Karla Kirkegaard

Administrative Appointments

• Chair, Stanford University School of Medicine - Microbiology & Immunology , (2006– present )

Postdoctoral Advisees

• Eric Freundt, Roberto Mateo Fernandez, Jennifer Ptacek, Andres Tellez

Web Site Links

• My Lab's Web Site

Research Interests

For many subcellular viruses and parasites, RNA, not DNA, is the carrier of genetic information. This has several interesting consequences for the genetics and biology of the virus. Poliovirus serves as a model to increase our understanding of positive-strand RNA viruses for which no vaccine is available and which remain a significant health hazard: examples include other picornaviruses, such as rhinoviruses, coxsackieviruses and the deadly enterovirus 71 as well as more distantly related positive-strand RNA viruses such as hepatitis C and Dengue fever.

Questions currently under scrutiny are posed below, and discussed in greater detail in our web site.

1. How does the biochemistry of RNA-dependent RNA polymerases affect the biology of RNA viruses?

2. How are the membranous structures on which viral RNA replication complexes assemble form, and
from what intracellular organelles do they derive?

3. Why are the genetic properties of many RNA genomes different from DNA genomes? How does the error-prone nature of RNA-dependent RNA replication and the membrane association of the RNA replication complexes affect these genetic properties?

4. How does the inhibition of the protein secretory apparatus by the 3A and 2B proteins of picornaviruses such as poliovirus affect their pathogenesis? What would happen to the secretion of interferons, and to the presentation of antigens in the context of MHC class I molecules, if the host secretory pathway were not inhibited during infection by polioviruses, rhinoviruses and coxsackieviruses?

Publications

• Potential subversion of autophagosomal pathway by picornaviruses. Taylor MP,  Kirkegaard K.  Autophagy.  2008; 4 (3): 286-9
• Modification of cellular autophagy protein LC3 by poliovirus. Taylor MP,  Kirkegaard K.  J Virol.  2007; 81 (22): 12543-53
• Intramolecular and intermolecular uridylylation by poliovirus RNA-dependent RNA polymerase. Richards OC,  Spagnolo JF, Lyle JM, Vleck SE, Kuchta RD, Kirkegaard K.  J Virol.  2006; 80 (15): 7405-15
• Nucleotide channel of RNA-dependent RNA polymerase used for intermolecular uridylylation of protein primer. Tellez AB,  Crowder S, Spagnolo JF, Thompson AA, Peersen OB, Brutlag DL, Kirkegaard K.  J Mol Biol.  2006; 357 (2): 665-75
• Bottleneck-mediated quasispecies restriction during spread of an RNA virus from inoculation site to brain. Pfeiffer JK,  Kirkegaard K.  Proc Natl Acad Sci U S A.  2006; 103 (14): 5520-5
• Topology of double-membraned vesicles and the opportunity for non-lytic release of cytoplasm. Kirkegaard K,  Jackson WT.  Autophagy.  2005 Oct-Dec; 1 (3): 182-4
• Ribavirin resistance in hepatitis C virus replicon-containing cell lines conferred by changes in the cell line or mutations in the replicon RNA. Pfeiffer JK,  Kirkegaard K.  J Virol.  2005; 79 (4): 2346-55
• Inhibition of cellular protein secretion by picornaviral 3A proteins. Choe SS,  Dodd DA, Kirkegaard K.  Virology.  2005; 337 (1): 18-29
• Allosteric effects of ligands and mutations on poliovirus RNA-dependent RNA polymerase. Boerner JE,  Lyle JM, Daijogo S, Semler BL, Schultz SC, Kirkegaard K, Richards OC.  J Virol.  2005; 79 (12): 7803-11
• Trans-dominant inhibition of RNA viral replication can slow growth of drug-resistant viruses. Crowder S,  Kirkegaard K.  Nat Genet.  2005; 37 (7): 701-9
• Subversion of cellular autophagosomal machinery by RNA viruses. Jackson WT,  Giddings TH, Taylor MP, Mulinyawe S, Rabinovitch M, Kopito RR, Kirkegaard K.  PLoS Biol.  2005; 3 (5): e156
• Increased fidelity reduces poliovirus fitness and virulence under selective pressure in mice. Pfeiffer JK,  Kirkegaard K.  PLoS Pathog.  2005; 1 (2): e11
• Intracellular topology and epitope shielding of poliovirus 3A protein. Choe SS,  Kirkegaard K.  J Virol.  2004; 78 (11): 5973-82
• Cellular autophagy: surrender, avoidance and subversion by microorganisms. Kirkegaard K,  Taylor MP, Jackson WT.  Nat Rev Microbiol.  2004; 2 (4): 301-14
• A single mutation in poliovirus RNA-dependent RNA polymerase confers resistance to mutagenic nucleotide analogs via increased fidelity. Pfeiffer JK,  Kirkegaard K.  Proc Natl Acad Sci U S A.  2003; 100 (12): 7289-94
• Nonstructural protein precursor NS4A/B from hepatitis C virus alters function and ultrastructure of host secretory apparatus. Konan KV,  Giddings TH, Ikeda M, Li K, Lemon SM, Kirkegaard K.  J Virol.  2003; 77 (14): 7843-55
• Visualization and functional analysis of RNA-dependent RNA polymerase lattices. Lyle JM,  Bullitt E, Bienz K, Kirkegaard K.  Science.  2002; 296 (5576): 2218-22
• Oligomerization and cooperative RNA synthesis activity of hepatitis C virus RNA-dependent RNA polymerase. Wang QM,  Hockman MA, Staschke K, Johnson RB, Case KA, Lu J, Parsons S, Zhang F, Rathnachalam R, Kirkegaard K, Colacino JM.  J Virol.  2002; 76 (8): 3865-72
• Similar structural basis for membrane localization and protein priming by an RNA-dependent RNA polymerase. Lyle JM,  Clewell A, Richmond K, Richards OC, Hope DA, Schultz SC, Kirkegaard K.  J Biol Chem.  2002; 277 (18): 16324-31
• Poliovirus 3A protein limits interleukin-6 (IL-6), IL-8, and beta interferon secretion during viral infection. Dodd DA,  Giddings TH, Kirkegaard K.  J Virol.  2001; 75 (17): 8158-65
• Remodeling the endoplasmic reticulum by poliovirus infection and by individual viral proteins: an autophagy-like origin for virus-induced vesicles. Suhy DA,  Giddings TH, Kirkegaard K.  J Virol.  2000; 74 (19): 8953-65
• MHC I-dependent antigen presentation is inhibited by poliovirus protein 3A. Deitz SB,  Dodd DA, Cooper S, Parham P, Kirkegaard K.  Proc Natl Acad Sci U S A.  2000; 97 (25): 13790-5
• Functional coupling between replication and packaging of poliovirus replicon RNA. Nugent CI,  Johnson KL, Sarnow P, Kirkegaard K.  J Virol.  1999; 73 (1): 427-35
• KH domain integrity is required for wild-type localization of Sam68. McBride AE,  Taylor SJ, Shalloway D, Kirkegaard K.  Exp Cell Res.  1998; 241 (1): 84-95
• Site size of cooperative single-stranded RNA binding by poliovirus RNA-dependent RNA polymerase. Beckman MT,  Kirkegaard K.  J Biol Chem.  1998; 273 (12): 6724-30
• Poliovirus RNA recombination in cell-free extracts. Tang RS,  Barton DJ, Flanegan JB, Kirkegaard K.  RNA.  1997; 3 (6): 624-33
• Inhibition of endoplasmic reticulum-to-Golgi traffic by poliovirus protein 3A: genetic and ultrastructural analysis. Doedens JR,  Giddings TH, Kirkegaard K.  J Virol.  1997; 71 (12): 9054-64
• Cellular origin and ultrastructure of membranes induced during poliovirus infection. Schlegel A,  Giddings TH, Ladinsky MS, Kirkegaard K.  J Virol.  1996; 70 (10): 6576-88