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

2019 ◽  
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.

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

2016 ◽  
Vol 7 (1) ◽  
Author(s):  
Teresa L. M. Thurston ◽  
Sophie A. Matthews ◽  
Elliott Jennings ◽  
Eric Alix ◽  
Feng Shao ◽  
...  
Keyword(s):  
Cell Death ◽  
Growth Inhibition ◽  
Host Cell ◽  
Caspase 1 ◽  
Host Cell Death

scholarly journals Human caspase-4 mediates noncanonical inflammasome activation against gram-negative bacterial pathogens

2015 ◽  
Vol 112 (21) ◽  
pp. 6688-6693 ◽  
Author(s):  
Cierra N. Casson ◽  
Janet Yu ◽  
Valeria M. Reyes ◽  
Frances O. Taschuk ◽  
Anjana Yadav ◽  
...  
Keyword(s):  
Cell Death ◽  
Bacterial Pathogens ◽  
Inflammasome Activation ◽  
Gram Negative Bacteria ◽  
Secretion Systems ◽  
Gram Negative ◽  
Human Macrophages ◽  
Caspase 1 ◽  
Inflammatory Caspases ◽  
Human Caspase

Inflammasomes are critical for host defense against bacterial pathogens. In murine macrophages infected by gram-negative bacteria, the canonical inflammasome activates caspase-1 to mediate pyroptotic cell death and release of IL-1 family cytokines. Additionally, a noncanonical inflammasome controlled by caspase-11 induces cell death and IL-1 release. However, humans do not encode caspase-11. Instead, humans encode two putative orthologs: caspase-4 and caspase-5. Whether either ortholog functions similar to caspase-11 is poorly defined. Therefore, we sought to define the inflammatory caspases in primary human macrophages that regulate inflammasome responses to gram-negative bacteria. We find that human macrophages activate inflammasomes specifically in response to diverse gram-negative bacterial pathogens that introduce bacterial products into the host cytosol using specialized secretion systems. In primary human macrophages, IL-1β secretion requires the caspase-1 inflammasome, whereas IL-1α release and cell death are caspase-1–independent. Instead, caspase-4 mediates IL-1α release and cell death. Our findings implicate human caspase-4 as a critical regulator of noncanonical inflammasome activation that initiates defense against bacterial pathogens in primary human macrophages.

scholarly journals Trichomonas vaginalis Induces NLRP3 Inflammasome Activation and Pyroptotic Cell Death in Human Macrophages

2018 ◽  
Vol 11 (1) ◽  
pp. 86-98 ◽  
Author(s):  
Angelica Montenegro Riestra ◽  
J. Andrés Valderrama ◽  
Kathryn A. Patras ◽  
Sharon D. Booth ◽  
Xing Yen Quek ◽  
...  
Keyword(s):  
Cell Death ◽  
Host Cell ◽  
Nlrp3 Inflammasome ◽  
Trichomonas Vaginalis ◽  
Inflammasome Activation ◽  
Cell Detection ◽  
Human Macrophages ◽  
Sexually Transmitted ◽  
Caspase 1 ◽  
Nlrp3 Inflammasome Activation

Trichomonas vaginalis is a sexually transmitted, eukaryotic parasite that causes trichomoniasis, the most common nonviral, sexually transmitted disease in the USA and worldwide. Little is known about the molecular mechanisms involved in the host immune response to this widespread parasite. Here we report that T. vaginalis induces NLRP3 inflammasome activation in human macrophages, leading to caspase-1 activation and the processing of pro-IL-1β to the mature and bioactive form of the cytokine. Using inhibitor-based approaches, we show that NLRP3 activation by T. vaginalis involves host cell detection of extracellular ATP via P2X7 receptors and potassium efflux. In addition, our data reveal that T. vaginalis inflammasome activation induces macrophage inflammatory cell death by pyroptosis, known to occur via caspase-1 cleavage of the gasdermin D protein, which assembles to form pores in the host cell membrane. We found that T. vaginalis-induced cytolysis of macrophages is attenuated in gasdermin D knockout cells. Lastly, in a murine challenge model, we detected IL-1β production in vaginal fluids in response to T. vaginalis infection in vivo. Together, our findings mechanistically dissect how T. vaginalis contributes to the production of the proinflammatory IL-1β cytokine and uncover pyroptosis as a mechanism by which the parasite can trigger host macrophage cell death.

scholarly journals A tolC Mutant of Francisella tularensis Is Hypercytotoxic Compared to the Wild Type and Elicits Increased Proinflammatory Responses from Host Cells

2009 ◽  
Vol 78 (3) ◽  
pp. 1022-1031 ◽  
Author(s):  
Gabrielle J. Platz ◽  
DeAnna C. Bublitz ◽  
Patricio Mena ◽  
Jorge L. Benach ◽  
Martha B. Furie ◽  
...  
Keyword(s):  
Cell Death ◽  
Host Cell ◽  
Francisella Tularensis ◽  
Host Cells ◽  
Type I ◽  
Wild Type ◽  
Human Macrophages ◽  
Host Immune Responses ◽  
Host Cell Death ◽  
Proinflammatory Responses

ABSTRACT The highly infectious bacterium Francisella tularensis is a facultative intracellular pathogen and the causative agent of tularemia. TolC, which is an outer membrane protein involved in drug efflux and type I protein secretion, is required for the virulence of the F. tularensis live vaccine strain (LVS) in mice. Here, we show that an LVS ΔtolC mutant colonizes livers, spleens, and lungs of mice infected intradermally or intranasally, but it is present at lower numbers in these organs than in those infected with the parental LVS. For both routes of infection, colonization by the ΔtolC mutant is most severely affected in the lungs, suggesting that TolC function is particularly important in this organ. The ΔtolC mutant is hypercytotoxic to murine and human macrophages compared to the wild-type LVS, and it elicits the increased secretion of proinflammatory chemokines from human macrophages and endothelial cells. Taken together, these data suggest that TolC function is required for F. tularensis to inhibit host cell death and dampen host immune responses. We propose that, in the absence of TolC, F. tularensis induces excessive host cell death, causing the bacterium to lose its intracellular replicative niche. This results in lower bacterial numbers, which then are cleared by the increased innate immune response of the host.

scholarly journals Pathogen induced subversion of NAD+ metabolism mediating host cell death: a target for development of chemotherapeutics

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Ayushi Chaurasiya ◽  
Swati Garg ◽  
Ashish Khanna ◽  
Chintam Narayana ◽  
Ved Prakash Dwivedi ◽  
...  
Keyword(s):  
Cell Death ◽  
Host Cell ◽  
Nicotinamide Adenine Dinucleotide ◽  
Malaria Parasite ◽  
Host Cells ◽  
Nicotinamide Adenine ◽  
Targeted Therapeutics ◽  
Nad Metabolism ◽  
Host Cell Death ◽  
Nanomolar Range

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.

scholarly journals VX765 Attenuates Pyroptosis and HMGB1/TLR4/NF-κB Pathways to Improve Functional Outcomes in TBI Mice

2020 ◽  
Vol 2020 ◽  
pp. 1-21 ◽  
Author(s):  
Zhezhe Sun ◽  
Mark Nyanzu ◽  
Su Yang ◽  
Xiaohong Zhu ◽  
Kankai Wang ◽  
...  
Keyword(s):  
Cell Death ◽  
Blood Brain Barrier ◽  
High Mobility ◽  
Brain Barrier ◽  
Neurological Deficits ◽  
Nf Kappa B ◽  
Neuroprotective Effects ◽  
Caspase 1 ◽  
Area Of Interest ◽  
Blood Brain

Background. Traumatic brain injury (TBI) refers to temporary or permanent damage to brain function caused by penetrating objects or blunt force trauma. TBI activates inflammasome-mediated pathways and other cell death pathways to remove inactive and damaged cells, however, they are also harmful to the central nervous system. The newly discovered cell death pattern termed pyroptosis has become an area of interest. It mainly relies on caspase-1-mediated pathways, leading to cell death. Methods. Our research focus is VX765, a known caspase-1 inhibitor which may offer neuroprotection after the process of TBI. We established a controlled cortical impact (CCI) mouse model and then controlled the degree of pyroptosis in TBI with VX765. The effects of caspase-1 inhibition on inflammatory response, pyroptosis, blood-brain barrier (BBB), apoptosis, and microglia activation, in addition to neurological deficits, were investigated. Results. We found that TBI led to NOD-like receptors (NLRs) as well as absent in melanoma 2 (AIM2) inflammasome-mediated pyroptosis in the damaged cerebral cortex. VX765 curbed the expressions of indispensable inflammatory subunits (caspase-1 as well as key downstream proinflammatory cytokines such as interleukin- (IL-) 1β and IL-18). It also inhibited gasdermin D (GSDMD) cleavage and apoptosis-associated spot-like protein (ASC) oligomerization in the injured cortex. In addition to the above, VX765 also inhibited the inflammatory activity of the high-mobility cassette -1/Toll-like receptor 4/nuclear factor-kappa B (HMGB1/TLR4/NF-kappa B) pathway. By inhibiting pyroptosis and inflammatory mediator expression, we demonstrated that VX765 can decrease blood-brain barrier (BBB) leakage, apoptosis, and microglia polarization to exhibit its neuroprotective effects. Conclusion. In conclusion, VX765 can counteract neurological damage after TBI by reducing pyroptosis and HMGB1/TLR4/NF-κB pathway activities. VX765 may have a good therapeutic effect on TBI.

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