Abstract
BackgroundThe human innate immune system relies on the coordinated activity of macrophages and polymorphonuclear leukocytes (neutrophils or PMNs) for defense against bacterial pathogens. Yersinia spp. subvert the innate immune response to cause disease in humans. In particular, the Yersinia outer protein YopJ (Y. pestis and Y. pseudotuberculosis) and YopP (Y. enterocolitica) rapidly induce apoptosis in murine macrophages and dendritic cells. However, the effects of Yersinia Yop J/P on neutrophil fate are not clearly defined.Methodology/Principal FindingsIn this study, we utilized wild-type and mutant strains of Yersinia to test the contribution of YopJ and YopP on induction of apoptosis in human monocyte-derived macrophages (HMDM) and neutrophils. Whereas YopJ and YopP similarly induced apoptosis in HMDMs, interaction of human neutrophils with virulence plasmid-containing Yersinia did not result in PMN caspase activation, release of LDH, or loss of membrane integrity greater than PMN controls. In contrast, interaction of human PMNs with the virulence plasmid-deficient Y. pestis strain KIM6 resulted in increased surface exposure of phosphatidylserine (PS) and cell death. PMN reactive oxygen species (ROS) production was inhibited in a virulence plasmid-dependent but YopJ/YopP-independent manner. Following phagocytic interaction with Y. pestis strain KIM6, inhibition of PMN ROS production with diphenyleneiodonium chloride resulted in a reduction of PMN cell death similar to that induced by the virulence plasmid-containing strain Y. pestis KIM5.ConclusionsOur findings showed that Yersinia YopJ and/or YopP did not induce pronounced apoptosis in human neutrophils. Furthermore, robust PMN ROS production in response to virulence plasmid-deficient Yersinia was associated with increased PMN cell death, suggesting that Yersinia inhibition of PMN ROS production plays a role in evasion of the human innate immune response in part by limiting PMN apoptosis.
Highlights
The cellular arm of the human innate immune system includes the myeloid progenitor-derived mononuclear and polymorphonuclear phagocytes, which recognize and eliminate a diverse array of bacterial pathogens
Our findings showed that Yersinia YopJ and/or YopP did not induce pronounced apoptosis in human neutrophils
Robust PMN reactive oxygen species (ROS) production in response to virulence plasmid-deficient Yersinia was associated with increased PMN cell death, suggesting that Yersinia inhibition of PMN ROS production plays a role in evasion of the human innate immune response in part by limiting PMN apoptosis
Summary
The cellular arm of the human innate immune system includes the myeloid progenitor-derived mononuclear and polymorphonuclear phagocytes, which recognize and eliminate a diverse array of bacterial pathogens. PMNs destroy pathogens by releasing highly microbicidal NADPH oxidase-derived reactive oxygen species (ROS) and a broad array of potent antimicrobial components into the pathogen-containing vacuoles [2]. The innate immune system is highly efficient and essential for human health and subversion of the innate immune system is linked to increased bacterial pathogenicity [9]. The human innate immune system relies on the coordinated activity of macrophages and polymorphonuclear leukocytes (neutrophils or PMNs) for defense against bacterial pathogens. The Yersinia outer protein YopJ (Y. pestis and Y. pseudotuberculosis) and YopP (Y. enterocolitica) rapidly induce apoptosis in murine macrophages and dendritic cells. The effects of Yersinia Yop J/P on neutrophil fate are not clearly defined
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