The enigmatic mechanisms that control the human immune system are essential for the body to mount a proper defense against microbial invaders. A greater understanding of these defensive pathways would allow scientists to develop therapies that could precisely modulate the immune response in the treatment of virulent pathogens.
Now, immunologists at St. Jude Children's Research Hospital have identified the protein trigger in the body's quick-reaction innate immune system that specifically recognizes the influenza virus in infected cells and triggers their death. The researchers believe that the protein they identified—called ZBP1—could provide much-needed hope for developing drugs to protect against influenza's sometimes lethal complication of pneumonia.
Viral pneumonia from influenza is often exacerbated by lung inflammation and cell damage caused by an overreaction of the innate immune system. The development of new therapies that would modulate ZBP1's action could allow the body to fight the virus by killing infected cells, but preventing that overreaction.
In the new study, the investigators sought to understand how the body's innate immune system is alerted to the presence of the virus and mobilizes to trigger infected cells to commit suicide. The innate immune system triggers the body's “emergency response” to invaders such as infections. This rapid attack gives the body's adaptive immune system time to generate antibodies that specifically target the virus or bacterium. Flu vaccines train this adaptive immune system to attack specific viral strains.
First, the research team uncovered the specific machinery that the innate immune system uses to induce cell suicide—as controlled by type I interferon. Subsequently, the researchers began to search for the protein molecule that recognizes the virus and triggers the cell death machinery. Their experiments used cells from genetically altered mouse strains, in which genes for particular proteins are removed selectively, to discover whether the cells lacking that protein would commit suicide when infected with influenza.
Amazingly, they found that cells lacking ZBP1 were completely resistant to viral-induced cell death. The result was surprising because ZBP1 was known to sense foreign DNA in the cell, but the influenza virus uses RNA as its genetic material.
“Our discovery was totally unexpected,” explained senior study author Thirumala-Devi Kanneganti, Ph.D., a member of the St. Jude Department of Immunology. “We never thought we would actually identify this molecule to be important in influenza viral infection because there is no DNA stage in the influenza life cycle.”
Further experiments revealed that ZBP1 was, indeed, a “master assassin” in the cell, responsible for triggering three separate cell-death pathways. Moreover, the team discovered that ZBP1 was particular for recognizing influenza. The sensor did not trigger cell death in response to other similar viruses or bacteria
The findings from this study were published recently in Science Immunology in an article entitled “ZBP1/DAI Is an Innate Sensor of Influenza Virus Triggering the NLRP3 Inflammasome and Programmed Cell Death Pathways.”
The St. Jude’s team work also revealed that ZBP1 acts as a protein detector, not a DNA detector, sensing telltale viral-produced proteins in the infected cell. The scientists moved their studies into Zbp1-knockout mice strains infected with influenza. Due to the fact that the innate immune system wasn't killing off infected cells, the mice showed an increased viral load and delayed recovery. However, because the immune system wasn't able to overreact, the mice showed reduced lung inflammation and damage to lung cells and were protected from mortality.
“Since the pathology that we saw in the mice matches what is seen in humans, we will now explore translating these findings to humans,” Dr. Kanneganti noted. “If we can somehow modulate the activation of this pathway, then that will help to decrease the exaggerated inflammatory response that causes mortality during influenza infection.”
Lead author Teneema Kuriakose, Ph.D., a postdoctoral research associate in Dr. Kanneganti’s laboratory, added that the timing of such drug treatment would be extremely critical, stating that “ZBP1 does an amazing job of killing off infected cells, but it would be very useful to modulate ZBP1 in later stages of the infection, when the uncontrolled inflammation causes damage.”
“We have shown that these molecules are important in viral infections, but now we want to test their role in other inflammatory conditions,” Dr. Kanneganti concluded. “ZBP1 is likely not dedicated to attacking only the influenza virus. Maybe it also plays other roles, and if we fully understand those roles, we can learn how to manipulate immune responses.”