AUTHOR=Kroes Michiel M. , Mariman Rob , Hijdra Daniëlle , Hamstra Hendrik-Jan , van Boxtel Karlijn J. W. M. , van Putten Jos P. M. , de Wit Jelle , Pinelli Elena 

TITLE=Activation of Human NK Cells by Bordetella pertussis Requires Inflammasome Activation in Macrophages

JOURNAL=Frontiers in Immunology

VOLUME=10

YEAR=2019

URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2019.02030

DOI=10.3389/fimmu.2019.02030

ISSN=1664-3224

ABSTRACT=<p>Pertussis is a highly contagious respiratory infection caused by the bacterium <italic>Bordetella pertussis</italic>. Humans are the only known natural reservoir of <italic>B. pertussis</italic>. In mice, macrophages and NK cells have a key role in confining <italic>B. pertussis</italic> to the respiratory tract. However, the mechanisms underlying this process, particularly during human infections, remain unclear. Here we characterized the activation of human macrophages and NK cells in response to <italic>B. pertussis</italic> and unraveled the role of inflammasomes in this process. NLRP3 inflammasome activation by <italic>B. pertussis</italic> in human macrophage-like THP-1 cells and primary monocyte-derived macrophages (mo-MΦ) was shown by the visualization of ASC-speck formation, pyroptosis, and the secretion of caspase-mediated IL-1β and IL-18. In contrast to macrophages, stimulation of human CD56<sup>+</sup>CD3<sup>−</sup> NK cells by <italic>B. pertussis</italic> alone did not result in activation of these cells. However, co-culture of <italic>B. pertussis</italic>-stimulated mo-MΦ and autologous NK cells resulted in high amounts of IFNγ secretion and an increased frequency of IL-2Rα<sup>+</sup> and HLA-DR<sup>+</sup> NK cells, indicating NK cell activation. This activation was significantly reduced upon inhibition of inflammasome activity or blocking of IL-18 in the mo-MΦ/NK cell co-culture. Furthermore, we observed increased secretion of proinflammatory cytokines in the <italic>B. pertussis</italic>-stimulated mo-MΦ/NK co-culture compared to the mo-MΦ single culture. Our results demonstrate that <italic>B. pertussis</italic> induces inflammasome activation in human macrophages and that the IL-18 produced by these cells is required for the activation of human NK cells, which in turn enhances the pro-inflammatory response to this pathogen. Our data provides a better understanding of the underlying mechanisms involved in the induction of innate immune responses against <italic>B. pertussis</italic>. These findings contribute to the knowledge required for the development of improved intervention strategies to control this highly contagious disease.</p>