Pathogens produce an enornrious variety of factors that interact with host components to promote infections. Many such factors resemble or mimic host proteins. Proteins involved in these host-pathogen interactions are some ofthe most rapidly evolving factors in genomes. Yet little is known about the consequences ofthis rapid evolution on host-pathogen relationships. This research program aims to examine rapid evolution of interacting host and pathogen proteins by focusing on the model poxvirus, vaccinia.
Aim 1 investigates the origins and evolution of a fast evolving poxvirus protein called K3L that mimics the substrate ofthe anti-viral Protein kinase R (PKR) to disrupt anti-viral activity. Evolutionary analysis will guide the reconstruction of ancestral K3L variants, while cellular assays and experimental viral infections will test the potency ofthese reconstructed evolutionary steps.
Aim 2 investigates the evolution of K3L from smallpox, a devastating human pathogen. Experiments focusing on K3L sensitivity to PKR from rodents will test the hypothesis that smallpox emerged from a specific rodent host.
Aim 3 ofthis program entails experimental evolution of vaccinia virus in different host cell lines. Vaccinia will be repeatedly passaged in cell lines under controlled conditions and monitored for genomic changes and potential adaptations.
This aim, along with Aim 2, will be initiated during the K99 phase ofthe project, and will provide extensive data on evolutionary adaptations between interacting host and pathogen factors. The data generated from these experiments will be the foundation of continuing projects proposed in Aim 1 and Aim 3 that will be conducted during the independent phase ofthe project. All the experimental aims ofthis program will develop important skills for establishing an independent research laboratory. This investigation ofthe evolutionary dynamics between interacting host and pathogen factors will provide new insights into the evolutionary strategies of poxviruses, a potentially dangerous class of pathogens poised for natural epidemics and/or use as agents of bio-terrorism.
Poxviruses are large DNA viruses that infect animals and humans. Smallpox is a CDC high-threat (Category A) agent and monkeypox may be poised for epidemic infections of human populations. This project takes an evolutionary approach to understanding how poxviruses adapt to exploit their hosts, so that these evolutionary strategies might be counteracted for the protection of human health.
|Orzalli, Megan H; Broekema, Nicole M; Diner, Benjamin A et al. (2015) cGAS-mediated stabilization of IFI16 promotes innate signaling during herpes simplex virus infection. Proc Natl Acad Sci U S A 112:E1773-81|
|Li, John J; Cao, Chune; Fixsen, Sarah M et al. (2015) Baculovirus protein PK2 subverts eIF2? kinase function by mimicry of its kinase domain C-lobe. Proc Natl Acad Sci U S A 112:E4364-73|
|Hancks, Dustin C; Hartley, Melissa K; Hagan, Celia et al. (2015) Overlapping Patterns of Rapid Evolution in the Nucleic Acid Sensors cGAS and OAS1 Suggest a Common Mechanism of Pathogen Antagonism and Escape. PLoS Genet 11:e1005203|
|Barber, Matthew F; Elde, Nels C (2015) Buried Treasure: Evolutionary Perspectives on Microbial Iron Piracy. Trends Genet 31:627-636|
|Galati, Domenico F; Bonney, Stephanie; Kronenberg, Zev et al. (2014) DisAp-dependent striated fiber elongation is required to organize ciliary arrays. J Cell Biol 207:705-15|
|Barber, Matthew F; Elde, Nels C (2014) Nutritional immunity. Escape from bacterial iron piracy through rapid evolution of transferrin. Science 346:1362-6|
|Barber, Matthew F; Elde, Nels C (2013) Evolutionary biology: Mimicry all the way down. Nature 501:38-9|
|Elde, Nels C (2012) Poliovirus evolution: the strong, silent type. Cell Host Microbe 12:605-6|
|Sawyer, Sara L; Elde, Nels C (2012) A cross-species view on viruses. Curr Opin Virol 2:561-8|
|Elde, Nels C; Child, Stephanie J; Eickbush, Michael T et al. (2012) Poxviruses deploy genomic accordions to adapt rapidly against host antiviral defenses. Cell 150:831-41|
Showing the most recent 10 out of 11 publications