Targeting Host Responses to Prevent Virus-Induced ARDS in the Nonhuman Primate Model
Abstract
A new approach to treating virus-induced acute lung injury. Respiratory viral infections can produce primary viral pneumonia, which in severe cases progresses to acute respiratory distress syndrome (ARDS), an extremely serious condition in which the lung becomes hemorrhagic and filled with fluid. In 60% of ARDS cases, the lungs fail to function and shut down, resulting in death. The great paradox in virus-induced ARDS is that the damage is caused primarily by the host response to infection, even though it is virus replication within tissues that begins the process. This understanding has opened the way to develop an entirely new approach to therapy of acute lung injury caused by virus infection, which is to target the host innate response to infection. The innate response to primary viral pneumonia is characterized by intense inflammation and cell death, and the early initiator of this inflammatory cascade within cells is an enzyme called caspase-1, which is switched on through a process involving virus proteins. By inhibiting the activity of caspase-1 early in infection, we can block the inflammation and the devastating effects of cell death within the lung, and thereby prevent ARDS and save lives. Influenza and Middle East respiratory syndrome are major threats to the military. Seasonal influenza can progress to fatal ARDS, and influenza-associated illnesses are one of the top 10 causes of death in the United States. Treatment with antiviral drugs are not effective after the first 48 hours, and severely ill patients must rely on supportive care. Of particular concern to military Service members stationed overseas is avian influenza, including the H5N1 and H7N9 strains that are endemic in Asia and the Middle East. These viruses circulate in poultry but also infect humans, and 30%-50% of the time these infections are fatal. Avian influenza viruses are spreading throughout the world, and H5N1 is now widespread throughout all aspects of the poultry industry in Egypt. Should these highly pathogenic influenza viruses gain the ability to transmit easily from person to person, a global pandemic will result. The influenza pandemic of 1918 known as Spanish flu was the worst disaster in human history and took a particular toll on the military. Another new threat is the virus that causes Middle East respiratory syndrome, called MERS-CoV, which is entrenched in 10 countries on the Arabian Peninsula, including Qatar, where a large number of US military Service members are deployed. MERS is lethal in 30%-40% of human cases. A risk with MERS-CoV is that it spreads from human to human within hospitals, and introduction of the virus into a military infirmary could be devastating. We have no effective antiviral therapy for avian influenza or for MERS. An effective therapy targeting the host innate response would bring about a sea change in the way we treat influenza and other primary viral pneumonias, and could be life-saving for millions of individuals should we face a new influenza pandemic. A breakthrough monkey model of ARDS caused by H5N1 influenza – a means to test new therapies. Using our highly specialized biocontainment facilities at the University of Pittsburgh, we have developed a model of acute lung injury caused by H5N1 influenza in macaque monkeys, one that utilizes aerosolization of virus to penetrate the depths of the lung. This is the only model to replicate human-like disease caused by influenza in monkeys, and we are uniquely qualified to work with it within the confines of our facility. This model enables us to test for the first time ways to target the host innate response and prevent virus-induced ARDS. Testing clinically approved caspase-1 inhibitor in human lung cells and H5N1-infected monkeys. In this proposal, we will work with human lung cells in the laboratory to critically evaluate the role of caspase-1 in H5N1 and MERS-CoV infection and demonstrate the effectiveness of caspas
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1810643
Entities
People
- Simon Barratt Boyes
Organizations
- United States Army
- University of Pittsburgh