Opioid abuse and host defense against streptococcus pneumoniae lung infection
Principal Investigator: Jinghua Wang
Abstract: [unreadable] DESCRIPTION (provided by applicant): Bacterial pneumoniae and invasive pneumococcal disease are strongly associated with HIV-1 infection. Drug abusers have a higher incidence of pneumococcal pneumoniae co-infected with HIV, which increases their mortality rate. The overall goal of this application is to determine the mechanism(s) underlying opioid abuse increased susceptibility to severe pneumococcal pneumoniae. Our recent studies revealed that morphine abuse in a mouse model markedly increases mortality and compromises the innate immune response and increase susceptibility to S. pneumoniae infection. However, the signal transducing receptors and the cellular and molecular mechanisms for these effects are poorly understood. Our preliminary data indicates that morphine significantly decreases NF-kappaB activation, which is a key step for an appropriate innate immune response. Furthermore in our preliminary data we also show that morphine's effect is attenuated in the mu- opioid receptor knock out (MORKO) mice, but completely abolished by naltrexone. Based on these observations, we hypothesize that morphine induced defects in innate immunity is mediated through the opioid receptor by altering signal transducing that lead to NF-kappaB activation. This hypothesis will be addressed through two independent but interrelated specific aims. In specific Aim 1 we will investigate the type of opioid receptor that mediates morphine's effect using an in vivo S. pneumoniae infection model. MORKO and wild type (WT) mice will be used to determine the receptor type in the presence of delta and kappa antagonist. In specific Aim 2, we will investigate the cellular and molecular mechanisms by which morphine modulates NF-kappaB signaling and thereby impairs innate immune response to Streptococcus pneumoniae. An in vitro alveolar macrophage and lung epithelial cells infection model will be used to investigate cell population involved in morphine modulation initiation of innate immune response to pnumococcal infection, and to determine the signaling pathways underlying morphine regulation of S. pneumoniae induced TLRs dependent NF-:B activity. The proposed study should lead to better understanding of how opioid abuse increases the host's susceptibility to pulmonary infection and may guide the development of new treatment regimens for substance-abusing associated pneumoniae. Project Narrative: Drug abusers experience a higher rate of pneumoccocal infection, as well as, a higher mortality rate when co-infected with HIV. The proposed studies represent a unique series of experiments directed towards better understanding the underlying processes of an immune response, as well as, the role opioid abuse plays in suppressing such a response. Ultimately, the studies will afford better development and design options when treating substance-abusing associated pneumoniae. [unreadable] [unreadable] [unreadable]
Funding Period: 2007-09-25 - 2010-02-28
more information: NIH RePORT
- Morphine induces defects in early response of alveolar macrophages to Streptococcus pneumoniae by modulating TLR9-NF-kappa B signalingJinghua Wang
Division of Basic and Translational Research, Department of Surgery, University of Minnesota, Minneapolis, MN 55455, USA
J Immunol 180:3594-600. 2008..pneumoniae infection in resident macrophages during the early stages of infection, leading to a compromised innate immune response...
- Opiate abuse, innate immunity, and bacterial infectious diseasesJinghua Wang
Division of Basic and Translational Research, Department of Surgery, University of Minnesota, Mayo Mail Code 195, 420 Delaware Street Southeast, Minneapolis, MN, 55455, USA
Arch Immunol Ther Exp (Warsz) 56:299-309. 2008....
- Morphine disrupts interleukin-23 (IL-23)/IL-17-mediated pulmonary mucosal host defense against Streptococcus pneumoniae infectionJing Ma
Division of Basic and Translational Research, Department of Surgery, University of Minnesota, MMC 195, 420 Delaware Street SE, Minneapolis, MN 55455, USA
Infect Immun 78:830-7. 2010..pneumoniae lung infection. This leads to diminished release of antimicrobial S100A8/A9 proteins, compromised neutrophil recruitment, and more-severe infection...
- Morphine inhibits murine dendritic cell IL-23 production by modulating Toll-like receptor 2 and Nod2 signalingJinghua Wang
Division of Basic and Translational Research, Department of Surgery, University of Minnesota, Minneapolis, Minnesota 55455, USA
J Biol Chem 286:10225-32. 2011..Taken together, our study shows that morphine impairs S. pneumoniae induced IL-23 production through MyD88-IRAK1/4-dependent TLR2 and Nod2 signaling in DCs...