Research in the Kirkegaard Laboatory

We study the genetics, immunology, cell biology, and biochemistry of positive-strand RNA viral propagation.
(Visit our Laboratory Members page for research summaries.)

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 -- rhinoviruses, coxsackieviruses, and echoviruses -- as well as more distantly related positive-strand RNA viruses such as hepatitis C virus, dengue virus, and West Nile virus.

Our Laboratory is interested in the mechanism of the RNA-dependent RNA amplification utilized by positive-strand RNA viruses, such as poliovirus, rhinoviruses, hepatitis C virus and dengue virus in their replication. Genetically, this process is highly error-prone, due to the low fidelity of the viral RNA polymerases. This low fidelity results in a ‘quasispecies’ of RNA genomes, even within any individual infected cell. It is in this milieu that new mutations that might confer advantage, such as drug resistance, arise. A recent emphasis is to learn how to suppress the diversity of such viruses, and the outgrowth of potentially drug-resistant viruses, by understanding the nature of this intracellular mileau. The cell biology of RNA amplification is also a focus of the laboratory. All positive-strand viruses of eukaryotes replicate their genomes on intracellular membranes, which are rearranged and exploited differently by different viruses. Poliovirus, which has been the subject of most of the laboratory’s investigations, induces the formation of double-membraned vesicles that resemble cellular autophagosomes.

Our Biological Questions
How does the biochemistry of RNA-dependent RNA polymerases affect the biology of RNA viruses?

Can less fit viral genomes inhibit the growth of more fit viral genomes within the same cell? Mutations in which viral genes are needed to exert this dominant negative effect?

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

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?

How does the inhibition of the protein secretory apparatus by the 3A and 2B proteins of picornaviruses 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?

Copyright 2006 - 2010. The Laboratory of Karla Kirkegaard, Ph.D. All rights reserved.