PMID- 22291977
OWN - NLM
STAT- MEDLINE
DCOM- 20120604
LR  - 20211021
IS  - 1932-6203 (Electronic)
IS  - 1932-6203 (Linking)
VI  - 7
IP  - 1
DP  - 2012
TI  - Lethality in a murine model of pulmonary anthrax is reduced by combining nuclear 
      transport modifier with antimicrobial therapy.
PG  - e30527
LID - 10.1371/journal.pone.0030527 [doi]
LID - e30527
AB  - BACKGROUND: In the last ten years, bioterrorism has become a serious threat and 
      challenge to public health worldwide. Pulmonary anthrax caused by airborne 
      Bacillus anthracis spores is a life-threatening disease often refractory to 
      antimicrobial therapy. Inhaled spores germinate into vegetative forms that 
      elaborate an anti-phagocytic capsule along with potent exotoxins which disrupt 
      the signaling pathways governing the innate and adaptive immune responses and 
      cause endothelial cell dysfunction leading to vascular injury in the lung, 
      hypoxia, hemorrhage, and death. METHODS/PRINCIPAL FINDINGS: Using a murine model 
      of pulmonary anthrax disease, we showed that a nuclear transport modifier 
      restored markers of the innate immune response in spore-infected animals. An 
      8-day protocol of single-dose ciprofloxacin had no significant effect on 
      mortality (4% survival) of A/J mice lethally infected with B. anthracis Sterne. 
      Strikingly, mice were much more likely to survive infection (52% survival) when 
      treated with ciprofloxacin and a cell-penetrating peptide modifier of host 
      nuclear transport, termed cSN50. In B. anthracis-infected animals treated with 
      antibiotic alone, we detected a muted innate immune response manifested by 
      cytokines, tumor necrosis factor alpha (TNFalpha), interleukin (IL)-6, and chemokine 
      monocyte chemoattractant protein-1 (MCP-1), while the hypoxia biomarker, 
      erythropoietin (EPO), was greatly elevated. In contrast, cSN50-treated mice 
      receiving ciprofloxacin demonstrated a restored innate immune responsiveness and 
      reduced EPO level. Consistent with this improvement of innate immunity response 
      and suppression of hypoxia biomarker, surviving mice in the combination treatment 
      group displayed minimal histopathologic signs of vascular injury and a marked 
      reduction of anthrax bacilli in the lungs. CONCLUSIONS: We demonstrate, for the 
      first time, that regulating nuclear transport with a cell-penetrating modifier 
      provides a cytoprotective effect, which enables the host's immune system to 
      reduce its susceptibility to lethal B. anthracis infection. Thus, by combining a 
      nuclear transport modifier with antimicrobial therapy we offer a novel adjunctive 
      measure to control florid pulmonary anthrax disease.
FAU - Veach, Ruth Ann
AU  - Veach RA
AD  - Department of Microbiology and Immunology, Vanderbilt University School of 
      Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, United 
      States of America.
FAU - Zienkiewicz, Jozef
AU  - Zienkiewicz J
FAU - Collins, Robert D
AU  - Collins RD
FAU - Hawiger, Jacek
AU  - Hawiger J
LA  - eng
GR  - R01 HL069452/HL/NHLBI NIH HHS/United States
GR  - 2 R01 HL069542/HL/NHLBI NIH HHS/United States
PT  - Evaluation Study
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
DEP - 20120126
PL  - United States
TA  - PLoS One
JT  - PloS one
JID - 101285081
RN  - 0 (Anti-Infective Agents)
RN  - 0 (Cell-Penetrating Peptides)
RN  - 0 (Cytokines)
RN  - 0 (Drug Combinations)
RN  - 0 (Membrane Proteins)
RN  - 0 (Peptides, Cyclic)
RN  - 0 (cSN50 peptide)
RN  - 5E8K9I0O4U (Ciprofloxacin)
SB  - IM
MH  - Active Transport, Cell Nucleus/drug effects
MH  - Animals
MH  - Anthrax/complications/*drug therapy/*mortality/pathology
MH  - Anti-Infective Agents/*administration & dosage/pharmacology
MH  - Cell-Penetrating Peptides/administration & dosage/pharmacology
MH  - Ciprofloxacin/administration & dosage/pharmacology
MH  - Cytokines/blood/metabolism
MH  - Disease Models, Animal
MH  - Drug Combinations
MH  - Female
MH  - Lung Diseases/*drug therapy/etiology/*mortality/pathology
MH  - Membrane Proteins/administration & dosage/pharmacology
MH  - Mice
MH  - Peptides, Cyclic/administration & dosage/pharmacology
MH  - Survival Analysis
MH  - Treatment Outcome
PMC - PMC3266913
COIS- Competing Interests: The authors have declared that no competing interests exist.
EDAT- 2012/02/01 06:00
MHDA- 2012/06/05 06:00
PMCR- 2012/01/26
CRDT- 2012/02/01 06:00
PHST- 2011/07/08 00:00 [received]
PHST- 2011/12/22 00:00 [accepted]
PHST- 2012/02/01 06:00 [entrez]
PHST- 2012/02/01 06:00 [pubmed]
PHST- 2012/06/05 06:00 [medline]
PHST- 2012/01/26 00:00 [pmc-release]
AID - PONE-D-11-13071 [pii]
AID - 10.1371/journal.pone.0030527 [doi]
PST - ppublish
SO  - PLoS One. 2012;7(1):e30527. doi: 10.1371/journal.pone.0030527. Epub 2012 Jan 26.