Yersinia pseudotuberculosis Blocks Neutrophil Degranulation

Abstract

bNeutrophils are essential components of immunity and are rapidly recruited to infected or injured tissue. Upon their activation, neutrophils release granules to the cell's exterior, through a process called degranulation. These granules contain proteins with antimicrobial properties that help combat infection. The enteropathogenic bacterium Yersinia pseudotuberculosis successfully persists as an extracellular bacterium during infection by virtue of its translocation of virulence effectors (Yersinia outer proteins [Yops]) that act in the cytosol of host immune cells to subvert phagocytosis and proinflammatory responses. Here, we investigated the effect of Y. pseudotuberculosis on neutrophil degranulation upon cell contact. We found that virulent Y. pseudotuberculosis was able to prevent secondary granule release. The blocking effect was general, as the release of primary and tertiary granules was also reduced. Degranulation of secondary granules was also blocked in primed neutrophils, suggesting that this mechanism could be an important element of immune evasion. Further, wild-type bacteria conferred a transient block on neutrophils that prevented their degranulation upon contact with plasmid-cured, avirulent Y. pseudotuberculosis and Escherichia coli. Detailed analyses showed that the block was strictly dependent on the cooperative actions of the two antiphagocytic effectors, YopE and YopH, suggesting that the neutrophil target structures constituting signaling molecules needed to initiate both phagocytosis and general degranulation. Thus, via these virulence effectors, Yersinia can impair several mechanisms of the neutrophil's antimicrobial arsenal, which underscores the power of its virulence effector machinery. N eutrophils are an important element of the innate immune response. Circulating neutrophils are recruited into tissues upon injury or infection in order to play key roles in the defense against bacterial or fungal pathogens. Several mechanisms are used to eliminate microbial invaders such as phagocytosis, neutrophil extracellular trap (NET) formation, and degranulation. Degranulation is triggered upon the activation of neutrophils by microbial or inflammatory stimuli and leads to the release of granule contents. Neutrophils contain four types of granules and are categorized as peroxidase-positive (azurophilic or primary) granules, peroxidase-negative (specific or secondary, and gelatinase or tertiary) granules, and secretory vesicles (1, 2). Secretory vesicles and tertiary granules are released during adhesion and transmigration through the endothelium, respectively, whereas the primary and secondary granules hold the majority of the cell's antimicrobial activity and are released at the infectious site (1-3). Primary granules contain high quantities of myeloperoxidase (MPO), as well as defensins, elastase, heparin binding proteins, and proteinases. Secondary granules are rich in lactoferrin and enzymes such as collagenase and gelatinase, as well as the LL-37 precursor hCAP-18. However, these granules...

Redundant and Cooperative Roles for Yersinia pestis Yop Effectors in the Inhibition of Human Neutrophil Exocytic Responses Revealed by Gain-of-Function Approach

“…Recently it was shown that Yersinia pseudotuberculosis inhibits neutrophil degranulation in a T3SS-dependent manner, which was dependent on the actions of YopE and YopH (73). Here, we show T3SS-dependent inhibition of neutrophil degranulation by Y. pestis, as well as roles of both YopE and YopH in inhibition.…”

Human Neutrophil Granule Exocytosis in Response to Mycobacterium smegmatis

“…To the best of our knowledge, the immediate pattern of exocytosis of human neutrophil granules is unique to M. smegmatis. While other bacteria have been shown to block or induce degranulation of some or all neutrophil granule subtypes [32,[49][50][51][52][53][54][55][56][57][58][59], release of only gelatinase granules at early time points has not been seen with bacteria other than M. smegmatis. An important distinction is that M. smegmatis is not preventing granule release to other stimuli, since granule mobilization was not affected upon fMLF stimulation by human neutrophils cultured with M. smegmatis.…”

Neutrophil Function Impairment Is a Host Susceptibility Factor to Bacterial Infection in Diabetes

“…After neutrophil migration, degranulation occurs, which is the process mediated by microbial or inflammatory stimuli in which neutrophils release the granule contents, such as MPO, defensins, cathepsin G, neutrophil elastase, and collagenase. These granule contents are released by exocytosis or into the phagosome to kill microorganisms [24].…”