Matthew Daugherty

Research

"It takes all the running you can do, to keep in the same place."
- The Red Queen to Alice, in Lewis Carroll’s Through the Looking Glass

Pathogens and their hosts are locked in a constant struggle for evolutionary dominance. Any host adaptation that leads to more effective defense against a pathogen will almost inevitably drive adaptation in the pathogen to escape such defenses. Thus, the only way either side can survive is to continually adapt, as proposed in Leigh Van Valen’s ‘Red Queen hypothesis’. These escalating arms races play out at the level of rapid evolution of host-pathogen interactions, constantly selecting for molecular innovations that either protect the host or evade host defenses. However, the molecular details of these rapidly evolving host-pathogen interactions, and the consequences of these conflicts on human susceptibility to current and emerging infectious diseases, are mostly unexplored.

Our research aims to use these evolutionary principles, combined with virology and mechanistic biochemistry, to understand how our immune system has evolved to defend against pathogens and how pathogens counter-evolve to defeat host immunity. One of the approaches we take is to use comparative genomics to identify characteristic signatures of pathogen-driven innovation (e.g. rapid sequence evolution, horizontal gene transfer, gene birth and death, and gene recombination). Interestingly, we expect these rapidly evolving genes to be at the center of host-pathogen conflicts, yet many of them are almost entirely uncharacterized. This provides an opportunity to use pathogens to discover novel biological functions that are involved in not only pathogen immunity but also more global cellular regulation. Current projects in the lab focus on functional characterization of two such poorly understood systems: post-transcriptional modification of RNA to molecularly distinguish between different RNAs (e.g. host RNA versus viral RNA), and post-translational modifications of proteins to regulate their function. The ultimate goal of our research is to understand the rapidly evolving molecular means by which hosts and pathogens battle each other, while at the same time providing insight into how genetic variation resulting from these conflicts contributes to differences in human susceptibility to infectious diseases.

Select Publications

Tsu, B.V.*, Fay, E.J.*, Nguyen, K.T., Corley, M.R., Hosuru, B., Dominguez, V.A., and M.D. Daugherty. (2021). Running with scissors: evolutionary conflicts between viral proteases and the host immune system. Frontiers in Immunology. 12, 769543. * - these authors contributed equally
Sundaramoorthy, E., Ryan, A.P., Fulzele, A., Leonard, M., Daugherty, M.D.*, and E.J. Bennett*. (2021). Ribosome quality control activity potentiates vaccinia virus protein synthesis during infection. J Cell Science. 134, jcs257188. * - co-corresponding author
Tsu, B.V.*, Beierschmitt, C.*, Ryan, A.P., Agarwal, R., Mitchell, P.S., and M.D. Daugherty. (2021). Diverse viral proteases activate the NLRP1 inflammasome. eLife. 10, e60609. * - these authors contributed equally
Mudla, A., Jiang, Y., Arimoto, K.I., Xu, B., Rajesh, A., Ryan, A.P., Wang, W., Daugherty, M.D., Zhang, D.E., and N. Hao. (2020). Cell-cycle-gated feedback control mediates desensitization to interferon stimulation. eLife. 9, e58825.
Garrigues, J.M., Tsu, B.V., Daugherty, M.D., and A.E. Pasquinelli. (2019). Diversification of the Caenorhabditis heat shock response by Helitron transposable elements. eLife. 8, e51139.
Schwerk, J., Soveg, F.W., Ryan, A.P., Thomas, K.R., Aarreberg, A.D., Ozarkar, S., Forero, A., Kell, A.M., Roby, J.A., So, L. Hyde, J.L., Gale Jr, M., Daugherty, M.D.* and R. Savan*. (2019). RNA-binding protein isoforms ZAP-S and ZAP-L have distinct antiviral and immune resolution functions. Nat Immunol. 20, 1610-1620. * - co-corresponding author
Daugherty, M.D.* and S.E. Zanders*. (2019). Gene conversion generates evolutionary novelty that fuels genetic conflicts. Curr Opin Genet Dev. 58-59, 49-54. * - co-corresponding author
Chavarria-Smith, J., Mitchell, P.S., Ho, A.M., Daugherty, M.D.* and R.E. Vance*. (* co-corresponding authors) (2016). Functional and Evolutionary Analyses Identify Proteolysis as a General Mechanism for NLRP1 Inflammasome Activation. PLoS Pathogens. 12, e1006052. * - co-corresponding author
Daugherty, M.D.*, Schaller, A.M., Geballe, A.P, and H.S. Malik*. (2016). Evolution-guided functional analyses reveal diverse antiviral specificities encoded by IFIT1 genes in mammals. eLife. 5, e14228. * - co-corresponding author
Chou, S.*, Daugherty, M.D.*, Peterson, S.B., Biboy, J., Yang, Y., Jutras, B.L., Fritz-Laylin, L.K., Ferrin, M.A., Harding, B.N., Jacobs-Wagner, C., Yang, X.F., Vollmer, W., Malik, H.S. and J.D. Mougous. (2015). Transferred interbacterial antagonism genes augment eukaryotic innate immune function. Nature. 518, 98-101. * - these authors contributed equally
Daugherty, M.D., Young, J.M., Kerns, J.A., and H.S. Malik. (2014). Rapid evolution of PARP genes suggests a broad role for ADP-ribosylation in host-virus conflicts. PLoS Genetics. 10, e1004403.
Carter, J.J.*, Daugherty, M.D.*, Qi, X., Bheda-Malge, A., Wipf, G.C., Robinson, K., Roman, A., Malik, H.S. and D.A. Galloway. (2013). Identification of an overprinting gene in Merkel cell polyomavirus provides evolutionary insight into the birth of viral genes. Proceedings of the National Academy of Sciences. 110, 12744-9. * - these authors contributed equally
Daugherty, M.D. and H.S. Malik. 2012. Rules of engagement: molecular insights from host-virus arms races. Annual Review of Genetics. 46, 677-700.

Biography

Matt Daugherty received his undergraduate degree from Wesleyan University and then spent three years working for a start-up biotech company in Chicago. He received his Ph.D. from UC San Francisco and did his postdoctoral training at the Fred Hutchinson Cancer Research Center in Seattle WA. He joined the Division of Biological Sciences at UCSD in 2016.