Lung infections are a major cause of morbidity and mortality worldwide. Serious lung infections lead to respiratory distress syndrome for which there is no specific treatment available. In the wake of rise in lung infections caused by multi-drug resistant pathogens and unavailability of a """"""""wonder-drug"""""""" to control associated inflammation, it is important to develop novel therapies. An ideal therapeutic would be the one that can suppress the inflammatory response but preserve the anti-pathogen host defense and lung homeostasis. Our long term goal is to develop therapies based on boosting the natural host defense mechanisms mediated by pathogen-recognition receptors. Surfactant protein (SP)-A and Toll-like receptor (TLR) are known as """"""""secretory"""""""" and """"""""signaling"""""""" pathogen-recognition receptors, respectively. Interaction between SP-A and TLR4 inhibits the TNF-a response but preserves the phagocytic activity of antigen-presenting cells. Thus, a TLR4-interacting region of SP-A, mimicking these properties of SP-A may be developed into a novel SP-A-based immunotherapeutic. Using cutting-edge technology, we have recently identified a TLR4-interacfing region of SP-A (SPA4 peptide). The objective of this application is to define the biological relevance and determine the mechanism of action of SPA4 peptide. We hypothesize that the SPA4 peptide will inhibit TLR4-induced inflammation, while maintaining TLR4-mediated bacterial-phagocytosis and clearance.
The specific aims are to: (1) determine if SPA4 peptide inhibits inflammatory responses and improves clinical symptoms in an animal model of lung inflammation, (2) determine if SPA4 peptide inhibits the inflammatory response and maintains the phagocytic response at a cellular level, and (3) assess the biological effects of SPA4 peptide in clinically-relevant animal models of lung infection and inflammation. This project is innovative because it uses a unique concept of developing an immunotherapeutic that will not only control inflammation, but also help maintain anti-pathogen responses and lung homeostasis. It is expected that an SP-A-based therapeutic will have a significant impact on improving lung health during infection and inflammation.
Lung infections and the resulting lung injury and inflammation are global public health concerns for which there is a compelling need to develop potent new therapeutics. This project evaluates therapeutic benefits and determines mechanism(s) of action of an immunomodulator derived from surfactant protein. The results of the study will help develop a novel immunotherapeutic to overcome infection and modulate inflammation.
|Mishra, Amarjit; Guo, Yujie; Zhang, Li et al. (2016) A Critical Role for P2X7 Receptor-Induced VCAM-1 Shedding and Neutrophil Infiltration during Acute Lung Injury. J Immunol 197:2828-37|
|Wu, Wenxin; Zhang, Wei; Booth, J Leland et al. (2016) Human primary airway epithelial cells isolated from active smokers have epigenetically impaired antiviral responses. Respir Res 17:111|
|Wang, Lingyan; Li, Wenjun; Li, Shitao (2016) A High Throughput Assay for Screening Host Restriction Factors and Antivirals Targeting Influenza A Virus. Front Microbiol 7:858|
|Wu, Lei; Guo, Xin; Wang, Weiqun et al. (2016) Molecular aspects of Î², Î²-carotene-9', 10'-oxygenase 2 in carotenoid metabolism and diseases. Exp Biol Med (Maywood) 241:1879-1887|
|Sahoo, Kaustuv; Koralege, Rangika S Hikkaduwa; Flynn, Nicholas et al. (2016) Nanoparticle Attachment to Erythrocyte Via the Glycophorin A Targeted ERY1 Ligand Enhances Binding without Impacting Cellular Function. Pharm Res 33:1191-203|
|Patel, Vineet Indrajit; Metcalf, Jordan Patrick (2016) Identification and characterization of human dendritic cell subsets in the steady state: a review of our current knowledge. J Investig Med 64:833-47|
|Rudd, Jennifer M; Ashar, Harshini K; Chow, Vincent Tk et al. (2016) Lethal Synergism between Influenza and Streptococcus pneumoniae. J Infect Pulm Dis 2:|
|Narasaraju, Teluguakula; Harshini, Ashar (2016) Neutrophils as Possible Therapeutic Targets in Severe Influenza Pneumonia. J Infect Pulm Dis 2:|
|Xiao, Xiao; Huang, Chaoqun; Zhao, Chunling et al. (2015) Regulation of myofibroblast differentiation by miR-424 during epithelial-to-mesenchymal transition. Arch Biochem Biophys 566:49-57|
|Wu, Wenxin; Zhang, Wei; Duggan, Elizabeth S et al. (2015) RIG-I and TLR3 are both required for maximum interferon induction by influenza virus in human lung alveolar epithelial cells. Virology 482:181-8|
Showing the most recent 10 out of 20 publications