title: Cytosolic phospholipase A2 contributes to innate immune defense against Candida albicans lung infection.
abstract: The lung is exposed to airborne fungal spores, and fungi that colonize the oral cavity such as Candida albicans, but does not develop disease to opportunistic fungal pathogens unless the immune system is compromised. The Group IVA cytosolic phospholipase A2 (cPLA2α) is activated in response to Candida albicans infection resulting in the release of arachidonic acid for eicosanoid production. Although eicosanoids such as prostaglandins and leukotrienes modulate inflammation and immune responses, the role of cPLA2α and eicosanoids in regulating C. albicans lung infection is not understood.
  
  
  
  The responses of cPLA2α(+/+) and cPLA2α(-/-) Balb/c mice to intratracheal instillation of C. albicans were compared. After challenge, we evaluated weight loss, organ fungal burden, and the recruitment of cells and the levels of cytokines and eicosanoids in bronchoalveolar lavage fluid. The ability of macrophages and neutrophils from cPLA2α(+/+) and cPLA2α(-/-) mice to recognize and kill C. albicans was also compared.
  
  
  
  After C. albicans instillation, cPLA2α(+/+) mice recovered a modest weight loss by 48 h and completely cleared fungi from the lung by 12 h with no dissemination to the kidneys. In cPLA2α(-/-) mice, weight loss continued for 72 h, C. albicans was not completely cleared from the lung and disseminated to the kidneys. cPLA2α(-/-) mice exhibited greater signs of inflammation including higher neutrophil influx, and elevated levels of albumin and pro-inflammatory cytokines/chemokines (IL1α, IL1β, TNFα, IL6, CSF2, CXCL1, CCL20) in bronchoalveolar lavage fluid. The amounts of cysteinyl leukotrienes, thromboxane B2 and prostaglandin E2 were significantly lower in bronchoalveolar lavage fluid from C. albicans-infected cPLA2α(-/-) mice compared to cPLA2α(+/+) mice. Alveolar macrophages and neutrophils from uninfected cPLA2α(-/-) mice exhibited less killing of C. albicans in vitro than cells from cPLA2α(+/+) mice. In addition alveolar macrophages from cPLA2α(-/-) mice isolated 6 h after instillation of GFP-C. albicans contained fewer internalized fungi than cPLA2α(+/+) macrophages.
  
  
  
  The results demonstrate that cPLA2α contributes to immune surveillance and host defense in the lung to prevent infection by the commensal fungus C. albicans and to dampen inflammation.
authors: Department of Pediatrics, National Jewish Health, 1400 Jackson St., Denver, Colorado, 80206, USA.
authors: Sabarirajan
authors: S
authors: Jayaraja
authors: Department of Pediatrics, National Jewish Health, 1400 Jackson St., Denver, Colorado, 80206, USA.
authors: Azzeddine
authors: A
authors: Dakhama
authors: Department of Pediatrics, National Jewish Health, 1400 Jackson St., Denver, Colorado, 80206, USA.
authors: Bogeon
authors: B
authors: Yun
authors: Department of Pediatrics, National Jewish Health, 1400 Jackson St., Denver, Colorado, 80206, USA.
authors: Moumita
authors: M
authors: Ghosh
authors: Department of Pediatrics, National Jewish Health, 1400 Jackson St., Denver, Colorado, 80206, USA.
authors: HeeJung
authors: H
authors: Lee
authors: Department of Pediatrics, National Jewish Health, 1400 Jackson St., Denver, Colorado, 80206, USA.
authors: Elizabeth F
authors: EF
authors: Redente
authors: Department of Pharmacology, University of Colorado Denver, Aurora, Colorado, USA.
authors: Charis L
authors: CL
authors: Uhlson
authors: Department of Pharmacology, University of Colorado Denver, Aurora, Colorado, USA.
authors: Robert C
authors: RC
authors: Murphy
authors: Department of Pediatrics, National Jewish Health, 1400 Jackson St., Denver, Colorado, 80206, USA. lesliec@njhealth.org.|Department of Pharmacology, University of Colorado Denver, Aurora, Colorado, USA. lesliec@njhealth.org.|Department of Pathology, University of Colorado Denver, Aurora, Colorado, USA. lesliec@njhealth.org.
authors: Christina C
authors: CC
authors: Leslie
mesh_terms: D000818:Animals; D016718:Arachidonic Acid / Q000378:metabolism; D002176:Candida albicans / Q000276:immunology*; D002177:Candidiasis / Q000276:immunology*; D002465:Cell Movement; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D015777:Eicosanoids / Q000378:metabolism; D007113:Immunity, Innate; D018836:Inflammation Mediators / Q000378:metabolism; D008168:Lung / Q000276:immunology* / Q000382:microbiology; D008172:Lung Diseases, Fungal / Q000276:immunology*; D016676:Macrophages, Alveolar / Q000382:microbiology / Q000502:physiology*; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D009504:Neutrophils / Q000382:microbiology / Q000502:physiology*; D054467:Phospholipases A2 / Q000235:genetics / Q000276:immunology / Q000378:metabolism*
chemical_list: D016207:Cytokines; D015777:Eicosanoids; D018836:Inflammation Mediators; D016718:Arachidonic Acid; D054467:Phospholipases A2
keywords: Candida albicans; Cytosolic phospholipase A2; Inflammation; Leukotrienes; Macrophages; Neutrophils; Prostaglandins