Jeffrey Houpt Distinguished Investigator
Professor and Chair
6012 Marsico Hall
Viral Genome Replication
Our laboratory is contributing to pandemic preparedness by elucidating the details of genome replication using the most tractable models for several families of RNA viruses.
Viral infection poses a never-ending threat to human health. It is nearly impossible to predict the next viral outbreak of concern because of the ever-evolving nature of viruses and the potential for new human pathogens to originate in non-human members of the animal kingdom. Readiness for a viral epidemic of unknown etiology requires broad-spectrum, antiviral therapeutics and universal strategies for viral attenuation, for example strategies based on attenuating changes to the activity of a conserved viral enzyme. Our laboratory has had a longstanding interest in discovering fundamental biological knowledge relevant to the treatment and/or prevention of viral infection.
The era of biology on the single-cell level is well underway, and we have become a standard-bearer for “single-cell virology.” Currently, most studies emphasize the between-cell variability of populations in terms of gene expression. Even those studies with viral infection as the focus emphasize end-point differences in yield of virus or viral nucleic acid. No doubt there is much to learn from these studies. However, there is also much to be learned by evaluating viral infection dynamics on the single-cell level.
We have developed a microfluidics-based, cell-culturing, imaging, and data-analysis platform that enables high-throughput, kinetic analysis of single, isolated cells infected with a viral population harboring fluorescent reporters. We have observed unprecedented between-cell variation in the onset, speed, and yield of replication, as well as variation in lysis, both if and when lysis occurs. Our studies demonstrate that analysis of viral infection dynamics on the single-cell level yields knowledge about virus-host interactions and the response of the host to viral infection eluded by population methods.
Selected Preprints and Publications
- Seifert, M., Bera, S.C., van Nies, P., Kirchdoerfer, R.N., Shannon, A., Le, T-T-N., Grove, T.L., Papini, F.S., Arnold, J.J., Almo, S.C., Canard, B., Depken, M., Cameron, C.E., and Dulin, D. (2021). Signatures and mechanisms of efficacious therapeutic ribonucleotides against SARS-CoV-2 revealed by analysis of its replicase using magnetic tweezers. bioRxiv 2020.08.06.240325; doi: https://doi.org/10.1101/2020.08.06.240325
- Janissen, R., Woodman, A., Lee, K.-M., Moustafa, I, Fitzgerald, F., Huang, P.-N., Kuijpers, L., Perkins, A.L., Harki, D.A., Arnold, J.J., Solano B., Shih, S.-R., Cameron, C.E., and Dekker N.H. (2020). Induced copy-back RNA synthesis as a novel therapeutic mechanism against RNA viruses. bioRxiv 2020.02.12.946558; doi: https://doi.org/10.1101/2020.02.12.946558
- Kim, H., Ellis, V. D. 3rd, Woodman, A., Zhao, Y., Arnold, J. J., and Cameron, C. E. (2019). RNA-dependent RNA polymerase speed and fidelity are not the only determinants of the mechanism of efficiency of recombination. Genes 10, pii: E968.
- Liu, W., Calgar, M. U., Mao, Z., Woodman, A., Arnold, J. J., Wilke, C. O., and Cameron, C. E. (2019). More than efficacy revealed by single-cell analysis of antiviral therapeutics. Sci Adv 5, eaax4761.
- Woodman, A., Lee, K. M., Janissen, R., Gong, Y. N., Dekker, N. H., Shih, S. R., and Cameron, C. E. (2019). Predicting intraserotypic recombination in enterovirus 71. J Virol 93, pii: e02057-18.
- Gizzi, A. S., Grove, T. L., Arnold, J. J., Jose, J., Jangra, R. K., Garforth, S. J., Du, Q., Cahill, S. M., Dulyaninova, N. G., Love, J. D., Chandran, K., Bresnick, A. R., Cameron, C. E., and Almo, S. C. (2018). A naturally occurring antiviral ribonucleotide encoded by the human genome. Nature 558, 610-614.
- Banerjee, S., Aponte-Diaz, D., Yeager, C., Sharma, S. D., Ning, G., Oh, H. S., Han, Q., Umeda, M., Hara, Y., Wang, R. Y. L., and Cameron, C. E. (2018). Hijacking of multiple phospholipid biosynthetic pathways and induction of membrane biogenesis by a picornaviral 3CD protein. PLoS Pathog. 14, e1007086.
- Shengjuler, D., Chan, Y. M., Sun, S., Moustafa, I. M., Li, Z. L., Gohara, D. W., Buck, M., Cremer, P. S., Boehr, D. D., and Cameron, C. E. (2017). The RNA-Binding Site of Poliovirus 3C Protein Doubles as a Phosphoinositide-Binding Domain. Structure 25, 1875-1886 e1877.
- Guo, F., Li, S., Caglar, M. U., Mao, Z., Liu, W., Woodman, A., Arnold, J. J., Wilke, C. O., Huang, T. J., and Cameron, C. E. (2017). Single-Cell Virology: On-Chip Investigation of Viral Infection Dynamics. Cell Rep 21, 1692-1704.