Neutrophils Are Resistant to Yersinia YopJ/P-Induced Apoptosis and Are Protected from ROS-Mediated Cell Death by the Type III Secretion System

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.

Neutrophil Extracellular Traps Exhibit Antibacterial Activity against Burkholderia pseudomallei and Are Influenced by Bacterial and Host Factors

“…Indeed, it is known that Salmonella uses a T3SS encoded by Salmonella pathogenicity island 2 (SPI-2) to inhibit NADPH oxidase assembly on the membrane of Salmonella-containing vacuoles, leading to reduced production of ROS and improved intracellular net replication (14,36). Moreover, the Yersinia pestis T3SS inhibits the respiratory burst of human PMNs and contributes to extracellular survival via the injection of Yop proteins, albeit intracellular survival of Y. pestis appears to be independent of T3SS-mediated inhibition of neutrophil ROS production (26,27). In contrast to these organisms, B. pseudomallei has been reported to rapidly escape from phagosomes, and further studies are needed to determine if the events described above apply during interactions with primary human PMNs.…”

Role of YopK in Yersinia pseudotuberculosis Resistance against Polymorphonuclear Leukocyte Defense

“…Generally, killing macrophages can be beneficial for pathogens, whereas bacterium-induced PMN death has an opposite effect, since this contributes to the resolution of bacterial infections (46). This seems plausible for infections with Yersinia, where the virulence effector YopJ mediates the induction of apoptosis in macrophages but not in PMNs (53). The control of PMN death has also been reported for other pathogens, such as Mycobacterium tuberculosis, where such a mechanism allows optimal growth, survival, and transmission of the bacteria (54).…”

Resistance to Yersinia pestis Infection Decreases with Age in B10.T(6R) Mice

“…We hypothesize that in our model, the key to bacterial clearance is the recruitment of neutrophils to sites of bacterial replication early in infection. Neutrophils are resistant to YopJ-induced apoptosis (38), and human PMNs are able to successfully phagocytize and kill Y. pestis (37). Ablation of Gr ϩ neutrophils increases the virulence of Y. pestis in a lung infection model (24).…”