PMID- 30452484
OWN - NLM
STAT- MEDLINE
DCOM- 20190215
LR  - 20190215
IS  - 1553-7374 (Electronic)
IS  - 1553-7366 (Linking)
VI  - 14
IP  - 11
DP  - 2018 Nov
TI  - Macrophage activation by IFN-gamma triggers restriction of phagosomal copper from
      intracellular pathogens.
PG  - e1007444
LID - 10.1371/journal.ppat.1007444 [doi]
AB  - Copper toxicity and copper limitation can both be effective host defense
      mechanisms against pathogens. Tolerance of high copper by fungi makes toxicity as
      a defense mechanism largely ineffective against fungal pathogens. A forward
      genetic screen for Histoplasma capsulatum mutant yeasts unable to replicate
      within macrophages showed the Ctr3 copper transporter is required for
      intramacrophage proliferation. Ctr3 mediates copper uptake and is required for
      growth in low copper. Transcription of the CTR3 gene is induced by
      differentiation of H. capsulatum into pathogenic yeasts and by low available
      copper, but not decreased iron. Low expression of a CTR3 transcriptional reporter
      by intracellular yeasts implies that phagosomes of non-activated macrophages have
      moderate copper levels. This is further supported by the replication of
      Ctr3-deficient yeasts within the phagosome of non-activated macrophages. However,
      IFN-gamma activation of phagocytes causes restriction of phagosomal copper as
      shown by upregulation of the CTR3 transcriptional reporter and by the failure of 
      Ctr3-deficient yeasts, but not Ctr3 expressing yeasts, to proliferate within
      these macrophages. Accordingly, in a respiratory model of histoplasmosis,
      Ctr3-deficient yeasts are fully virulent during phases of the innate immune
      response but are attenuated after the onset of adaptive immunity. Thus, while
      technical limitations prevent direct measurement of phagosomal copper
      concentrations and copper-independent factors can influence gene expression, both
      the CTR3 promoter induction and the attenuation of Ctr3-deficient yeasts indicate
      activation of macrophages switches the phagosome from a copper-replete to a
      copper-depleted environment, forcing H. capsulatum reliance on Ctr3 for copper
      acquisition.
FAU - Shen, Qian
AU  - Shen Q
AD  - Department of Microbiology, Ohio State University, Columbus, OH, United States of
      America.
FAU - Beucler, Matthew J
AU  - Beucler MJ
AUID- ORCID: 0000-0001-8334-7736
AD  - Department of Microbiology, Ohio State University, Columbus, OH, United States of
      America.
FAU - Ray, Stephanie C
AU  - Ray SC
AUID- ORCID: 0000-0002-6390-6198
AD  - Department of Microbiology, Ohio State University, Columbus, OH, United States of
      America.
FAU - Rappleye, Chad A
AU  - Rappleye CA
AUID- ORCID: 0000-0001-7880-5958
AD  - Department of Microbiology, Ohio State University, Columbus, OH, United States of
      America.
LA  - eng
GR  - R03 AI111015/AI/NIAID NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20181119
PL  - United States
TA  - PLoS Pathog
JT  - PLoS pathogens
JID - 101238921
RN  - 0 (Antiporters)
RN  - 0 (Cation Transport Proteins)
RN  - 789U1901C5 (Copper)
RN  - 82115-62-6 (Interferon-gamma)
RN  - E1UOL152H7 (Iron)
SB  - IM
MH  - Animals
MH  - Antiporters/metabolism
MH  - Cation Transport Proteins/metabolism
MH  - Cell Line
MH  - Copper/*metabolism/toxicity
MH  - Histoplasma/immunology/metabolism
MH  - Histoplasmosis/metabolism
MH  - Interferon-gamma/*metabolism
MH  - Iron/metabolism
MH  - Macrophage Activation/physiology
MH  - Macrophages
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Phagosomes/*metabolism
PMC - PMC6277122
COIS- The authors have declared that no competing interests exist.
EDAT- 2018/11/20 06:00
MHDA- 2019/02/16 06:00
CRDT- 2018/11/20 06:00
PHST- 2018/07/31 00:00 [received]
PHST- 2018/10/30 00:00 [accepted]
PHST- 2018/12/03 00:00 [revised]
PHST- 2018/11/20 06:00 [pubmed]
PHST- 2019/02/16 06:00 [medline]
PHST- 2018/11/20 06:00 [entrez]
AID - 10.1371/journal.ppat.1007444 [doi]
AID - PPATHOGENS-D-18-01537 [pii]
PST - epublish
SO  - PLoS Pathog. 2018 Nov 19;14(11):e1007444. doi: 10.1371/journal.ppat.1007444.
      eCollection 2018 Nov.