title: Circumventing Y. pestis Virulence by Early Recruitment of Neutrophils to the Lungs during Pneumonic Plague.
abstract: Pneumonic plague is a fatal disease caused by Yersinia pestis that is associated with a delayed immune response in the lungs. Because neutrophils are the first immune cells recruited to sites of infection, we investigated the mechanisms responsible for their delayed homing to the lung. During the first 24 hr after pulmonary infection with a fully virulent Y. pestis strain, no significant changes were observed in the lungs in the levels of neutrophils infiltrate, expression of adhesion molecules, or the expression of the major neutrophil chemoattractants keratinocyte cell-derived chemokine (KC), macrophage inflammatory protein 2 (MIP-2) and granulocyte colony stimulating factor (G-CSF). In contrast, early induction of chemokines, rapid neutrophil infiltration and a reduced bacterial burden were observed in the lungs of mice infected with an avirulent Y. pestis strain. In vitro infection of lung-derived cell-lines with a YopJ mutant revealed the involvement of YopJ in the inhibition of chemoattractants expression. However, the recruitment of neutrophils to the lungs of mice infected with the mutant was still delayed and associated with rapid bacterial propagation and mortality. Interestingly, whereas KC, MIP-2 and G-CSF mRNA levels in the lungs were up-regulated early after infection with the mutant, their protein levels remained constant, suggesting that Y. pestis may employ additional mechanisms to suppress early chemoattractants induction in the lung. It therefore seems that prevention of the early influx of neutrophils to the lungs is of major importance for Y. pestis virulence. Indeed, pulmonary instillation of KC and MIP-2 to G-CSF-treated mice infected with Y. pestis led to rapid homing of neutrophils to the lung followed by a reduction in bacterial counts at 24 hr post-infection and improved survival rates. These observations shed new light on the virulence mechanisms of Y. pestis during pneumonic plague, and have implications for the development of novel therapies against this pathogen.
authors.affiliation: Department of Biochemistry and Molecular Genetics, Israel Institute for Biological Research, Ness Ziona, Israel.
authors.forename: Yaron
authors.initials: Y
authors.lastname: Vagima
authors.affiliation: Department of Biochemistry and Molecular Genetics, Israel Institute for Biological Research, Ness Ziona, Israel.
authors.forename: Ayelet
authors.initials: A
authors.lastname: Zauberman
authors.affiliation: Department of Biochemistry and Molecular Genetics, Israel Institute for Biological Research, Ness Ziona, Israel.
authors.forename: Yinon
authors.initials: Y
authors.lastname: Levy
authors.affiliation: Department of Biochemistry and Molecular Genetics, Israel Institute for Biological Research, Ness Ziona, Israel.
authors.forename: David
authors.initials: D
authors.lastname: Gur
authors.affiliation: Department of Biochemistry and Molecular Genetics, Israel Institute for Biological Research, Ness Ziona, Israel.
authors.forename: Avital
authors.initials: A
authors.lastname: Tidhar
authors.affiliation: Department of Biochemistry and Molecular Genetics, Israel Institute for Biological Research, Ness Ziona, Israel.
authors.forename: Moshe
authors.initials: M
authors.lastname: Aftalion
authors.affiliation: Department of Biochemistry and Molecular Genetics, Israel Institute for Biological Research, Ness Ziona, Israel.
authors.forename: Avigdor
authors.initials: A
authors.lastname: Shafferman
authors.affiliation: Department of Biochemistry and Molecular Genetics, Israel Institute for Biological Research, Ness Ziona, Israel.
authors.forename: Emanuelle
authors.initials: E
authors.lastname: Mamroud
mesh_terms: D000818:Animals; D001426:Bacterial Proteins / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D018925:Chemokines / Q000235:genetics / Q000378:metabolism; D005260:Female; D017353:Gene Deletion; D054884:Host-Pathogen Interactions; D018928:Immunity, Mucosal; D008168:Lung / Q000276:immunology* / Q000378:metabolism / Q000382:microbiology; D008262:Macrophage Activation; D016676:Macrophages, Alveolar / Q000276:immunology / Q000378:metabolism / Q000382:microbiology; D008810:Mice, Inbred C57BL; D050296:Microbial Viability; D009154:Mutation; D020556:Neutrophil Infiltration; D009504:Neutrophils / Q000276:immunology* / Q000378:metabolism / Q000382:microbiology; D010587:Phagocytosis; D010930:Plague / Q000276:immunology* / Q000378:metabolism / Q000382:microbiology; D020545:Respiratory Mucosa / Q000276:immunology* / Q000378:metabolism / Q000382:microbiology; D016019:Survival Analysis; D014774:Virulence; D015010:Yersinia pestis / Q000254:growth & development / Q000276:immunology* / Q000378:metabolism / Q000472:pathogenicity
chemical_list: D001426:Bacterial Proteins; D018925:Chemokines; C109227:YopP protein, Yersinia