Macrophage-derived nanoparticles as an adjuvant therapy for severe bacterial pneumonia

PROJECT SUMMARY / ABSTRACT Severe bacterial pneumonia can progress to acute lung injury (ALI) and acute respiratory distress syndrome (ARDS), in which the host hyperinflammatory immune response causes damage to the alveolar-capillary barrier in the lung. Although neutrophils are critical for host defense, their dysregulated recruitment, activation, and cell death can result in the excessive release of injurious mediators, which can cause collateral damage to the surrounding lung tissue and contribute to ALI / ARDS pathophysiology. While certain antibiotics are effective at killing pathogens, they do not specifically target the hyperinflammatory immune response. Thus, there is a significant knowledge gap in controlling neutrophil-driven inflammation in severe pneumonia while preserving neutrophils’ beneficial antibacterial functions. This study investigates a novel therapeutic concept, known as macrophage membrane-coated nanoparticles (MΦ-NPs), as a potential adjuvant therapy for treating severe bacterial pneumonia caused by methicillin-resistant Staphylococcus aureus (MRSA). MΦ-NPs consist of human macrophage cell membranes wrapped around a biodegradable PLGA polymeric core. Their macrophage surface receptors render them capable of neutralizing host cytokines, inflammatory pathogen-associated molecular patterns (PAMPs), and bacterial toxins. The central hypothesis of this proposal is that MΦ-NPs can protect lung tissue from neutrophil-driven inflammation and improve outcomes in severe MRSA pneumonia. Specifically, the two aims of this proposal are: 1) to test the hypothesis that MΦ-NPs modulate key neutrophil responses to MRSA to limit neutrophil-driven inflammation in vitro, and 2) to test the hypothesis that MΦ-NPs have in vivo efficacy in reducing inflammatory lung damage and improving survival in a murine model of severe MRSA pneumonia. These studies will enhance our understanding of neutrophilic inflammation and the translational potential of MΦ-NPs as a therapy for severe bacterial pneumonia caused by MRSA. The proposed research will occur in the Nizet laboratory, which has > 25 years of experience in taking collaborative approaches to study host-microbe interactions and novel therapeutics. Hunter will develop skills in nanoengineering, proteomics, immunohistochemistry, and mouse models of infectious diseases through mentorship, coursework, and hands-on experimentation with the Nizet lab and collaborators. He will also develop his clinical and professional skills through clinical volunteering, conference participation, and teaching.