Anti-Inflammatory Viral Proteins to Treat Sepsis
Abstract
This proposal looks to improve the health and well-being of the active military, Veterans, and beneficiaries by specifically addressing the Fiscal Year 2019 (FY19) Peer Reviewed Medical Research Program (PRMRP) topic area: Emerging Infectious Diseases. By addressing the problems associated with treatment of viral sepsis, this program targets the FY19 PRMRP Areas of Encouragement: defining the immune correlates of protection for emerging infectious disease, and understanding viral sepsis. Deployed military personnel are at a greater risk for encountering emerging infectious diseases. Emerging infectious diseases including dengue (DENV), Murray Valley encephalitis (MVE), Japanese encephalitis virus (JEV), Venezuelan encephalitis (VEE), and influenza (IAV) are all known to cause viral sepsis. The critical problem this proposal seeks to address is the lack of available treatments for nonbacterial sepsis. A solution to this problem will have a direct impact on saving the lives of military personnel as well as the civilian population. Viral sepsis is a preventable cause of morbidity and mortality for the U.S. military. One-third of people who develop sepsis die, and many of those who do survive have chronic health problems. Sepsis is an uncontrolled inflammatory response caused by a systemic infection. Sepsis is difficult to treat because the onset is very rapid, and in many cases septic shock occurs before the completion of any diagnostic tests to determine the cause of sepsis. Because over half of the cases of sepsis are caused by bacteria, large amounts of antibiotics are given whenever there is a risk for sepsis prior to any diagnostic test to determine if the cause of the infection is indeed bacterial. However, over 30 percent of all sepsis cases are caused by viruses instead of bacteria; in these cases, antibiotics are ineffective, and as a result, the rate of mortality from nonbacterial sepsis is over 50 percent. Currently, there is no other treatment for sepsis after antibiotics. This discovery proposal is designed to test novel treatments for sepsis which could be used alongside antibiotics to save lives. As it is the immune inflammation that is causing the symptoms of disease and the high mortality associated with sepsis, our approach is to reduce the inflammation by administering an anti-inflammatory. This approach will not target the infection that has instigated the sepsis; rather, it is designed to “buy the time” needed for diagnosis and administration effective treatments against the infection. The idea is to get the septic patient passed the crisis point, so they are receptive to treatments to alleviate the infection. The mouse model used in this study mimics the clinical features of sepsis including rapid mortality within 72 hours of the administration of a viral infection. This model has been used previously to study the development of sepsis and identify possible treatments for virally induced sepsis. The main innovation of this proposal is the proposed use of virally encoded anti-inflammatories to treat sepsis. Poxviruses are known to encode many proteins that alter the immune response, including over 20 known anti-inflammatories. This discovery proposal tests two known viral anti-inflammatory proteins as possible treatments for sepsis. The two proteins chosen target two separate pathways known to cause the inflammatory diseases associated with sepsis — complement and the cytokine TNF-alpha. We hypothesize that inhibition of these pathways by these viral anti-inflammatories will block the inflammation associated with sepsis, providing the much needed time to diagnosis infection and treat the disease. By the end of this project, we will have characterized two novel anti-inflammatory proteins that can be further developed and tested to treat sepsis.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 10, 2021
- Source ID
- W81XWH2010132
Entities
People
- Amelia K Pinto
Organizations
- Saint Louis University
- United States Army