PMID- 23184522
OWN - NLM
STAT- MEDLINE
DCOM- 20130605
LR  - 20211021
IS  - 1098-5522 (Electronic)
IS  - 0019-9567 (Print)
IS  - 0019-9567 (Linking)
VI  - 81
IP  - 2
DP  - 2013 Feb
TI  - The 3-hydroxy-methylglutaryl coenzyme A lyase HCL1 is required for macrophage 
      colonization by human fungal pathogen Histoplasma capsulatum.
PG  - 411-20
LID - 10.1128/IAI.00833-12 [doi]
AB  - Histoplasma capsulatum is a fungal respiratory pathogen that survives and 
      replicates within the phagolysosome of macrophages. The molecular factors it 
      utilizes to subvert macrophage antimicrobial defenses are largely unknown. 
      Although the ability of H. capsulatum to prevent acidification of the macrophage 
      phagolysosome is thought to be critical for intracellular survival, this 
      hypothesis has not been tested since H. capsulatum mutants that experience 
      decreased phagosomal pH have not been identified. In a screen to identify H. 
      capsulatum genes required for lysis of bone marrow-derived macrophages (BMDMs), 
      we identified an insertion mutation disrupting the H. capsulatum homolog of 
      3-hydroxy-methylglutaryl coenzyme A (HMG CoA) lyase (HCL1). In addition to its 
      inability to lyse macrophages, the hcl1 mutant had a severe growth defect in 
      BMDMs, indicating that HMG CoA lyase gene function is critical for macrophage 
      colonization. In other organisms, HMG CoA lyase catalyzes the last step in the 
      leucine catabolism pathway. In addition, both fungi and humans deficient in HMG 
      CoA lyase accumulate acidic intermediates as a consequence of their inability to 
      catabolize leucine. Consistent with observations in other organisms, the H. 
      capsulatum hcl1 mutant was unable to grow on leucine as the major carbon source, 
      caused acidification of its growth medium in vitro, and resided in an acidified 
      vacuole within macrophages. Mice infected with the hcl1 mutant took significantly 
      longer to succumb to infection than mice infected with the wild-type strain. 
      Taken together, these data indicate the importance of Hcl1 function in H. 
      capsulatum replication in the harsh growth environment of the macrophage 
      phagosome.
FAU - Isaac, Dervla T
AU  - Isaac DT
AD  - Department of Microbiology and Immunology, University of California San 
      Francisco, San Francisco, CA, USA.
FAU - Coady, Alison
AU  - Coady A
FAU - Van Prooyen, Nancy
AU  - Van Prooyen N
FAU - Sil, Anita
AU  - Sil A
LA  - eng
GR  - P01AI063302/AI/NIAID NIH HHS/United States
GR  - R01AI066224/AI/NIAID NIH HHS/United States
GR  - R01 AI066224/AI/NIAID NIH HHS/United States
GR  - R01AI093640/AI/NIAID NIH HHS/United States
GR  - P01 AI063302/AI/NIAID NIH HHS/United States
GR  - R01 AI093640/AI/NIAID NIH HHS/United States
GR  - R25 GM056847/GM/NIGMS NIH HHS/United States
GR  - 1R25GM56847/GM/NIGMS NIH HHS/United States
GR  - T32 A1060537/PHS HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, Non-P.H.S.
DEP - 20121126
PL  - United States
TA  - Infect Immun
JT  - Infection and immunity
JID - 0246127
RN  - EC 2.3.1.9 (Acetyl-CoA C-Acetyltransferase)
RN  - EC 4.1.3.- (Oxo-Acid-Lyases)
RN  - EC 4.1.3.4 (3-hydroxy-3-methylglutaryl-coenzyme A lyase)
RN  - GMW67QNF9C (Leucine)
RN  - 3-Hydroxy-3-Methylglutaryl-CoA Lyase Deficiency
SB  - IM
MH  - Acetyl-CoA C-Acetyltransferase/deficiency/genetics/metabolism
MH  - Amino Acid Metabolism, Inborn Errors/genetics/metabolism
MH  - Amino Acid Sequence
MH  - Animals
MH  - Female
MH  - Histoplasma/genetics/*metabolism/pathogenicity
MH  - Histoplasmosis/genetics/*metabolism/microbiology
MH  - Humans
MH  - Hydrogen-Ion Concentration
MH  - Leucine/genetics/metabolism
MH  - Macrophages/enzymology/*metabolism/microbiology
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Molecular Sequence Data
MH  - Mutagenesis, Insertional
MH  - Oxo-Acid-Lyases/deficiency/genetics/*metabolism
MH  - Phagosomes/genetics/metabolism/microbiology
PMC - PMC3553812
EDAT- 2012/11/28 06:00
MHDA- 2013/06/06 06:00
PMCR- 2013/08/01
CRDT- 2012/11/28 06:00
PHST- 2012/11/28 06:00 [entrez]
PHST- 2012/11/28 06:00 [pubmed]
PHST- 2013/06/06 06:00 [medline]
PHST- 2013/08/01 00:00 [pmc-release]
AID - IAI.00833-12 [pii]
AID - 00833-12 [pii]
AID - 10.1128/IAI.00833-12 [doi]
PST - ppublish
SO  - Infect Immun. 2013 Feb;81(2):411-20. doi: 10.1128/IAI.00833-12. Epub 2012 Nov 26.