Opportunistic fungal infection is a common cause of serious morbidity and mortality in immunocompromised individuals, including AIDS patients, cancer patients under chemotherapy, and immunosuppressed transplant recipients. A key predisposing factor for opportunistic fungal infections is impaired adaptive immunity. However, in the absence of adaptive immunity, we found that osteopontin (OPN) plays a critical role in defense against an opportunistic fungus, Pneumocystis, which causes Pneumocystis pneumonia (PCP). The finding suggested that innate immunity alone can make a significant difference in resistance against fungi. Involvement of OPN in anti-fungal immunity was suggested by several previous studies, but the mechanism is not known. Although OPN has been studied as an extracellular molecule (secreted OPN;sOPN), our preliminary data strongly suggested that a novel intracellular OPN isoform (iOPN) is the main player in OPN-mediated anti-fungal responses. The goal of this proposed research is to elucidate the mechanism by which OPN protects immunocompromised hosts from Pneumocystis infection. To achieve the goal, we will test the following central hypothesis in this proposal: iOPN enhances anti-fungal innate immunity, and it does so by participating in forming fungal pattern recognition receptor (PRR) clusters and in transducing signals from the receptors as a cytoplasmic adaptor protein. Here, we will pursue the following specific aims:
(Aim 1) Elucidate the mechanism by which iOPN participates in fungal PRR cluster formation, (Aim 2) Elucidate the mechanism by which iOPN plays a role in signal transduction of fungal PRRs, and (Aim 3) Determine whether fungal clearance is enhanced by DCs and macrophages that express iOPN.
In Aim 1 and 2, we will use biochemical and cell biological approaches to elucidate how iOPN is involved in cellular responses upon fungal detection.
In Aim 3, we will use in vitro and in vivo approaches to test the iOPN- mediated clearance of Pneumocystis. Upon successful completion, our study will have an important positive impact on the research field of pathogen recognition by hosts. OPN is a well-studied protein, but virtually all the studies of OPN in the past focused on sOPN. Thus, understanding the biology of iOPN, a novel OPN isoform, has a great impact on the field of immunology. Furthermore, results from this study will provide better understanding in molecular mechanisms of fungal detection by innate immunity.

Public Health Relevance

Opportunistic fungal infection is a common cause of serious morbidity and mortality in immunocompromised individuals, including AIDS patients, cancer patients under chemotherapy, and immunosuppressed transplant recipients. This study will use mouse model systems to better understand how our bodies can enhance resistance against fungal infection. Relevance of this study to public health, upon successful completion, is to apply findings from this study to develop new approaches in prophylaxis and treatment of fungal infection in immunocompromised patients.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI088100-02
Application #
8227935
Study Section
Innate Immunity and Inflammation Study Section (III)
Program Officer
Duncan, Rory A
Project Start
2011-02-15
Project End
2016-01-31
Budget Start
2012-02-01
Budget End
2013-01-31
Support Year
2
Fiscal Year
2012
Total Cost
$390,018
Indirect Cost
$140,018
Name
Duke University
Department
Neurosciences
Type
Schools of Medicine
DUNS #
044387793
City
Durham
State
NC
Country
United States
Zip Code
27705
Inoue, Makoto; Arikawa, Tomohiro; Chen, Yu-Hsun et al. (2014) T cells down-regulate macrophage TNF production by IRAK1-mediated IL-10 expression and control innate hyperinflammation. Proc Natl Acad Sci U S A 111:5295-300
Wang, Bin; Rao, Yan-Hua; Inoue, Makoto et al. (2014) Microtubule acetylation amplifies p38 kinase signalling and anti-inflammatory IL-10 production. Nat Commun 5:3479
Inoue, Makoto; Shinohara, Mari L (2014) Clustering of pattern recognition receptors for fungal detection. PLoS Pathog 10:e1003873
Baliga, Sunanda S; Merrill, Gary F; Shinohara, Mari L et al. (2011) Osteopontin expression during early cerebral ischemia-reperfusion in rats: enhanced expression in the right cortex is suppressed by acetaminophen. PLoS One 6:e14568
Inoue, Makoto; Moriwaki, Yasuhiro; Arikawa, Tomohiro et al. (2011) Cutting edge: critical role of intracellular osteopontin in antifungal innate immune responses. J Immunol 186:19-23
Inoue, Makoto; Shinohara, Mari L (2011) Intracellular osteopontin (iOPN) and immunity. Immunol Res 49:160-72