PMID- 26371121
OWN - NLM
STAT- MEDLINE
DCOM- 20160216
LR  - 20231213
IS  - 1098-5522 (Electronic)
IS  - 0019-9567 (Print)
IS  - 0019-9567 (Linking)
VI  - 83
IP  - 12
DP  - 2015 Dec
TI  - Neither classical nor alternative macrophage activation is required for 
      Pneumocystis clearance during immune reconstitution inflammatory syndrome.
PG  - 4594-603
LID - 10.1128/IAI.00763-15 [doi]
AB  - Pneumocystis is a respiratory fungal pathogen that causes pneumonia (Pneumocystis 
      pneumonia [PcP]) in immunocompromised patients. Alveolar macrophages are critical 
      effectors for CD4(+) T cell-dependent clearance of Pneumocystis, and previous 
      studies found that alternative macrophage activation accelerates fungal clearance 
      during PcP-related immune reconstitution inflammatory syndrome (IRIS). However, 
      the requirement for either classically or alternatively activated macrophages for 
      Pneumocystis clearance has not been determined. Therefore, RAG2(-/-) mice lacking 
      either the interferon gamma (IFN-gamma) receptor (IFN-gammaR) or interleukin 4 receptor 
      alpha (IL-4Ralpha) were infected with Pneumocystis. These mice were then immune 
      reconstituted with wild-type lymphocytes to preserve the normal T helper response 
      while preventing downstream effects of Th1 or Th2 effector cytokines on 
      macrophage polarization. As expected, RAG2(-/-) mice developed severe disease but 
      effectively cleared Pneumocystis and resolved IRIS. Neither RAG/IFN-gammaR(-/-) nor 
      RAG/IL-4Ralpha(-/-) mice displayed impaired Pneumocystis clearance. However, 
      RAG/IFN-gammaR(-/-) mice developed a dysregulated immune response, with exacerbated 
      IRIS and greater pulmonary function deficits than those in RAG2 and 
      RAG/IL-4Ralpha(-/-) mice. RAG/IFN-gammaR(-/-) mice had elevated numbers of lung CD4(+) T 
      cells, neutrophils, eosinophils, and NK cells but severely depressed numbers of 
      lung CD8(+) T suppressor cells. Impaired lung CD8(+) T cell responses in 
      RAG/IFN-gammaR(-/-) mice were associated with elevated lung IFN-gamma levels, and 
      neutralization of IFN-gamma restored the CD8 response. These data demonstrate that 
      restricting the ability of macrophages to polarize in response to Th1 or Th2 
      cytokines does not impair Pneumocystis clearance. However, a cell type-specific 
      IFN-gamma/IFN-gammaR-dependent mechanism regulates CD8(+) T suppressor cell recruitment, 
      limits immunopathogenesis, preserves lung function, and enhances the resolution 
      of PcP-related IRIS.
CI  - Copyright (c) 2015, American Society for Microbiology. All Rights Reserved.
FAU - Zhang, Zhuo-Qian
AU  - Zhang ZQ
AD  - Department of Microbiology and Immunology, University of Rochester School of 
      Medicine and Dentistry, Rochester, New York, USA.
FAU - Wang, Jing
AU  - Wang J
AD  - Department of Pediatrics, University of Rochester School of Medicine and 
      Dentistry, Rochester, New York, USA.
FAU - Hoy, Zachary
AU  - Hoy Z
AD  - Department of Pediatrics, University of Rochester School of Medicine and 
      Dentistry, Rochester, New York, USA.
FAU - Keegan, Achsah
AU  - Keegan A
AD  - Center for Vascular and Inflammatory Diseases, Department of Microbiology and 
      Immunology, University of Maryland School of Medicine, Baltimore, Maryland, USA.
FAU - Bhagwat, Samir
AU  - Bhagwat S
AD  - Department of Pediatrics, University of Rochester School of Medicine and 
      Dentistry, Rochester, New York, USA.
FAU - Gigliotti, Francis
AU  - Gigliotti F
AD  - Department of Microbiology and Immunology, University of Rochester School of 
      Medicine and Dentistry, Rochester, New York, USA Department of Pediatrics, 
      University of Rochester School of Medicine and Dentistry, Rochester, New York, 
      USA.
FAU - Wright, Terry W
AU  - Wright TW
AD  - Department of Microbiology and Immunology, University of Rochester School of 
      Medicine and Dentistry, Rochester, New York, USA Department of Pediatrics, 
      University of Rochester School of Medicine and Dentistry, Rochester, New York, 
      USA Terry_Wright@urmc.rochester.edu.
LA  - eng
GR  - R01 HL113495/HL/NHLBI NIH HHS/United States
PT  - Journal Article
DEP - 20150914
PL  - United States
TA  - Infect Immun
JT  - Infection and immunity
JID - 0246127
RN  - 0 (DNA-Binding Proteins)
RN  - 0 (Il4ra protein, mouse)
RN  - 0 (Rag2 protein, mouse)
RN  - 0 (Receptors, Cell Surface)
RN  - 0 (Receptors, Interferon)
SB  - IM
MH  - Animals
MH  - CD8-Positive T-Lymphocytes/*immunology/microbiology/pathology
MH  - DNA-Binding Proteins/deficiency/genetics/immunology
MH  - Eosinophils/immunology/microbiology/pathology
MH  - Gene Expression Regulation
MH  - Host-Pathogen Interactions
MH  - Immune Reconstitution Inflammatory 
      Syndrome/genetics/*immunology/microbiology/pathology
MH  - Killer Cells, Natural/immunology/microbiology/pathology
MH  - Lung/immunology/microbiology/pathology
MH  - Macrophage Activation
MH  - Macrophages, Alveolar/*immunology/microbiology/pathology
MH  - Mice
MH  - Mice, Knockout
MH  - Mice, SCID
MH  - Neutrophils/immunology/microbiology/pathology
MH  - Pneumocystis/*immunology/pathogenicity
MH  - Pneumonia, Pneumocystis/genetics/*immunology/microbiology/pathology
MH  - Receptors, Cell Surface/deficiency/genetics/immunology
MH  - Receptors, Interferon/deficiency/genetics/immunology
MH  - Signal Transduction
MH  - T-Lymphocytes, Helper-Inducer/*immunology/microbiology/pathology
MH  - Th1-Th2 Balance
MH  - Interferon gamma Receptor
PMC - PMC4645389
EDAT- 2015/09/16 06:00
MHDA- 2016/02/18 06:00
PMCR- 2016/06/01
CRDT- 2015/09/16 06:00
PHST- 2015/06/12 00:00 [received]
PHST- 2015/09/05 00:00 [accepted]
PHST- 2015/09/16 06:00 [entrez]
PHST- 2015/09/16 06:00 [pubmed]
PHST- 2016/02/18 06:00 [medline]
PHST- 2016/06/01 00:00 [pmc-release]
AID - IAI.00763-15 [pii]
AID - 00763-15 [pii]
AID - 10.1128/IAI.00763-15 [doi]
PST - ppublish
SO  - Infect Immun. 2015 Dec;83(12):4594-603. doi: 10.1128/IAI.00763-15. Epub 2015 Sep 
      14.