Cytosolic flagellin-induced lysosomal pathway regulates inflammasome-dependent and -independent macrophage responses

Lage, Silvia Lucena; Buzzo, Carina L.; Amaral, Eduardo Pinheiro; Matteucci, Kely C.; Massis, Liliana M.; Icimoto, Marcelo Yudi; Carmona, Adriana K.; Lima, Maria Regina D’Império; Rodrigues, Maurício M.; Ferreira, Luís Carlos de Souza; Amarante-Mendes, Gustavo P.; Bortoluci, Karina Ramalho

doi:10.1073/pnas.1305316110

Cited by 50 publications

(60 citation statements)

References 68 publications

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“…4h,i). This is likely to be a non-specific consequence of overwhelming intracellular bacterial growth and/or a cathepsin-dependent cell death that occurs following the enhanced exposure of cytosolic flagellin43.…”

Section: Resultsmentioning

confidence: 99%

Growth inhibition of cytosolic Salmonella by caspase-1 and caspase-11 precedes host cell death

et al. 2016

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Sensing bacterial products in the cytosol of mammalian cells by NOD-like receptors leads to the activation of caspase-1 inflammasomes, and the production of the pro-inflammatory cytokines interleukin (IL)-18 and IL-1β. In addition, mouse caspase-11 (represented in humans by its orthologs, caspase-4 and caspase-5) detects cytosolic bacterial LPS directly. Activation of caspase-1 and caspase-11 initiates pyroptotic host cell death that releases potentially harmful bacteria from the nutrient-rich host cell cytosol into the extracellular environment. Here we use single cell analysis and time-lapse microscopy to identify a subpopulation of host cells, in which growth of cytosolic Salmonella Typhimurium is inhibited independently or prior to the onset of cell death. The enzymatic activities of caspase-1 and caspase-11 are required for growth inhibition in different cell types. Our results reveal that these proteases have important functions beyond the direct induction of pyroptosis and proinflammatory cytokine secretion in the control of growth and elimination of cytosolic bacteria.

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Section: Resultsmentioning

confidence: 99%

Growth inhibition of cytosolic Salmonella by caspase-1 and caspase-11 precedes host cell death

et al. 2016

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“…Cytosolic bacterial flagellin activates the NAIP5/NLRC4 inflammasome, promoting caspase-1 activation and IL-1b processing (Zhao et al, 2011). Interestingly, flagellin also promotes lysis of infected cells, through caspase-dependent and independent mechanisms (Miao et al, 2010;Lage et al, 2013). Similarly, the AIM2 inflammasome responds to intracellular DNA detection by instigating caspase-dependent IL-1b processing and pyroptosis (Rathinam et al, 2010;Wu et al, 2010) as does the NLRP1 inflammasome in response to anthrax lethal toxin (Masters et al, 2012).…”

Section: Discussionmentioning

confidence: 99%

Diverse Activators of the NLRP3 Inflammasome Promote IL-1β Secretion by Triggering Necrosis

et al. 2015

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The NLRP3 inflammasome is involved in caspase-1-dependent maturation of IL-1β in many contexts. A two-signal model has emerged for IL-1β maturation, with LPS providing "signal I" and diverse agents such as ATP, Nigericin, streptolysin O, uric acid crystals, and alum salts capable of acting as "signal II." In the absence of signal II, pro-IL-1β is upregulated but typically fails to be processed or released. What unites signal II stimuli has been debated, with the ability to promote K+ efflux suggested as a common factor, but the mechanism of IL-1β release remains unclear. Here, we show that all examined inflammasome signal II agents triggered necrosis, which was highly correlated with their ability to promote IL-1β release. IL-1β secretion occurred in tandem with the release of many additional proteins and was confined to necrotic cells. Thus, signal II agents initiate inflammation by promoting necrosis-driven IL-1β release, suggesting that IL-1β represents an inducible danger signal.

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“…SteC, on the other hand, promotes actin rearrangement by activating the MEK/ERK/myosin light-chain kinase (MLCK)/myosin IIB pathway and limits intracellular replication (14). This may be critical for the maintenance of the intracellular niche of S. Typhimurium, since increased bacterial numbers may significantly enhance the level of flagellin (FliC) translocated to the host cell cytoplasm (33), leading to cell death by inflammasome activation, as well as apoptosis induced by lysosomal membrane permeabilization (LMP). However, expression of flagellin by intracellular S. Typhi is inhibited by the regulatory protein TviA, resulting in negligible death of the infected macrophages (34).…”

Section: Discussionmentioning

confidence: 99%

An Inducible and Secreted Eukaryote-Like Serine/Threonine Kinase of Salmonella enterica Serovar Typhi Promotes Intracellular Survival and Pathogenesis

Theeya

Das

et al. 2015

Infect Immun

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e Eukaryote-like serine/threonine kinases (eSTKs) constitute an important family of bacterial virulence factors. Genome analysis had predicted putative eSTKs in Salmonella enterica serovar Typhi, although their functional characterization and the elucidation of their role in pathogenesis are still awaited. We show here that the primary sequence and secondary structure of the t4519 locus of Salmonella Typhi Ty2 have all the signatures of eukaryotic superfamily kinases. t4519 encodes a ϳ39-kDa protein (T4519), which shows serine/threonine kinase activities in vitro. Recombinant T4519 (rT4519) is autophosphorylated and phosphorylates the universal substrate myelin basic protein. Infection of macrophages results in decreased viability of the mutant (Ty2⌬t4519) strain, which is reversed by gene complementation. Moreover, reactive oxygen species produced by the macrophages signal to the bacteria to induce T4519, which is translocated to the host cell cytoplasm. That T4519 may target a host substrate(s) is further supported by the activation of host cellular signaling pathways and the induction of cytokines/chemokines. Finally, the role of T4519 in the pathogenesis of Salmonella Typhi is underscored by the significantly decreased mortality of mice infected with the Ty2⌬t4519 strain and the fact that the competitive index of this strain for causing systemic infection is 0.25% that of the wild-type strain. This study characterizes the first eSTK of Salmonella Typhi and demonstrates its role in promoting phagosomal survival of the bacteria within macrophages, which is a key determinant of pathogenesis. This, to the best of our knowledge, is the first study to describe the essential role of eSTKs in the in vivo pathogenesis of Salmonella spp.

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Cytosolic flagellin-induced lysosomal pathway regulates inflammasome-dependent and -independent macrophage responses

Cited by 50 publications

References 68 publications

Growth inhibition of cytosolic Salmonella by caspase-1 and caspase-11 precedes host cell death

Growth inhibition of cytosolic Salmonella by caspase-1 and caspase-11 precedes host cell death

Diverse Activators of the NLRP3 Inflammasome Promote IL-1β Secretion by Triggering Necrosis

An Inducible and Secreted Eukaryote-Like Serine/Threonine Kinase of Salmonella enterica Serovar Typhi Promotes Intracellular Survival and Pathogenesis

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