title: The Interaction ofPneumocystiswith the C-Type Lectin Receptor Mincle Exerts a Significant Role in Host Defense against Infection.
abstract: Pneumocystispneumonia (PCP) remains a major cause of morbidity and mortality within immunocompromised patients. In this study, we examined the potential role of macrophage-inducible C-type lectin (Mincle) for host defense againstPneumocystisBinding assays implementing soluble Mincle carbohydrate recognition domain fusion proteins demonstrated binding to intactPneumocystis cariniias well as to organism homogenates, and they purified major surface glycoprotein/glycoprotein A derived from the organism. Additional experiments showed that rats with PCP expressed increased Mincle mRNA levels. Mouse macrophages overexpressing Mincle displayed increased binding toP. cariniilife forms and enhanced protein tyrosine phosphorylation. The binding ofP. cariniito Mincle resulted in activation of FcRγ-mediated cell signaling. RNA silencing of Mincle in mouse macrophages resulted in decreased activation of Syk kinase afterP. cariniichallenge, critical in downstream inflammatory signaling. Mincle-deficient CD4-depleted (Mincle-/-) mice showed a significant defect in organism clearance from the lungs with higher organism burdens and altered lung cytokine responses duringPneumocystis murinapneumonia. Interestingly, Mincle-/-mice did not demonstrate worsened survival during PCP compared with wild-type mice, despite the markedly increased organism burdens. This may be related to increased expression of anti-inflammatory factors such as IL-1Ra during infection in the Mincle-/-mice. Of note, theP. murina-infected Mincle-/-mice demonstrated increased expression of known C-type lectin receptors Dectin-1, Dectin-2, and MCL compared with infected wild-type mice. Taken together, these data support a significant role for Mincle inPneumocystismodulating host defense during infection.
authors.affiliation: Thoracic Diseases Research Unit, Department of Medicine, Mayo Clinic College of Medicine, Rochester, MN 55905.|Department of Biochemistry, Mayo Clinic College of Medicine, Rochester, MN 55905.
authors.forename: Theodore J
authors.initials: TJ
authors.lastname: Kottom
authors.affiliation: Thoracic Diseases Research Unit, Department of Medicine, Mayo Clinic College of Medicine, Rochester, MN 55905.|Department of Biochemistry, Mayo Clinic College of Medicine, Rochester, MN 55905.
authors.forename: Deanne M
authors.initials: DM
authors.lastname: Hebrink
authors.affiliation: Thoracic Diseases Research Unit, Department of Medicine, Mayo Clinic College of Medicine, Rochester, MN 55905.|Department of Biochemistry, Mayo Clinic College of Medicine, Rochester, MN 55905.
authors.forename: Paige E
authors.initials: PE
authors.lastname: Jenson
authors.affiliation: Thoracic Diseases Research Unit, Department of Medicine, Mayo Clinic College of Medicine, Rochester, MN 55905.|Department of Biochemistry, Mayo Clinic College of Medicine, Rochester, MN 55905.
authors.forename: Vijayalakshmi
authors.initials: V
authors.lastname: Nandakumar
authors.affiliation: Department of Pediatrics, University of Wisconsin Medical School, University of Wisconsin Hospital and Clinics, Madison, WI 53792.
authors.forename: Marcel
authors.initials: M
authors.lastname: Wüthrich
authors.affiliation: Department of Pediatrics, University of Wisconsin Medical School, University of Wisconsin Hospital and Clinics, Madison, WI 53792.
authors.forename: Huafeng
authors.identifier: 0000-0003-2002-4125
authors.initials: H
authors.lastname: Wang
authors.affiliation: Department of Pediatrics, University of Wisconsin Medical School, University of Wisconsin Hospital and Clinics, Madison, WI 53792.|Department of Internal Medicine, University of Wisconsin Medical School, University of Wisconsin Hospital and Clinics, Madison, WI 53792.|Department of Medical Microbiology and Immunology, University of Wisconsin Medical School, University of Wisconsin Hospital and Clinics, Madison, WI 53792.
authors.forename: Bruce
authors.initials: B
authors.lastname: Klein
authors.affiliation: Division of Molecular Immunology, Medical Institute of Bioregulation, Kyushu University, Fukuoka 812-8582, Japan; and.
authors.forename: Sho
authors.initials: S
authors.lastname: Yamasaki
authors.affiliation: University of Veterinary Medicine Hannover, Foundation, Hannover 30559, Germany.
authors.forename: Bernd
authors.initials: B
authors.lastname: Lepenies
authors.affiliation: Thoracic Diseases Research Unit, Department of Medicine, Mayo Clinic College of Medicine, Rochester, MN 55905; limper.andrew@mayo.edu.|Department of Biochemistry, Mayo Clinic College of Medicine, Rochester, MN 55905.
authors.forename: Andrew H
authors.initials: AH
authors.lastname: Limper
mesh_terms: D000818:Animals; D005260:Female; D054884:Host-Pathogen Interactions; D006801:Humans; D037181:Lectins, C-Type / Q000235:genetics / Q000378:metabolism*; D008264:Macrophages / Q000276:immunology* / Q000382:microbiology; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D045363:Pneumocystis carinii / Q000276:immunology*; D011020:Pneumonia, Pneumocystis / Q000276:immunology*; D000067996:RAW 264.7 Cells; D034741:RNA, Small Interfering / Q000235:genetics; D051381:Rats; D011919:Rats, Inbred Strains; D015398:Signal Transduction / Q000235:genetics; D000072377:Syk Kinase / Q000378:metabolism
chemical_list: C113583:Clecsf8 protein, mouse; D037181:Lectins, C-Type; D008565:Membrane Proteins; D034741:RNA, Small Interfering; D000072377:Syk Kinase; C000606897:Syk protein, mouse