Respiratory Syncytial Virus (RSV) is a major cause of lower respiratory tract infection (LRTI) globally, and can trigger a cycle of uncontrolled lung inflammation that can be fatal despite maximal supportive care. No effective therapies exist to combat severe RSV infection, highlighting an urgent need to identify new potential therapeutic targets for this common but dangerous infectious disease. Resolution physiology is an emerging field of research in which Specialized Pro-resolving Mediators (SPMs) have been shown to promote tissue catabasis in multiple animal models of injury, including acute lung injury via acid aspiration, acute bacterial infection, allergic airway inflammation, and wound healing. However, the relationship between SPMs and viral-mediated acute lung injury is incompletely understood. The proposed project will address this need by specifically exploring the generation, impact and mechanisms of SPMs during the resolution of self-limited RSV-mediated lung inflammation, using murine models of RSV infection and cell-based assays. Specific lines of inquiry include (1) establishing the relationship between endogenous SPM production and recruitment of host anti-viral effector mechanisms after RSV infection, in the context of viral replication and pulmonary inflammation in a murine model, and (2) determining mechanisms for SPM regulation of RSV-mediated lung infection and inflammation, focusing on cytotoxic lymphocyte effector functions and cytokine signaling. Determining roles for SPMs in the resolution of RSV infection and inflammation will achieve a critical next step towards evaluating SPMs as a potential new, desperately-needed therapy to reduce the morbidity and mortality associated with viral LRTI from RSV and possibly other viruses such as influenza. As such, the project has the potential to significantly impact the management of viral respiratory infections. Two years of NRSA support for the candidate, Dr. Katherine Walker, would enable her to obtain new investigative skills and pursue the research in this application. She will undertake this project within the Division of Pulmonary and Critical Care Medicine at Brigham and Women?s Hospital, under the close mentorship of her sponsor Dr. Bruce Levy, and with the support and guidance of the expert members of her scientific advisory committee. Completion of this proposal, which represents the core of her research fellowship training, is expected to yield further discoveries into how inflammation is regulated during viral infection in the lung and lay the foundation for her physician-scientist career. Poised within the collaborative environment of her division and with access to the intellectual and technical resources of the greater Harvard community, she will be ideally positioned to gain the training and expertise necessary to successfully accomplish these aims and establish her academic medical career in the field of pulmonary inflammation and resolution.
/ RELEVANCE Respiratory Syncytial Virus (RSV) infects over 2 million and kills over 17,000 patients each year in the United States alone, with severe and fatal infections marked by exuberant inflammation causing respiratory failure. Specialized Pro-resolving Mediators (SPMs) endogenously drive the resolution of acute inflammatory processes to restore tissue homeostasis. We propose a research plan to determine which SPMs are generated during RSV infection and how they facilitate resolution of RSV infection and inflammation, with the ultimate goal of identifying novel therapies to optimize the host response to infection.
|Krishnamoorthy, Nandini; Abdulnour, Raja-Elie E; Walker, Katherine H et al. (2018) Specialized Proresolving Mediators in Innate and Adaptive Immune Responses in Airway Diseases. Physiol Rev 98:1335-1370|
|Sham, Ho Pan; Walker, Katherine H; Abdulnour, Raja-Elie E et al. (2018) 15-epi-Lipoxin A4, Resolvin D2, and Resolvin D3 Induce NF-?B Regulators in Bacterial Pneumonia. J Immunol 200:2757-2766|