β-Glucans Are Masked but Contribute to Pulmonary Inflammation During Pneumocystis Pneumonia.
β-glucans, which can activate innate immune responses, are a major component in the cell wall of the cyst form of Pneumocystis In the current study, we examined whether β-1,3-glucans are masked by surface proteins in Pneumocystis and what role β-glucans play in Pneumocystis-associated inflammation. For 3 species, including Pneumocystis jirovecii, which causes Pneumocystis pneumonia in humans, Pneumocystis carinii, and Pneumocystis murina, β-1,3-glucans were masked in most organisms, as demonstrated by increased exposure following trypsin treatment. Using quantitative polymerase chain reaction and microarray techniques, we demonstrated in a mouse model of Pneumocystis pneumonia that treatment with caspofungin, an inhibitor of β-1,3-glucan synthesis, for 21 days decreased expression of a broad panel of inflammatory markers, including interferon γ, tumor necrosis factor α, interleukin 1β, interleukin 6, and multiple chemokines/chemokine ligands. Thus, β-glucans in Pneumocystis cysts are largely masked, which likely decreases innate immune activation; this mechanism presumably was developed for interactions with immunocompetent hosts, in whom organism loads are substantially lower. In immunosuppressed hosts with a high organism burden, organism death and release of glucans appears to be an important contributor to deleterious host inflammatory responses.
Critical Care Medicine Department, National Institutes of Health Clinical Center, National Institutes of Health, Bethesda.
Geetha
G
Kutty
Diagnostic Medicine/Pathobiology, Kansas State University College of Veterinary Medicine, Manhattan.
A Sally
AS
Davis
Critical Care Medicine Department, National Institutes of Health Clinical Center, National Institutes of Health, Bethesda.
Gabriela A
GA
Ferreyra
Laboratory of Immunopathogenesis and Bioinformatics, Leidos Biomedical Research, Frederick National Laboratory for Cancer Research, Maryland.
Ju
J
Qiu
Laboratory of Immunopathogenesis and Bioinformatics, Leidos Biomedical Research, Frederick National Laboratory for Cancer Research, Maryland.
Da Wei
da W
Huang
Critical Care Medicine Department, National Institutes of Health Clinical Center, National Institutes of Health, Bethesda.
Monica
M
Sassi
Critical Care Medicine Department, National Institutes of Health Clinical Center, National Institutes of Health, Bethesda.
Lisa
L
Bishop
Critical Care Medicine Department, National Institutes of Health Clinical Center, National Institutes of Health, Bethesda.
Grace
G
Handley
Laboratory of Immunopathogenesis and Bioinformatics, Leidos Biomedical Research, Frederick National Laboratory for Cancer Research, Maryland.
Brad
B
Sherman
Laboratory of Immunopathogenesis and Bioinformatics, Leidos Biomedical Research, Frederick National Laboratory for Cancer Research, Maryland.
Richard
R
Lempicki
Critical Care Medicine Department, National Institutes of Health Clinical Center, National Institutes of Health, Bethesda.
Joseph A
JA
Kovacs
D000818:Animals; D000935:Antifungal Agents / Q000008:administration & dosage; D000077336:Caspofungin; D016207:Cytokines / Q000032:analysis; D004195:Disease Models, Animal; D054714:Echinocandins / Q000008:administration & dosage; D055666:Lipopeptides / Q000008:administration & dosage; D018345:Mice, Knockout; D046228:Microarray Analysis; D011010:Pneumocystis / Q000276:immunology*; D011014:Pneumonia / Q000473:pathology*; D011020:Pneumonia, Pneumocystis / Q000382:microbiology / Q000473:pathology*; D060888:Real-Time Polymerase Chain Reaction; D047071:beta-Glucans / Q000276:immunology*
D000935:Antifungal Agents; D016207:Cytokines; D054714:Echinocandins; D055666:Lipopeptides; D047071:beta-Glucans; C033363:beta-1,3-glucan; D000077336:Caspofungin
Msg; Pneumocystis; cell wall; glucan