The objectives of Project 1 are to study the mechanisms of activation of Group IVA cytosolic phospholipase A{2} (cPLA{2}a) in resident peritoneal and alveolar macrophages by the opportunistic fungal pathogens Candida albicans and Aspergillus fumigatus, and to determine the role of eicosanoids in regulating immune responses to fungal infection in vivo. Fungi activate cPLA{2}a in macrophages that promotes arachidonic acid release and production of prostaglandins and leukotrienes. Eicosanoids regulate acute inflammation and immune responses such as vascular permeability, emigration and function of leukocytes, production of cytokines, and lymphocyte differentiation. There has been considerable interest in elucidating mechanisms regulating host responses to fungal infection, however, the mechanisms regulating cPLA{2}a activation by C. albicans and A. fumigatus and the role of lipid mediators in regulating fungal infection are poorly understood. We hypothesize that C. albicans and A. fumigatus engage C-type lectin receptors (dectin-1 and dectin-2) and MyD88-dependent pathways to activate cPLA{2}a and eicosanoid production. A comparison of resident macrophages from the peritoneal cavity and from the lung, and fungal infection at these distinct sites, will provide insight into how these unique tissue environments influence responses to fungal infection.
The Specific Aims are: (1) to identify the pattern recognition receptors engaged by C. albicans and (2) the mechanisms for cPLA{2}a activation and eicosanoid production in peritoneal macrophages;(3) to elucidate how eicosanoids modulate responses of peritoneal macrophages to C. albicans in vitro and regulate inflammation in C. albicans peritonitis in vivo;and (4) to determine mechanisms of cPLA{2}a activation and eicosanoid production by C. albicans and A. fumigatus in mouse and human alveolar macrophages, and the role of cPLA{2}a in regulating host responses to A. fumigatus lung infection. We hypothesize that eicosanoids play a protective role in fungal host defense by modulating cell recruitment and the balance of cytokine production. Once infection is contained, cPLA{2}a activation and eicosanoid production also protect the lung from excess inflammation by enhancing clearance of apoptotic neutrophils through the novel lipid mediator lysophosphatidylserine (Project 2). However, environmental insults such as ozone (Project 3) can lead to production of novel lipid mediators that interfere with these protective pathways. We will define how lipid mediators regulate host defense, the amplitude of inflammation and its resolution.
This research is relevant to public health because it will provide new information about an important pathway that regulates host defense against infection. Elucidating the mechanisms of cPLA{2}a activation in macrophages, and the role of eicosanoids in regulating immune responses to fungal infection in vivo, is important for development of new approaches for controlling disease processes.
| Zemski Berry, Karin A; Murphy, Robert C; Kosmider, Beata et al. (2017) Lipidomic characterization and localization of phospholipids in the human lung. J Lipid Res 58:926-933 |
| Mould, Kara J; Barthel, Lea; Mohning, Michael P et al. (2017) Cell Origin Dictates Programming of Resident versus Recruited Macrophages during Acute Lung Injury. Am J Respir Cell Mol Biol 57:294-306 |
| Gibbings, Sophie L; Thomas, Stacey M; Atif, Shaikh M et al. (2017) Three Unique Interstitial Macrophages in the Murine Lung at Steady State. Am J Respir Cell Mol Biol 57:66-76 |
| Frasch, S Courtney; McNamee, Eóin N; Kominsky, Douglas et al. (2016) G2A Signaling Dampens Colitic Inflammation via Production of IFN-?. J Immunol 197:1425-34 |
| Janssen, William J; Bratton, Donna L; Jakubzick, Claudia V et al. (2016) Myeloid Cell Turnover and Clearance. Microbiol Spectr 4: |
| Yun, Bogeon; Lee, HeeJung; Jayaraja, Sabarirajan et al. (2016) Prostaglandins from Cytosolic Phospholipase A2?/Cyclooxygenase-1 Pathway and Mitogen-activated Protein Kinases Regulate Gene Expression in Candida albicans-infected Macrophages. J Biol Chem 291:7070-86 |
| Desch, A Nicole; Gibbings, Sophie L; Goyal, Rajni et al. (2016) Flow Cytometric Analysis of Mononuclear Phagocytes in Nondiseased Human Lung and Lung-Draining Lymph Nodes. Am J Respir Crit Care Med 193:614-26 |
| Jayaraja, Sabarirajan; Dakhama, Azzeddine; Yun, Bogeon et al. (2016) Cytosolic phospholipase A2 contributes to innate immune defense against Candida albicans lung infection. BMC Immunol 17:27 |
| Kandasamy, Pitchaimani; Numata, Mari; Berry, Karin Zemski et al. (2016) Structural analogs of pulmonary surfactant phosphatidylglycerol inhibit toll-like receptor 2 and 4 signaling. J Lipid Res 57:993-1005 |
| Zemski Berry, Karin A; Murphy, Robert C (2016) Phospholipid Ozonation Products Activate the 5-Lipoxygenase Pathway in Macrophages. Chem Res Toxicol 29:1355-64 |
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