Faculty & Staff

Clint Smith

Clint Smith

Assistant Professor of Biology
B.S. University of Central Arkansas, Ph.D. University of Kentucky

Interests and Expertise: virology, molecular biology, biochemistry, virus evolution, microbiology

Please see our lab website for more detailed research information, publications, and updates.

 RESEARCH BACKGROUND

 Viruses and viroids evolve more rapidly than any other biological entity. This enables viruses to evade our immune system, evolve resistance to antiviral drugs, and infect new species. 

 Viruses containing an RNA genome, such as HIV and influenza, are unable to correct mistakes (proofread) made while replicating their genome. Such error-prone, or low fidelity, replication means that most viral progeny will have mutations. However, viruses are capable of producing millions to billions of progeny virions during infection. Thus, even if 99.9% of the newly-made viruses are defective due to mutations, several thousand to millions still survive. These three characteristics – huge population sizes, rapid replication, and high mutations rates – help drive virus evolution.

 While my research interests are primarily virus-centric, many ecological and anthropomorphic factors also contribute to virus evolution and emergence. These include the domestication of animals, rainforest destruction, global warming, and air travel. Each can result in increased human-human and human-animal contact, thus contributing to the emergence of zoonotic infections. 

 RESEARCH INTERESTS

 I study how coronaviruses (CoV), such as SARS-CoV and MERS-CoV, replicate and evolve. Coronaviruses are unique among RNA virus: they can correct mistakes (proofread) made while replicating their RNA genome. The long-term goals of my research program are two-fold: (i) to understand how coronaviruses regulate their fidelity and (ii) to identify the molecular mechanisms (both viral and cellular) that contribute to the attenuation of altered-fidelity viruses.

 Our current research questions include:

 I: How does nsp14-ExoN regulate coronavirus fidelity?

II: What are the molecular mechanisms by which changes in fidelity impact viral replication and fitness?

III: Does decreased fidelity result in increased defective interfering (DI) particle production?

 Please see our lab website for more detailed information and background reading. 

STUDENT RESEARCH OPPORTUNITIES

 Students and I use a murine coronavirus, mouse hepatitis virus (MHV), as a model system. This system enables students to study viral replication safely and contribute directly to our knowledge about these medically and agriculturally important pathogens. My research relies heavily on biochemistry, virology, genetics, molecular biology, and evolutionary biology, thus enabling students to receive a wide range of technical training.

 Sewanee has exceptional facilities for undergraduate research. Here are examples of a few techniques we use routinely in the lab:

  • plaque assay
  • viral reverse genetics (engineering and recovering viruses containing mutations)
  • real-time quantitative PCR (RT-qPCR)
  • viral replication assays
  • mammalian cell culture
  • molecular biology and sequencing
  • luminescent assays to test compounds for anti-viral activity
  • immunoblot to detect viral and cellular proteins
  • passage studies to examine virus evolution

 SELECTED PUBLICATIONS (**indicates undergraduate co-author)

 Below are publications most relevant to our current research. Please see our lab website for a complete publications list and PDFs. 

 Sexton NR, Smith EC, Blanc H, Vignuzzi M, Peersen O, Denison MR. 2016. Homology-based identification of a mutation in the coronavirus RNA-dependent RNA polymerase that confers resistance to multiple mutagens. J Virol. (Epub ahead of print)

 Smith EC, Case JB, Blanc H, Isakov O, Shomron N, Vignuzzi M, Denison MR. 2015. Mutations in coronavirus nonstructural protein 10 decrease virus replication fidelity. J Virol. 89(12):6418-26.

 Smith EC, Sexton NR, Denison MR. 2014. Thinking outside the triangle: replication fidelity of the largest RNA viruses. Ann Rev of Virol. 1: 111-132.

 Smith EC, Blanc H, Surdel MC, Vignuzzi M, Denison MR. 2013. Coronaviruses lacking exoribonuclease activity are susceptible to lethal mutagenesis: evidence for proofreading and potential therapeutics.  PLOS Path. 9(8):e1003565. [Featured in Nature Reviews Microbiology]

 Smith EC and Denison MR. 2013. Coronaviruses as DNA wannabes: a new model for the regulation of RNA virus replication fidelity. PLOS Path. 9(12):e1003760.

 Smith EC and Denison MR. 2012. Implications of altered replication fidelity on the evolution and pathogenesis of coronaviruses.  Curr Opin Virol. 2(5):519-524.