Macrophage Activation Redirects Yersinia-Infected Host Cell Death from Apoptosis to Caspase-1-Dependent Pyroptosis

AbstractHijacking of host metabolic status by a pathogen for its regulated dissemination from the host is prerequisite for the propagation of infection. M. tuberculosis secretes an NAD+-glycohydrolase, TNT, to induce host necroptosis by hydrolyzing Nicotinamide adenine dinucleotide (NAD+). Herein, we expressed TNT in macrophages and erythrocytes; the host cells for M. tuberculosis and the malaria parasite respectively, and found that it reduced the NAD+ levels and thereby induced necroptosis and eryptosis resulting in premature dissemination of pathogen. Targeting TNT in M. tuberculosis or induced eryptosis in malaria parasite interferes with pathogen dissemination and reduction in the propagation of infection. Building upon our discovery that inhibition of pathogen-mediated host NAD+ modulation is a way forward for regulation of infection, we synthesized and screened some novel compounds that showed inhibition of NAD+-glycohydrolase activity and pathogen infection in the nanomolar range. Overall this study highlights the fundamental importance of pathogen-mediated modulation of host NAD+ homeostasis for its infection propagation and novel inhibitors as leads for host-targeted therapeutics.

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Transbilayer phospholipid asymmetry in Plasmodium knowlesi-infected host cell membrane

Science ◽

10.1126/science.7233198 ◽

1981 ◽

Vol 212 (4498) ◽

pp. 1047-1049 ◽

Cited By ~ 51

Author(s):

C. Gupta ◽

G. Mishra

Keyword(s):

Cell Membrane ◽

Host Cell ◽

Plasmodium Knowlesi ◽

Infected Host ◽

Host Cell Membrane ◽

Infected Host Cell ◽

Phospholipid Asymmetry

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Kinetic Effect of Silkworm Hemolymph on the Delayed Host Cell Death in an Insect Cell-Baculovirus System

Biotechnology Progress ◽

10.1021/bp990093s ◽

1999 ◽

Vol 15 (6) ◽

pp. 1028-1032 ◽

Cited By ~ 39

Author(s):

W.J. Rhee ◽

E.J. Kim ◽

T.H. Park

Keyword(s):

Cell Death ◽

Host Cell ◽

Insect Cell ◽

Kinetic Effect ◽

Silkworm Hemolymph ◽

Host Cell Death ◽

Baculovirus System

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TolC-Dependent Modulation of Host Cell Death by the Francisella tularensis Live Vaccine Strain

Infection and Immunity ◽

10.1128/iai.00044-14 ◽

2014 ◽

Vol 82 (5) ◽

pp. 2068-2078 ◽

Cited By ~ 16

Author(s):

Christopher R. Doyle ◽

Ji-An Pan ◽

Patricio Mena ◽

Wei-Xing Zong ◽

David G. Thanassi

Keyword(s):

Cell Death ◽

Immune Responses ◽

Host Cell ◽

Francisella Tularensis ◽

Vaccine Strain ◽

Live Vaccine ◽

Live Vaccine Strain ◽

Type I ◽

Content Type ◽

Host Cell Death

ABSTRACTFrancisella tularensisis a facultative intracellular, Gram-negative pathogen and the causative agent of tularemia. We previously identified TolC as a virulence factor of theF. tularensislive vaccine strain (LVS) and demonstrated that a ΔtolCmutant exhibits increased cytotoxicity toward host cells and elicits increased proinflammatory responses compared to those of the wild-type (WT) strain. TolC is the outer membrane channel component used by the type I secretion pathway to export toxins and other bacterial virulence factors. Here, we show that the LVS delays activation of the intrinsic apoptotic pathway in a TolC-dependent manner, both during infection of primary macrophages and during organ colonization in mice. The TolC-dependent delay in host cell death is required forF. tularensisto preserve its intracellular replicative niche. We demonstrate that TolC-mediated inhibition of apoptosis is an active process and not due to defects in the structural integrity of the ΔtolCmutant. These findings support a model wherein the immunomodulatory capacity ofF. tularensisrelies, at least in part, on TolC-secreted effectors. Finally, mice vaccinated with the ΔtolCLVS are protected from lethal challenge and clear challenge doses faster than WT-vaccinated mice, demonstrating that the altered host responses to primary infection with the ΔtolCmutant led to altered adaptive immune responses. Taken together, our data demonstrate that TolC is required for temporal modulation of host cell death during infection byF. tularensisand highlight how shifts in the magnitude and timing of host innate immune responses may lead to dramatic changes in the outcome of infection.

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Fusarium graminearum produces different xylanases causing host cell death that is prevented by the xylanase inhibitors XIP-I and TAXI-III in wheat

Plant Science ◽

10.1016/j.plantsci.2015.09.002 ◽

2015 ◽

Vol 240 ◽

pp. 161-169 ◽

Cited By ~ 15

Author(s):

Silvio Tundo ◽

Ilaria Moscetti ◽

Franco Faoro ◽

Mickaël Lafond ◽

Thierry Giardina ◽

...

Keyword(s):

Cell Death ◽

Host Cell ◽

Fusarium Graminearum ◽

Host Cell Death

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Pattern Recognition Receptors and the Host Cell Death Molecular Machinery

Frontiers in Immunology ◽

10.3389/fimmu.2018.02379 ◽

2018 ◽

Vol 9 ◽

Cited By ~ 56

Author(s):

Gustavo P. Amarante-Mendes ◽

Sandy Adjemian ◽

Laura Migliari Branco ◽

Larissa C. Zanetti ◽

Ricardo Weinlich ◽

...

Keyword(s):

Pattern Recognition ◽

Cell Death ◽

Host Cell ◽

Pattern Recognition Receptors ◽

Host Cell Death ◽

Molecular Machinery

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Entropic Forces Drive Clustering and Spatial Localization of Influenza A M2 During Viral Budding

10.1101/291120 ◽

2018 ◽

Author(s):

Jesper J. Madsen ◽

John M. A. Grime ◽

Jeremy S. Rossman ◽

Gregory A. Voth

Keyword(s):

Host Cell ◽

Influenza A ◽

Spatial Localization ◽

Membrane Curvature ◽

Infected Host ◽

Membrane Remodeling ◽

Infected Host Cell ◽

Viral Budding ◽

Virion Release ◽

Liquid Ordered

ABSTRACTThe influenza A matrix 2 (M2) transmembrane protein facilitates virion release from the infected host cell. In particular, M2 plays a role in the induction of membrane curvature and/or in the scission process whereby the envelope is cut upon virion release. Here we show using coarse-grained computer simulations that various M2 assembly geometries emerge due to an entropic driving force, resulting in compact clusters or linearly extended aggregates as a direct consequence of the lateral membrane stresses. Conditions under which these protein assemblies will cause the lipid membrane to curve are explored and we predict that a critical cluster size is required for this to happen. We go on to demonstrate that under the stress conditions taking place in the cellular membrane as it undergoes large-scale membrane remodeling, the M2 protein will in principle be able to both contribute to curvature induction and sense curvature in order to line up in manifolds where local membrane line tension is high. M2 is found to exhibit linactant behavior in liquid-disordered/liquid-ordered phase-separated lipid mixtures and to be excluded from the liquid-ordered phase, in near-quantitative agreement with experimental observations. Our findings support a role for M2 in membrane remodeling during influenza viral budding both as an inducer and a sensor of membrane curvature, and they suggest a mechanism by which localization of M2 can occur as the virion assembles and releases from the host cell, independent of how the membrane curvature is produced.SIGNIFICANCE STATEMENTFor influenza virus to release from the infected host cell, controlled viral budding must finalize with membrane scission of the viral envelope. Curiously, influenza carries its own protein, M2, which can sever the membrane of the constricted budding neck. Here we elucidate the physical mechanism of clustering and spatial localization of the M2 scission proteins through a combined computational and experimental approach. Our results provide fundamental insights into how M2 clustering and localization interplays with membrane curvature, membrane lateral stresses, and lipid bilayer phase behavior during viral budding in order to contribute to virion release.

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Human GBP1 differentially targets Salmonella and Toxoplasma to license recognition of microbial ligands and caspase-mediated death

10.1101/792804 ◽

2019 ◽

Cited By ~ 2

Author(s):

Daniel Fisch ◽

Barbara Clough ◽

Marie-Charlotte Domart ◽

Vesela Encheva ◽

Hironori Bando ◽

...

Keyword(s):

Cell Death ◽

Feedback Inhibition ◽

Human Macrophages ◽

Bacterial Surface ◽

Caspase 1 ◽

Host Cell Death ◽

Cell Assays ◽

A Site ◽

Detection Mechanisms ◽

Immune Detection

Guanylate binding proteins (GBPs), a family of interferon (IFN)-inducible GTPases, can promote cell-intrinsic defense by removal of intracellular microbial replicative niches through host cell death. GBPs target pathogen-containing vacuoles or the pathogen itself, and assist in membrane-disruption and release of microbial molecules that trigger cell death by activating the inflammasomes. We previously showed that GBP1 mediates atypical apoptosis or pyroptosis of human macrophages infected with Toxoplasma gondii (Tg) or Salmonella enterica Typhimurium (STm), respectively. In mice, the p47 Immunity-related GTPases (IRGs) control the recruitment of GBPs to microbe-containing vacuoles and subsequent cell death. However, humans are devoid of functional IRGs, and the pathogen-proximal immune detection mechanisms by GBP1 are poorly understood. Here, we describe two novel single-cell assays which show that GBP1 promotes the lysis of Tg-containing vacuoles and Tg plasma membrane, resulting in the cytosolic detection of Tg-DNA. In contrast, we show GBP1 only targets cytosolic STm and does not contribute to bacterial escape into the cytosol of human macrophages. GBP1 interacts with caspase-4 and recruits it directly to the bacterial surface, where caspase-4 can be activated by LPS. During STm infection, caspase-1 cleaves and inactivates GBP1 at Asp192, a site conserved in related mammalian GBP1 proteins but not in murine Gbps. STm-infected human macrophages expressing a cleavage-deficient GBP1 mutant exhibit higher pyroptosis due to the absence of caspase-1-mediated feedback inhibition of the GBP1-caspase-4 pathway. Our comparative studies elucidate microbe-specific spatiotemporal roles of GBP1 in detecting infection and the assembly and regulation of divergent caspase signaling platforms.

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