Michelle M. Arnold, PhD
Assistant Professor of Microbiology and Immunology
Bachelor of Science, Biochemistry and Molecular Biology (1999) – University of Wisconsin – Madison
PhD, Virology (2007) – Harvard University
Post-Doctoral Fellow, Infectious Diseases – National Institute of Allergy and Infectious Diseases,
National Institutes of Health
Latest NewsKellie Brown and Samantha Murphy presented talks at the American Society for Microbiology South Central Branch Meeting at the University of Mississippi in Oxford, Mississippi.
Members of the Arnold Lab presented at the 38th Annual Meeting of the American Society for Virology in Minneapolis, Minnesota. Kellie Brown was awarded a Graduate Student Travel Award for her presentation titled, “Role of Cul3 in rotavirus NSP1-mediated inhibition of IFN- β.” Samantha Murphy presented a talk titled, “Rotavirus NSP1 colocalizes with PML nuclear bodies in the nucleus.”
Samantha Murphy was awarded “Best Talk” at the LSU Health Shreveport Graduate Research Day in April 2019.
Samantha Murphy was awarded the Charles. S. McClesky Award for Outstanding Talk in Virology at the American Society for Microbiology South Central Branch Meeting at the University of Mississippi Medical Center in Jackson, Mississippi.
Major Research Interest
Rotavirus is the leading cause of severe, dehydrating diarrhea in infants and young children, resulting in more than 200,000 deaths worldwide each year. Most deaths attributable to rotavirus occur in low-income countries where vaccines are not highly effective or widely available. Given that rotavirus vaccine efficacy is significantly lower in the poorest areas of the world where the burden of disease is high, vaccine improvements are necessary to reduce deaths caused by rotavirus. The development of a robust adaptive immune response relies on production of type I interferon (IFN). Current live-attenuated rotavirus vaccines contain a wild-type IFN antagonist, NSP1, that inhibits the production of IFN. By reducing or eliminating the natural IFN inhibitory activity of NSP1, a better IFN response may result from vaccination that will augment the developing adaptive immune response. Unfortunately, the mechanisms of IFN antagonism and manipulation of host responses by NSP1 are not well understood.
Molecular mechanisms of NSP1 IFN inhibition. Rotavirus replication occurs within the cytoplasm where uncapped or incomplete transcripts are recognized by pattern recognition receptors that induce IFN activation. To combat the production of IFN, NSP1 induces proteasomal degradation of key signaling components required for IFN production, including IFN regulatory factors (IRFs) and β-TrCP. The substrate-binding domain of NSP1, which has been characterized in detail, mimics other IRF- or β-TrCP-binding proteins depending on the presence of specific sequence elements in the C terminus of NSP1. Our lab is interested in understanding the mechanism of NSP1-induced host protein degradation. NSP1 contains a highly conserved RING domain in the N-terminal region that, according to our own data, is required for substrate degradation, suggesting that NSP1 acts as an E3 ubiquitin ligase. Experiments identifying the molecular mechanism of NSP1-mediated degradation of proteins required for IFN induction are currently underway in our laboratory.
Rotavirus manipulation of PML nuclear bodies. PML is a member of the tripartite motif-containing (TRIM) superfamily and is an IFN-stimulated gene. Dozens of host proteins localize constitutively or transiently to PML nuclear bodies (PML-NBs), many of which are involved in transcriptional regulation. Viral manipulation of PML-NBs is common among DNA viruses, but RNA viruses have also been shown to disrupt PML-NB structure by a variety of mechanisms. The disorganization of PML-NBs by viral proteins is widely considered to be a strategy to evade the IFN response. In rotavirus-infected cells, we found that the NSP1 protein of some virus strains colocalize with PML-NBs and alter the size of PML-NBs. The NSP1 protein of different rotavirus strains significantly reduces the number of PML-NBs, suggesting that NSP1 may antagonize IFN or other host responses in ways other than protein degradation. We are currently investigating the role of NSP1 nuclear localization in rotavirus replication and how host response to rotavirus is altered by modification of PML-NBs.
Arnold MM. (2018) Rotavirus vaccines: why continued investment in research is necessary. Current Clinical Microbiology Reports. 5(1): 73-81. PMID: 29805958
Lutz LM, Pace CR, Arnold MM. (2016) Rotavirus NSP1 associates with components of the cullin RING ligase family of E3 ubiquitin ligases. Journal of Virology. 90(13): 6036-6048. PMID:27099313
Arnold MM. (2016) The rotavirus interferon antagonist NSP1: many targets, many questions. Journal of Virology 90(11): 5212-5215. PMID:27009959
Arnold MM. (2013) Sequestration strikes again: rotavirus-induced accumulation of cellular transcripts in the nucleus inhibits host protein translation. Future Virology 8(9): 841-844.
Arnold MM, Barro M, Patton JT. (2013) Rotavirus NSP1 mediates degradation of interferon regulatory factors through targeting of the dimerization domain. Journal of Virology 87(17): 9813-9821. PMID: 23824805
Arnold MM, Sen A, Greenberg HB, Patton JT. (2013) The battle between rotavirus and its host for control of the interferon signaling pathway. PLoS Pathogens 9(1): e1003064. PMID: 23359266
Arnold MM, Brownback CS, Taraporwala ZF, Patton JT. (2012) Rotavirus variant replicates efficiently although encoding an aberrant NSP3 that fails to induce nuclear localization of poly-A binding protein. Journal of General Virology 93(7): 1483-1494. PMID: 22442114
Arnold MM, Patton JT. (2011) Diversity of interferon antagonist activities mediated by NSP1 proteins of different rotavirus strains. Journal of Virology 85(5): 1970-1979. PMID: 21177809