baton Rouge, Louisiana, to parents Fred and Deborah Grunewald and has lived in multiple and varied cities across the U.S. He spent much of his childhood and adolescent years playing the bassoon, participating in academic and mathematic competitions, and spending time with his sister, Savannah. Throughout school, science and math classes were always his favorite courses, and he decided at a young age to spend his future career learning about biology and chemistry.

Matt attended Texas A&M University to pursue a dual degree in Biochemistry and Genetics, where he quickly developed a passion for the study of protein function and regulation. He worked in multiple Texas A&M labs, including studying protein delivery into cells in the lab of Dr. Jean-Philippe Pellois. During his summer breaks, he interned at multiple research sites, where he was introduced to a wide scope of biological fields. The focus of these projects included studying the neurologic effects of alcohol and stress on depression at the University of Mississippi Medical Center; the role of asymmetric cell division during blood cell differentiation at the Essen University Hospital in Essen, Germany; and the development of gene therapy models at the University of Pennsylvania. These internships introduced Matt to the clinical setting of research, sparking an interest in translational and clinical research. His summer gene therapy project in Philadelphia also helped him to realize his passion for virus pathology and immunology.

Matt enrolled in the University of Iowa Medical Scientist Training Program in 2012 and in the Department of Microbiology graduate program in 2014. He has worked under the mentorship of Dr. Stanley Perlman studying the effects of protein ADP-ribosylation during coronavirus infection. After finishing his clinical rotations, Matt plans to train in a pediatric residency, subspecialize in an area related to immunology, and eventually study as a physician scientist. Outside of the lab, Matt enjoys spending time with his wife, Nikki, traveling and exploring new places whenever they have the chance. Matt also enjoys watching movies, playing games, spending time outdoors, and relaxing with family and friends.

 

Date: 
Monday, May 13, 2019