When you see a medical emergency in a crowd, experts advise that you select a bystander and clearly direct them to call 911. Surprisingly, when a virus invades the body, our cells may follow similar advice as they call for help and warn their neighbors. How the body coordinates this response and pickswhich cells make the call is the focus of a recent study published in the journal PLOS Pathogens by Associate Professor Marta Gaglia. Prof. Gaglia and PhD student Machika Kaku at the Institute for Molecular Virology (IMV).
Virus-infected cells can produce powerful protein signals called interferons that can start anti-viral responses, stop cells from replicating, and call for immune system help. At the right levels, interferon signals are key to controlling viral infections, but when interferon levels are too high, they can cause tissue damage, autoimmune diseases, and even death. Previous work by Prof. Gaglia’s lab examined single cell’s responses to viral infection and foundthat only a fraction of infected cells call for help. So why would one cell call for help and another lie low?
To answer this question, Gaglia and Kaku worked with a virus known to generate anti-viral responses in cells, Kaposi’s sarcoma-associated herpesvirus (KSHV). KSHV can also cause cancer, especially in people with weakened immune systems. They developed and tested a reporter system where humanKSHV-infected cells were engineered to glow brightly when they produced interferons. They then looked at which cells produced a lot of interferons or are not much at all.
“Like we’d seen previously with other experimental systems, only a small subset, like 5%, of the reporter cells produced interferons. The real question that we wanted to answer is Why these cells?” said Gaglia.
Production of interferons in cells is a highly controlled process. It requires a cascade of events where a protein called interferon regulatory factor 3 (IRF3) is thought to be central to interferon production. IRF3 binds to a cell’s DNA to help initiate expression of interferon genes. When Gaglia and Kaku compared cells that produced interferons to those that did not, they made a surprising discovery.
“Activation of IRF3 was essentially identical between the 5% of cells that produce interferons and the 95% that don’t. If IRF3 activation levels are the same in all of the cells, there must be other signals controlling the interferon expression.” explained Gaglia.
Gaglia and Kaku started exploring several other proteins bind DNA and help express interferon genes. They found that activation of the protein RelA was only increased in the small subset of cells that produce interferon. Even more interesting, they discovered that the cells who called for help with had heightened levels of Activating Transcription Factor 2 (ATF2) compared to cells that didn’t.
“Our results suggest that even before cells sense a virus, some have more ATF2 than others. Baseline levels of ATF2 were approximately double in cells that produce interferon compared to those that don’t. Some cells come ready to call for help while others can’t.” said Kaku.
Understanding what signals tell cells to load up on ATF2 prior to viral infection or turn RelA on once infected are exciting future areas of research stemming from this study.
“Most studies only look at populations of cells. Our work further shows that individual cells possess distinct properties that dictate how they respond to viral infections.” said Gaglia.
Exploring the inner workings of cellular responses to viruses isn’t just a fascinating academic exercise. This kind of work exposes new targets for drugs to counteract viral infections or treat cancer.
“When we study how cells and viruses interact, especially in processes that can lead to cancer, we open new areas for drug development and improve understanding of diseases that affect people every day.” she added.
The Institute for Molecular Virology (IMV), administered by the University of Wisconsin-Madison Office of the Vice Chancellor for Research, supports interdisciplinary research and training focused on uncovering how viruses replicate, evolve, and cause disease, developing strategies for prevention and treatment of viral infections, and harnessing viruses as tools to understand biological processes. The IMV is composed of a core group of faculty from across the UW-Madison campus with tenure homes in the Departments of Oncology, Biochemistry, Medical Microbiology & Immunology, and Plant Pathology. Housed in the Robert M. Bock Laboratories, IMV anchors a much broader network of over 40 virology-focused researchers across UW-Madison who make up the Madison Virology Collective.