RNA and Viruses: the machinery of pathogenesis

Structured RNA molecules and helicase enzymes are essential for viral function, especially in the case of Hepatitis C virus (HCV) and flaviviruses (such as Dengue or Yellow Fever), which are major threats to world health.   Our goal is to solve the molecular structure of the HCV and flaviviral replicase machines, and to deduce their roles in pathogenicity.  In this way, we hope to develop new, broad-spectrum therapeutics against existing and emerging viruses.  We recently determined the molecular mechanism of RNA unwinding by the NS3 helicase from HCV using a combination of enzymology and crystallography.   Having established this foundation, we have are now developing approaches for visualizing intact replicases and monitoring their dynamical function in living cells.

Relevant Publications

A rapid RIG-I signaling relay mediates efficient antiviral response
Daniel T Thoresen, Drew Galls, Benjamin Götte, Wenshuai Wang, Anna M Pyle
Mol Cell 2022 () : in press
The RIG-I receptor adopts two different conformations for distinguishing host from viral RNA ligands
Wenshuai Wang, Anna Marie Pyle
Mol Cell 2022 (82) : 4131-4144.e6
Evolving a RIG-I antagonist: a modified DNA aptamer mimics viral RNA
Xiaoming Ren, Amy D. Gelinas, Melissa Linehan, Akiko Iwasaki, Wenshuai Wang, Nebojsa Janjic, Anna Marie Pyle
Journal of Molecular Biology 2021 (433) : 167227
NS3 from HCV strain JFH-1 is an unusually robust helicase that is primed to bind and unwind viral RNA
Ting Zhou, Xiaoming Ren, Rebecca L. Adams and Anna Marie Pyle
J Virol. 2018 (92) : e01253-17
Functional RNA structures throughout the Hepatitis C Virus genome
Rebecca L. Adams, Nathan Pirakitikulr and Anna Marie Pyle
Curr Opin Virol. 2017 (24) : 79-86
Temperature-dependent innate defense against the common cold virus limits viral replication at warm temperature in mouse airway cells
Ellen F. Foxman, James A. Storer, Megan E. Fitzgerald, Bethany R. Wasik, Lin Hou, Hongyu Zhao, Paul E. Turner, Anna Marie Pyle and Akiko Iwasaki
Proc. Natl. Acad. Sci. USA 2015 (112) : 827-832
The linker region of NS3 plays a critical role in the replication and infectivity of hepatitis C virus
Andrew Kohlway, Nathan Pirakitikulr, Steve C. Ding, Feng Yang, Dahai Luo, Brett D. Lindenbach and Anna Marie Pyle
J Virol. 2014 (18) : 10970-10974
An evolving arsenal: viral RNA detection by RIG-I-like receptors
Megan Fitzgerald, David C. Rawling, Adriana Vela and Anna Marie Pyle
Curr Opin Microbiol. 2014 (20) : 76-81
Hepatitis C virus RNA replication and virus particle assembly require specific dimerization of the NS4A protein transmembrane domain
Andrew Kohlway, Nathan Pirakitikulr, Francisco N. Barrera, Olga Potapova, Donald M. Engelman, Anna Marie Pyle and Brett D. Lindenbach
J Virol. 2014 (88) : 628-42
RNA helicases and remodeling proteins
Anna Marie Pyle
Curr Opin Chem Biol. 2011 (15) : 636-642
Unmasking the active helicase conformation of NS3 from Hepatitis C virus
Steve C. Ding, Andrew S. Kohlway and Anna Marie Pyle
J Virol. 2011 (85) : 4343-4353
The acidic domain of hepatitis C virus NS4A contributes to RNA replication and virus particle assembly
Tung Phan, Andrew Kohlway, Peniel Dimberu, Anna Marie Pyle and Brett D. Lindenbach
J Virol. 2011 (85) : 1193-1204
The NS4A protein from hepatitis C virus promotes RNA-coupled ATP hydrolysis by the NS3 helicase
Rudolf K. Beran, Brett D. Lindenbach. and Anna M. Pyle
J Virol. 2009 (83) : 3268-3275