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Orchestration of Human Macrophage NLRP3 Inflammasome Activation by Staphylococcus Aureus Extracellular Vesicles

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Orchestration of Human Macrophage NLRP3 Inflammasome Activation by Staphylococcus Aureus Extracellular Vesicles Orchestration of human macrophage NLRP3 inflammasome activation by Staphylococcus aureus extracellular vesicles Xiaogang Wanga, William J. Eagena, and Jean C. Leea,1 aDivision of Infectious Diseases, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA 02115 Edited by Richard P. Novick, New York University School of Medicine, New York, NY, and approved January 2, 2020 (received for review September 11, 2019) Release of extracellular vesicles (EVs) is a common feature among presents a barrier for EV release (8). However, specific eukaryotes, archaea, and bacteria. However, the biogenesis and mechanisms involved in EV biogenesis and the complex downstream biological effects of EVs released from gram-positive downstream effects of EV release on host cells remain poorly bacteria remain poorly characterized. Here, we report that EVs characterized. purified from a community-associated methicillin-resistant Staph- S. aureus EVs package a diverse array of bacterial compo- ylococcus aureus strain were internalized into human macro- nents, including cytosolic, surface, and membrane proteins, as phages in vitro and that this process was blocked by inhibition well as adhesins, lipoproteins, and secreted PFTs (8, 10–12), and of the dynamin-dependent endocytic pathway. Human macro- many of these components have been shown to play significant phages responded to S. aureus EVs by TLR2 signaling and activa- roles in bacterial virulence (13–16). S. aureus EVs were detected + tion of NLRP3 inflammasomes through K efflux, leading to the in vivo during experimental pneumonia (10), and EVs purified recruitment of ASC and activation of caspase-1. Cleavage of pro– from S. aureus strains have been shown to contain biologically interleukin (IL)-1β, pro-IL-18, and gasdermin-D by activated active toxins, exhibit cytotoxicity, and elicit proinflammatory caspase-1 resulted in the cellular release of the mature cytokines mediators (8, 10, 11, 17, 18). Thus, EVs may play a previously IL-1β and IL-18 and induction of pyroptosis. Consistent with this unrecognized role in staphylococcal pathogenesis although the result, a dose-dependent cytokine response was detected in the mechanisms whereby this occurs are unknown. extracellular fluids of mice challenged intraperitoneally with S. NLRP3 inflammasomes, multimeric cytosolic protein com- aureus EVs. Pore-forming toxins associated with S. aureus EVs plexes formed in myeloid cells in response to various pathogenic were critical for NLRP3-dependent caspase-1 activation of human or physiological stimuli, require two distinct steps for activation macrophages, but not for TLR2 signaling. In contrast, EV-associated (19). A bacterial stimulus such as lipoprotein or lipopolysac- lipoproteins not only mediated TLR2 signaling to initiate the priming charide (LPS) triggers a priming step through TLR2- or TLR4- step of NLRP3 activation but also modulated EV biogenesis and the mediated nuclear factor κB (NF-κB) signaling, resulting in the toxin content of EVs, resulting in alterations in IL-1β,IL-18,and production of pro–interleukin (IL)-1β and pro-IL-18 and tran- caspase-1 activity. Collectively, our study describes mechanisms by scription and posttranslational modification of NLRP3. A second which S. aureus EVs induce inflammasome activation and reveals an stimulus, such as bacterial toxins or adenosine 5′-triphosphate + unexpected role of staphylococcal lipoproteins in EV biogenesis. EVs (ATP), activates the inflammasome through K efflux, leading may serve as a novel secretory pathway for S. aureus to transport protected cargo in a concentrated form to host cells during infec- Significance tions to modulate cellular functions. The relevance and biological activities of extracellular vesicles Staphylococcus aureus | extracellular vesicles | inflammasomes | (EVs) from gram-positive bacteria are poorly understood. We lipoproteins | pore-forming toxins report that EVs released by Staphylococcus aureus are in- ternalized by human macrophages by an endocytic process, taphylococcus aureus is a primary cause of invasive human highlighting the role of EVs as a delivery system for bacterial Sinfections, such as bacteremia, endocarditis, pneumonia, and virulence determinants. Macrophages incubated with S. aureus surgical wound infections, leading to morbidity, mortality, and EVs undergo NLRP3 inflammasome activation that is dependent excessive healthcare costs (1). Many S. aureus isolates have de- on EV cargo, including pore-forming toxins and lipoproteins. We veloped resistance to commonly used antibiotics (2). To establish provide evidence that S. aureus lipoproteins modulate EV con- a successful infection and survive in a hostile host environment, tent and biogenesis, revealing a previously unrecognized role S. aureus employs a wide array of virulence determinants, in- for lipoproteins. This study advances our understanding of the cluding surface proteins and glycopolymers, as well as secreted biological activities of EVs from gram-positive bacteria and proteins, such as pore-forming toxins (PFTs), superantigens, and demonstrates their role as a vehicle for the delivery of microbial proteases. Such factors are either associated with the cell surface effector molecules into host cells. to facilitate colonization or secreted to the environment to Author contributions: X.W. and J.C.L. designed research; X.W. and W.J.E. performed re- damage host cells and evade innate and adaptive host immune search; X.W. and J.C.L. analyzed data; and X.W. and J.C.L. wrote the paper. mechanisms (3–5). The authors declare no competing interest. Extracellular vesicles (EVs) are nano-sized, spherical particles This article is a PNAS Direct Submission. that are enclosed by a bilayered membrane. Most cells secrete vesicles, including eukaryotes, archaea, and bacteria (6). Gen- Published under the PNAS license. Data deposition: Mass spectrometry proteomics data have been deposited in the Proteo- eration of EVs from gram-positive bacteria is a complex and meXchange Consortium, http://proteomecentral.proteomexchange.org/cgi/GetDataset poorly understood process since EVs released from the cyto- via the PRIDE partner repository (dataset identifier PXD014888). plasmic membrane must traverse a thick peptidoglycan cell wall 1To whom correspondence may be addressed. Email: [email protected]. – to reach the external environment (7 9). We demonstrated that This article contains supporting information online at https://www.pnas.org/lookup/suppl/ S. aureus alpha-type phenol-soluble modulins and autolysins pro- doi:10.1073/pnas.1915829117/-/DCSupplemental. mote EV production whereas highly cross-linked peptidoglycan First published January 27, 2020. 3174–3184 | PNAS | February 11, 2020 | vol. 117 | no. 6 www.pnas.org/cgi/doi/10.1073/pnas.1915829117 Downloaded by guest on October 2, 2021 to the recruitment of ASC and activation of caspase-1, resulting quenched at high concentrations in the cell membrane and in cleavage of pro–IL-1β and pro–IL-18. NLRP3 activation is “dequenched” when the probe is diluted by membrane fusion. characterized by cellular release of the mature cytokines IL-1β Thus, R18 fluorescence reflects an increase in EV internalization and IL-18 and induction of an inflammatory cell death termed or membrane fusion. The uptake of 5 μg/mL R18-labeled EVs by pyroptosis, a host defense mechanism allowing removal of human monocyte-derived MΦs after different incubation time damaged or infected host cells (20, 21). points was assessed by confocal microscopy. Fluorescence of Inflammasome activation plays an essential role in protection R18-labeled EVs, but not the sham control, was detected within against S. aureus infections (22, 23), particularly in mounting an MΦs after 45 min (SI Appendix, Fig. S1B), and longer incubation effective innate immune response, which may determine the of cells with EVs led to a greater distribution of fluorescent EVs outcome of infection by controlling the bacterial burden and within cells. The sham-treated control showed minimal fluores- shaping the nature and magnitude of the adaptive immune cence after 90 min (SI Appendix, Fig. S1B). Consistent with the response (24). Unregulated inflammasome activation, however, results obtained from the DiO-labeling experiment, pre- may result in an exaggerated innate immune response that treatment of THP-1 cells or monocyte-derived human MΦs with leads to host tissue damage (25). S. aureus culture supernatants, dynasore, but not the other inhibitors, prevented cellular entry of containing both secreted PFTs and lipoproteins, activate EVs (SI Appendix, Fig. S1 C). Quantification of cellular fluores- inflammasomes in vitro by providing both the priming and cence confirmed a significant (>fivefold) reduction in the R18- secondary stimulus (26, 27), but culture supernatants are not EV signal in MΦs treated with dynasore (SI Appendix, Fig. S1D). representative of the in vivo environment. Of note, S. aureus Subsequently, THP-1 MΦs were pretreated with endocytosis cells, purified PFTs, or lipoproteins alone are not sufficient to inhibitors or DMSO before incubation with R18-labeled EVs, activate the NLRP3 inflammasome (27). We postulate that and fluorescence was measured over time. THP-1 cells fluo- EVs serve as a unique S. aureus secretion system that transports resced within 40 min after the addition of R18-labeled EVs (SI its protected cargo, including lipoproteins and PFTs, to host Appendix, Fig. S1E). Pretreatment of THP-1 cells with dynasore,
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