Pneumolysin-Dependent Calpain Activation and Interleukin-1α Secretion in Macrophages Infected with Streptococcus pneumoniae

Fang, Rendong; Wu, Rui; Du, Huihui; Jin, Meilan; Liu, Yajing; Lei, Guihua; Bo, Jiang; Lei, Zehui; Peng, Yuanyi; Nie, Kun; Tsuchiya, Kazuo

doi:10.1128/iai.00201-17

Cited by 12 publications

(9 citation statements)

References 35 publications

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“…Previous in vitro studies showed that pneumolysin promotes release of both IL-1α and IL-1β by S . pneumoniae infected macrophages [ 19 , 38 ]. Daily i.n.…”

Section: Resultsmentioning

confidence: 99%

“…Recently, pore-forming toxins including Ply were found to trigger necroptosis, the major cell death pathway in respiratory epithelial cells, in mice and non-human primates during bacterial lung infection [ 50 ]. In in vitro macrophage models, Ply pore-formation also causes a passive release of alarmin IL-1α following rapid cell death [ 38 , 52 ]. Our RNA-seq analyses show more functional clustering of cell death pathways, including necroptosis and apoptosis, following pneumococcal colonization.…”

Section: Discussionmentioning

confidence: 99%

“…Our RNA-seq analyses show more functional clustering of cell death pathways, including necroptosis and apoptosis, following pneumococcal colonization. The IL-1α precursor protein, which is constitutively expressed in many cell types at the mucosal barrier, including both epithelial and myeloid lineages [ 38 – 40 , 52 , 53 ], does not require cleavage for binding to the IL-1 receptor [ 39 , 54 ], thus Ply-mediated passive release of IL-1α precursor could directly activate IL-1 signaling. In contrast, IL-1β precursor expression is induced in response to TLR stimulation, TNFα, and IL-1 itself, and requires active processing in order to bind the IL-1 receptor [ 37 ].…”

Section: Discussionmentioning

confidence: 99%

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Age-related differences in IL-1 signaling and capsule serotype affect persistence of Streptococcus pneumoniae colonization

et al. 2018

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Young age is a risk factor for prolonged colonization by common pathogens residing in their upper respiratory tract (URT). Why children present with more persistent colonization is unknown and there is relatively little insight into the host-pathogen interactions that contribute to persistent colonization. To identify factors permissive for persistent colonization during infancy, we utilized an infant mouse model of Streptococcus pneumoniae colonization in which clearance from the mucosal surface of the URT requires many weeks to months. Loss of a single bacterial factor, the pore-forming toxin pneumolysin (Ply), and loss of a single host factor, IL-1α, led to more persistent colonization. Exogenous administration of Ply promoted IL-1 responses and clearance, and intranasal treatment with IL-1α was sufficient to reduce colonization density. Major factors known to affect the duration of natural colonization include host age and pneumococcal capsular serotype. qRT-PCR analysis of the uninfected URT mucosa showed reduced baseline expression of genes involved in IL-1 signaling in infant compared to adult mice. In line with this observation, IL-1 signaling was important in initiating clearance in adult mice but had no effect on early colonization of infant mice. In contrast to the effect of age, isogenic constructs of different capsular serotype showed differences in colonization persistence but induced similar IL-1 responses. Altogether, this work underscores the importance of toxin-induced IL-1α responses in determining the outcome of colonization, clearance versus persistence. Our findings about IL-1 signaling as a function of host age may provide an explanation for the increased susceptibility and more prolonged colonization during early childhood.

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“…Previous in vitro studies showed that pneumolysin promotes release of both IL-1α and IL-1β by S . pneumoniae infected macrophages [ 19 , 38 ]. Daily i.n.…”

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Age-related differences in IL-1 signaling and capsule serotype affect persistence of Streptococcus pneumoniae colonization

et al. 2018

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“…Very recently, an alternative mechanism of PLY-mediated maturation of pro-IL-1α and secretion of the active cytokine has been described in isolated murine peritoneal macrophages following ingestion of a PLY-expressing D39 strain of the pneumococcus, but not by a corresponding ply gene knockout strain of the pathogen [70]. This mechanism was dependent on internalisation of the pneumococcus by macrophages, influx of extracellular Ca 2+ due to PLY-mediated formation of Ca 2+permeable membrane pores, and intracellular activation of the Ca 2+ -dependent cysteine proteinase, calpain, which, in turn, mediated cleavage of pro-IL-1α to the active form of the cytokine [70]. Although the existence of this mechanism of conversion of pro-IL-1β to IL-1α has not yet been described in human platelets, it is noteworthy that these cells, like macrophages, also possess calpain [71].…”

Section: Activation Of the Nlrp3 Inflammasome As A Potential Mechanismentioning

confidence: 99%

Review manuscript: Mechanisms of platelet activation by the pneumococcus and the role of platelets in community-acquired pneumonia

Feldman

2017

Journal of Infection

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There is increasing recognition of the involvement of platelets in orchestrating inflammatory responses, driving the activation of neutrophils, monocytes and vascular endothelium, which, if poorly controlled, may lead to microvascular dysfunction. Importantly, hyperreactivity of platelets has been implicated in the pathogenesis of myocardial injury and the associated particularly high prevalence of acute cardiovascular events in patients with severe community-acquired pneumonia (CAP), of which Streptococcus pneumoniae (pneumococcus) is the most commonly encountered aetiologic agent. In this context, it is noteworthy that a number of studies have documented various mechanisms by which the pneumococcus may directly promote platelet aggregation and activation. The major contributors to platelet activation include several different types of pneumococcal adhesin, the pore-forming toxin, pneumolysin, and possibly pathogen-derived hydrogen peroxide, which collectively represent a major focus of the current review. This is followed by an overview of the limited experimental studies together with a larger series of clinical studies mainly focused on all-cause CAP, which have provided evidence in support of associations between alterations in circulating platelet counts, most commonly thrombocytopenia, and a poor clinical outcome. The final section of the review covers, albeit briefly, systemic biomarkers of platelet activation which may have prognostic potential.

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“…Formation of sufficient numbers of these multimeric and mostly non-selective nanopores on the plasma membrane eventually leads to the disruption of vital signalling processes, cripples the selective permeability of the plasma membrane by causing unregulated transport of ions and small molecules, and causes cell death (Peraro & van der Goot, 2016; M. W. Parker & Feil, 2005), systemic inflammation (Los et al, 2013; Fang et al, 2017) and propagation of infection (Czuczman et al, 2014; Zafar et al, 2017). PFTs are mainly classified on a structural basis as α -PFTs or β -PFTs based on whether amphipathic α -helices or β -hairpins form the dominant secondary structure of the pore trans-membrane domain (M.…”

Section: Introductionmentioning

confidence: 99%

AnIn silicoAlgorithm for Identifying Amino Acids that Stabilize Oligomeric Membrane-Toxin Pores through Electrostatic Interactions

Desikan

Maiti

Ayappa

2019

Preprint

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Pore forming toxins (PFTs) are a class of proteins which have specifically evolved to form unregulated pores in target plasma membranes, and represent the single largest class of bacterial virulence factors. With increasingly prevalent antibiotic-resistant bacterial strains, next generation therapies are being developed to target bacterial PFTs rather than the pathogens themselves. However, structure-based design of inhibitors that could block pore formation are hampered by a paucity of structural information about pore intermediates. On similar lines, observations of the inter-subunit interfaces in fully-formed pore complexes to identify druggable residues, whose interactions could potentially be blocked to hamper pore formation or destabilize pore assemblies, are often limited because of the presence of a large number of protein-protein interaction sites across pore inter-subunit interfaces. Narrowing down the list of plausible target residues requires a quantitative assessment of their contributions towards pore stability, which cannot be gleaned from a single, static, crystal or cryo-EM pore structure.We overcome this limitation by developing an in silico screening algorithm that employs fully atomistic molecular dynamics simulations coupled with knowledge-based screening to identify residues engaged in persistent and stabilizing electrostatic interactions across inter-subunit interfaces in membrane-inserted PFT pores. Application of this algorithm to prototypical α-PFT (cytolysin A) and β-PFT (α-hemolysin) pores yielded a small predicted subset of highly interacting residues, blocking of which could destabilize pore complexes as shown in previous mutagenesis experiments for some of these predicted residues. The algorithm also yielded a novel set of residues in both cytolysin A and α-hemolysin pores for which no mutagenesis and stability data exists to the best of our knowledge, and therefore could serve as hitherto un-CONTACT Rajat Desikan, recognised potential targets for PFT inhibitors. The algorithm worked equally well for both α and β-PFT pores, and could thus be potentially applicable to all pores with known structures to generate a database of pore-destabilizing mutations, which could then serve as a starting point for experimental validation and structure-based PFT-inhibitor design. ABBREVIATIONSAHL α-hemolysin ClyA Cytolysin A DMPC 1,2-dimyristoyl-sn-glycero-3-phosphocholine PDB Protein data bank PFT(s) Pore-forming toxin(s) MD Molecular dynamics RSA Relative solvent accessibility RMSD Root mean square deviation SASA solvent accessible surface area

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Pneumolysin-Dependent Calpain Activation and Interleukin-1α Secretion in Macrophages Infected with Streptococcus pneumoniae

Cited by 12 publications

References 35 publications

Age-related differences in IL-1 signaling and capsule serotype affect persistence of Streptococcus pneumoniae colonization

Age-related differences in IL-1 signaling and capsule serotype affect persistence of Streptococcus pneumoniae colonization

Review manuscript: Mechanisms of platelet activation by the pneumococcus and the role of platelets in community-acquired pneumonia

AnIn silicoAlgorithm for Identifying Amino Acids that Stabilize Oligomeric Membrane-Toxin Pores through Electrostatic Interactions

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