Michaela Gack works at the interface of virology and immunology, as a trio of recent awards attests. An assistant professor in the HMS Department of Microbiology and Immunobiology, she and the scientists in her lab investigate the frontier where viruses slip by their hosts’ defenses. While a virus is intent on infecting the host’s cells, the cell’s sensors are on high alert for invaders, ready with an early warning system primed to induce a counterattack.
For the past eight years Gack has been drilling down into the detailed mechanisms that the human immune system marshals to fight viruses, first focusing on influenza, both in humans and in the birds or swine that can share the rapidly mutating microbe with us. Her work has expanded to other RNA viruses, including dengue, and paramyxovirus family members such as measles and mumps, all of which have RNA as their constantly shifting genetic material.
What she has discovered about innate immune sensing may lead to improved therapies that prevent or treat viral infections. Her research also has the potential to shed light on autoimmune diseases, which cause harm through the fallout from overactive immune responses.
Three major societies have honored Gack for her contributions to the fields of virology and immunology. The American Society for Virology chose her as an ASV Ann Palmenberg Junior Investigator for 2013, the European Society for Virology named her the 2013 ESV Junior Investigator, and the International Cytokine and Interferon Society selected her to receive the Christina Fleischmann Award to Young Women Investigators.
The common theme of her work follows the human innate immune sensing of pathogenic viruses, a critical capability in the human defense against infections. Gack investigates how cells recognize and respond to threats as well as how viruses block these powers.
Threat recognition starts with two sensors, RIG-I and MDA5, which detect viral RNA in various nonimmune cells, such as hepatocytes or lung epithelial cells. Unable to multiply on its own, the virus tries to enter the cell so it can hijack its replication machinery. But sensors need two cellular proteins to induce the infection fighter type 1 interferon. One of these activators is TRIM25, which Gack identified in 2007 while participating as a student in a joint training program administered by the University of Erlangen-Nuremberg in Germany and HMS. That work won her the GE & Science Prize for Young Life Scientists in 2009, an honor that included delivering a speech during the Nobel Prize celebrations in Sweden.
This year her work is attracting attention again for identifying a second molecule essential to this tightly regulated innate immune response. Two and a half years of work using a multipronged approach of RNAi screening, mass spectrometry, and other molecule-hunting technologies turned up a phosphatase known as PP1, which also activates the early immune response—or keeps it in check.
PP1 is a surprising player because it works in the opposite way one would expect it to. As a phosphatase, its chemical job is to remove phosphate groups from proteins. Usually this dephosphorylation process deactivates its targets.
PP1 is well known for its function in the brain and in muscle contraction, but no one had ever shown its role in virus sensing and the innate immune response. Phosphorylation of the sensors RIG-I and MDA5 appears to stop interferon or other infection fighters from combating viruses. Dephosphorylation, on the flip side, sends the antiviral troops into battle.
“In addition to identifying this new key player PP1, we have also identified a new concept of regulating these sensors,” she said. “If there’s no virus infection, the sensors must be kept inactive. Otherwise you would always produce cytokines or interferon, and eventually develop autoimmune disease.”
Having found that PP1 is a crucial regulator in the innate immune response, Gack reasoned that there must be viral proteins that somehow block PP1’s activity so they can get around the sensors.
“If you had a virus that had not evolved to block the host’s immune response, it would not make us sick,” she said.
PP1 has many functions in the body, controlled by distinct molecules. Gack’s challenge is to find what triggers its function as a regulator of innate immune sensors.
“Blocking PP1 everywhere simply would not be a good idea,” she said. “We’re trying to find this unique innate immune-specific regulatory subunit that then might be a therapeutic target that would leave all the other functions of PP1 intact.”
As a basic scientist, she’s laying the groundwork for drug and vaccine development. Refining the target for such therapeutics will go a long way toward improving what’s available now: nothing at all for dengue, and disappointing antivirals or vaccines for many other viruses.
“Our work provides the insights or the molecular details needed for future development of antivirals and new vaccines,” Gack said.
