In his laboratory, Derek Walsh, PhD, associate professor of Microbiology-Immunology, focuses on two key research areas: 1) cell signaling and protein synthesis during poxvirus infection and 2) microtubule regulation during herpesvirus infection.
His work has uncovered new regulatory processes in the fields of cell signaling, translational control and microtubule regulation that are critical to infection by a number of viruses. “Moreover, by exploiting viruses as genetic tools to dissect basic biological processes, my lab has helped provide insights into more fundamental aspects of cell signaling and translational control,” said Walsh, also a member of the Robert H. Lurie Comprehensive Cancer Center of Northwestern University.
Walsh, who joined Northwestern in 2014, earned his doctoral degree in biotechnology from Dublin City University and completed postdoctoral fellowships at Columbia University and New York University.
What are your research interests?
Our lab is interested in how large DNA viruses usurp different host cell functions. We primarily work on two very different topics. The first is how poxviruses take control of their host’s protein synthesis machinery in order to make viral proteins, both by manipulating upstream signaling pathways and by directly targeting host translation factors and ribosomes. The second is how herpesviruses — particularly herpes simplex virus type 1 (HSV-1) and human cytomegalovirus (HCMV) — exploit microtubule networks to infect and then completely remodel the host cell in order to replicate and spread.
Although we study viruses, as master manipulators of host processes, they end up teaching us a lot of fascinating and totally unexpected things about basic cell biology — even across different species. For example, we recently found that poxviruses modify our ribosomes so that they function more like plant ribosomes. It turns out that this is because poxviruses make strange mRNAs that are more like plant mRNAs. For that reason, I’m never sure whether to call ourselves virologists or cell biologists. I guess we are both.
What is the ultimate goal of your research?
Our primary goal is to try to understand some of the fine mechanistic details behind how poxviruses and herpesviruses manipulate specific host processes, as a means of contributing to our cumulative understanding of infection.
Most of the time our work would be considered hardcore basic research in virology with applications to cell biology. But now and then we stumble onto something that might be unexpectedly translational. For example, based on what many people would view as an extremely specialized focus on how the ends of microtubules are regulated during HCMV infection, in collaboration with a group at the University of Illinois at Chicago, we recently developed small peptides that can interfere with this process and inhibit HCMV replication. These proteins have such a specialized function in cells, yet the virus requires them, so the inhibitory peptides are not toxic and could one day form the basis of a new virus inhibitor. We have filed a joint invention disclosure on this, with the hope of testing its therapeutic potential down the line.
Nobody can predict where the next therapeutics will come from, which is why continued support for what seems like very basic research is so important.
How does your research advance medical science and knowledge?
Our research is helping to reveal how several medically important viruses replicate and cause disease. Poxviruses, for example, include the variola virus that caused smallpox, a disease that killed more people than any other human pathogen combined and ushered in the era of vaccines. We work on vaccinia virus, a variola-like poxvirus that was used in the global vaccine campaign against smallpox. Although smallpox was eradicated (in my opinion the biggest medical milestone of the last century), new zoonotic poxviruses are adapting to infect humans in the same way variola did, and these pose a serious future threat that we need to prepare for proactively.
In addition, poxviruses are now widely used as vaccine and gene therapy vectors, as well as oncolytics (viruses capable of killing cancer cells), so we need to understand them well. By contrast, HCMV is widespread in the human population and is a leading cause of congenital birth defects — yet there is no vaccine or cure. Clearly, understanding the basics of how these viruses replicate is of fundamental importance to the field of medical sciences.
Who makes up your research team and what role does each individual play in your research?
We are a relatively small team. Of our two graduate students, Colleen Furey works on the role of microtubules during HSV-1 infection of different natural target cell types, while Madeline Rollins works on how poxviruses manipulate host ribosomes to mimic plant translation strategies. Of our three postdoctoral fellows, Nathan Meade, PhD, works on how poxviruses control the metabolic sensor mTOR; Stephen DiGiuseppe, PhD, works on how poxviruses alter ribosome function; and Dean Procter, PhD, works on how HCMV uses microtubules to remodel host cells. I consider myself fortunate as a PI that they all share my intrigue and passion for research, which makes for a fun yet very focused and productive group.
Where have you recently published papers?
We have had a run of good luck with our publications in the past year or so. Our last poxvirus papers were published in Nature, Cell Reportsand Cell. Our HCMV paper, published this year in Developmental Cell, ended up as the cover image for the April 9th issue. We also have a long-standing collaboration with the laboratory of Mojgan Naghavi, PhD, which does some really cool work on HIV, and we have publishedsome collaborative papers with that team recently in Nature Communications.
How is your research funded?
We are very fortunate to be currently funded by the National Institutes of Health, through the National Institute of Allergy and Infectious Diseases and the National Institute of General Medical Sciences. We also receive important internal support from NUCATS and the Dean’s Office, and some of our projects were developed initially through invaluable support from the Third Coast Center for AIDS Research.