PMID- 23922243
OWN - NLM
STAT- MEDLINE
DCOM- 20131224
LR  - 20211021
IS  - 1528-3658 (Electronic)
IS  - 1076-1551 (Print)
IS  - 1076-1551 (Linking)
VI  - 19
IP  - 1
DP  - 2013 Aug 28
TI  - Immunomodulatory and antibacterial effects of cystatin 9 against Francisella 
      tularensis.
PG  - 263-75
LID - 10.2119/molmed.2013.00081 [doi]
AB  - Cystatin 9 (CST9) is a member of the type 2 cysteine protease inhibitor family, 
      which has been shown to have immunomodulatory effects that restrain inflammation, 
      but its functions against bacterial infections are unknown. Here, we report that 
      purified human recombinant (r)CST9 protects against the deadly bacterium 
      Francisella tularensis (Ft) in vitro and in vivo. Macrophages infected with the 
      Ft human pathogen Schu 4 (S4), then given 50 pg of rCST9 exhibited significantly 
      decreased intracellular bacterial replication and increased killing via 
      preventing the escape of S4 from the phagosome. Further, rCST9 induced autophagy 
      in macrophages via the regulation of the mammalian target of rapamycin (mTOR) 
      signaling pathways. rCST9 promoted the upregulation of macrophage proteins 
      involved in antiinflammation and antiapoptosis, while restraining 
      proinflammatory-associated proteins. Interestingly, the viability and virulence 
      of S4 also was decreased directly by rCST9. In a mouse model of Ft inhalation, 
      rCST9 significantly decreased organ bacterial burden and improved survival, which 
      was not accompanied by excessive cytokine secretion or subsequent immune cell 
      migration. The current report is the first to show the immunomodulatory and 
      antimicrobial functions of rCST9 against Ft. We hypothesize that the attenuation 
      of inflammation by rCST9 may be exploited for therapeutic purposes during 
      infection.
FAU - Eaves-Pyles, Tonyia
AU  - Eaves-Pyles T
AD  - Department of Microbiology and Immunology, University of Texas Medical Branch, 
      Galveston, Texas 77555, USA. tdeavesp@utmb.edu
FAU - Patel, Jignesh
AU  - Patel J
FAU - Arigi, Emma
AU  - Arigi E
FAU - Cong, Yingzi
AU  - Cong Y
FAU - Cao, Anthony
AU  - Cao A
FAU - Garg, Nisha
AU  - Garg N
FAU - Dhiman, Monisha
AU  - Dhiman M
FAU - Pyles, Richard B
AU  - Pyles RB
FAU - Arulanandam, Bernard
AU  - Arulanandam B
FAU - Miller, Aaron L
AU  - Miller AL
FAU - Popov, Vsevolod L
AU  - Popov VL
FAU - Soong, Lynn
AU  - Soong L
FAU - Carlsen, Eric D
AU  - Carlsen ED
FAU - Coletta, Ciro
AU  - Coletta C
FAU - Szabo, Csaba
AU  - Szabo C
FAU - Almeida, Igor C
AU  - Almeida IC
LA  - eng
GR  - G12M0007592/PHS HHS/United States
GR  - G12 RR008124/RR/NCRR NIH HHS/United States
GR  - 5G12RR008124-16A1/RR/NCRR NIH HHS/United States
GR  - R21-A106877402/PHS HHS/United States
GR  - 5G12RR008124-16A1S1/RR/NCRR NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
DEP - 20130828
PL  - England
TA  - Mol Med
JT  - Molecular medicine (Cambridge, Mass.)
JID - 9501023
RN  - 0 (Anti-Bacterial Agents)
RN  - 0 (CST9 protein, human)
RN  - 0 (Cystatins)
RN  - 0 (Immunologic Factors)
RN  - 0 (Recombinant Proteins)
SB  - IM
MH  - Animals
MH  - Anti-Bacterial Agents/*pharmacology/therapeutic use
MH  - Cell Movement/drug effects
MH  - Cystatins/genetics/*pharmacology/therapeutic use
MH  - Female
MH  - Francisella tularensis/*drug effects/pathogenicity
MH  - Humans
MH  - Immunologic Factors/*pharmacology/therapeutic use
MH  - Macrophages, Alveolar/drug effects/physiology
MH  - Mice
MH  - Mice, Inbred BALB C
MH  - Phagocytosis/drug effects
MH  - Recombinant Proteins/*pharmacology/therapeutic use
MH  - Tularemia/drug therapy/immunology/microbiology
MH  - Virulence/drug effects
PMC - PMC3769527
EDAT- 2013/08/08 06:00
MHDA- 2013/12/25 06:00
PMCR- 2013/08/02
CRDT- 2013/08/08 06:00
PHST- 2013/08/01 00:00 [received]
PHST- 2013/08/01 00:00 [accepted]
PHST- 2013/08/08 06:00 [entrez]
PHST- 2013/08/08 06:00 [pubmed]
PHST- 2013/12/25 06:00 [medline]
PHST- 2013/08/02 00:00 [pmc-release]
AID - molmed.2013.00081 [pii]
AID - 13_081_eaves-pyles [pii]
AID - 10.2119/molmed.2013.00081 [doi]
PST - epublish
SO  - Mol Med. 2013 Aug 28;19(1):263-75. doi: 10.2119/molmed.2013.00081.