title: Lethality in a murine model of pulmonary anthrax is reduced by combining nuclear transport modifier with antimicrobial therapy.
abstract: 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.
  
  
  RESULTS
  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 (TNFα), 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.
authors.affiliation: Department of Microbiology and Immunology, Vanderbilt University School of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, United States of America.
authors.forename: Ruth Ann
authors.initials: RA
authors.lastname: Veach
authors.forename: Jozef
authors.initials: J
authors.lastname: Zienkiewicz
authors.forename: Robert D
authors.initials: RD
authors.lastname: Collins
authors.forename: Jacek
authors.initials: J
authors.lastname: Hawiger
mesh_terms: D021581:Active Transport, Cell Nucleus / Q000187:drug effects; D000818:Animals; D000881:Anthrax / Q000150:complications / Q000188:drug therapy* / Q000401:mortality* / Q000473:pathology; D000890:Anti-Infective Agents / Q000008:administration & dosage* / Q000494:pharmacology; D057846:Cell-Penetrating Peptides / Q000008:administration & dosage / Q000494:pharmacology; D002939:Ciprofloxacin / Q000008:administration & dosage / Q000494:pharmacology; D016207:Cytokines / Q000097:blood / Q000378:metabolism; D004195:Disease Models, Animal; D004338:Drug Combinations; D005260:Female; D008171:Lung Diseases / Q000188:drug therapy* / Q000209:etiology / Q000401:mortality* / Q000473:pathology; D008565:Membrane Proteins / Q000008:administration & dosage / Q000494:pharmacology; D051379:Mice; D010456:Peptides, Cyclic / Q000008:administration & dosage / Q000494:pharmacology; D016019:Survival Analysis; D016896:Treatment Outcome
chemical_list: D000890:Anti-Infective Agents; D057846:Cell-Penetrating Peptides; D016207:Cytokines; D004338:Drug Combinations; D008565:Membrane Proteins; D010456:Peptides, Cyclic; C569011:cSN50 peptide; D002939:Ciprofloxacin