The human immune response to Toxoplasma: Autophagy versus cell death

Krishnamurthy, Shruthi; Konstantinou, Eleni K.; Young, Lucy H.; Gold, Daniel

doi:10.1371/journal.ppat.1006176

Cited by 33 publications

(29 citation statements)

References 23 publications

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“…In contrast, Irgm1 proteins were detected only in mouse cells, and not in human cells, in response to IFN-γ ( Fig. 4J ); notably, humans do not express Irgm1 but possess IRGM, a single human homolog of IRG whose significance remains unclear with respect to the anti- T. gondii human response ( 44 ). To directly examine the role of IRGM in Huh7 cells, we generated IRGM-KO Huh7 cells by CRISPR/Cas9 genome editing and tested for the ability to mount an IFN-γ-induced anti- T. gondii response ( Fig.…”

Section: Resultsmentioning

confidence: 99%

Inducible Nitric Oxide Synthase Is a Key Host Factor forToxoplasmaGRA15-Dependent Disruption of the Gamma Interferon-Induced Antiparasitic Human Response

Bando

Lee

Sakaguchi

et al. 2018

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Toxoplasma, an important intracellular parasite of humans and animals, causes life-threatening toxoplasmosis in immunocompromised individuals. Gamma interferon (IFN-γ) is produced in the host to inhibit the proliferation of this parasite and eventually cause its death. Unlike mouse disease models, which involve well-characterized virulence strategies that are used by Toxoplasma to suppress IFN-γ-dependent immunity, the strategies used by Toxoplasma in humans remain unclear. Here, we show that GRA15, a Toxoplasma effector protein, suppresses the IFN-γ-induced indole-2,3-dioxygenase 1-dependent antiparasite immune response in human cells. Because NLRP3-dependent production of IL-1β and nitric oxide (NO) in Toxoplasma-infected human cells is involved in the GRA15-dependent virulence mechanism, blocking NO or IL-1β production in the host could represent a novel therapeutic approach for treating human toxoplasmosis.

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Section: Resultsmentioning

confidence: 99%

Inducible Nitric Oxide Synthase Is a Key Host Factor forToxoplasmaGRA15-Dependent Disruption of the Gamma Interferon-Induced Antiparasitic Human Response

Bando

Lee

Sakaguchi

et al. 2018

mBio

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“…Both pathogens can induce cell death in the infected cell, which may promote the spread of infection within the host (Coburn et al , ; Krishnamurthy et al , ). Tg‐ induced host‐cell death can vary depending on the host species and IFNγ‐priming; mechanisms including pyroptosis and inhibition of apoptosis have been reported in Tg‐ infected naïve rodent and human cells.…”

Section: Introductionmentioning

confidence: 99%

Human GBP 1 is a microbe‐specific gatekeeper of macrophage apoptosis and pyroptosis

et al. 2019

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The guanylate binding protein (GBP) family of interferon‐inducible GTPases promotes antimicrobial immunity and cell death. During bacterial infection, multiple mouse Gbps, human GBP2, and GBP5 support the activation of caspase‐1‐containing inflammasome complexes or caspase‐4 which trigger pyroptosis. Whether GBPs regulate other forms of cell death is not known. The apicomplexan parasite Toxoplasma gondii causes macrophage death through unidentified mechanisms. Here we report that Toxoplasma‐induced death of human macrophages requires GBP1 and its ability to target Toxoplasma parasitophorous vacuoles through its GTPase activity and prenylation. Mechanistically, GBP1 promoted Toxoplasma detection by AIM2, which induced GSDMD‐independent, ASC‐, and caspase‐8‐dependent apoptosis. Identical molecular determinants targeted GBP1 to Salmonella‐containing vacuoles. GBP1 facilitated caspase‐4 recruitment to Salmonella leading to its enhanced activation and pyroptosis. Notably, GBP1 could be bypassed by the delivery of Toxoplasma DNA or bacterial LPS into the cytosol, pointing to its role in liberating microbial molecules. GBP1 thus acts as a gatekeeper of cell death pathways, which respond specifically to infecting microbes. Our findings expand the immune roles of human GBPs in regulating not only pyroptosis, but also apoptosis.

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“…Once the pathogen is in the cytoplasm, GBPs and IRGs can also mediate the vesiculation of the pathogen itself thereby exposing pathogen‐associated molecular patterns (PAMPs) to cytosolic PRRs, which can lead to the activation of the inflammasome (Man et al , ) and the induction of a form of cell death called pyroptosis (Broz & Dixit, ). Because host cell death removes the replication niche of intracellular pathogens, this is an efficient way of inhibiting pathogen growth (Krishnamurthy et al , ).…”

Section: Introductionmentioning

confidence: 99%

“…IFNγ‐stimulated human cells control Toxoplasma using diverse mechanisms dependent on the cell type (Krishnamurthy et al , ). For example, IFNγ‐mediated induction of indoleamine 2,3 dioxygenase (IDO) causes breakdown of L‐tryptophan, for which Toxoplasma is auxotrophic, which mediates inhibition of parasite growth in HeLa, HAP1, and fibroblast cells (Pfefferkorn, ; Pfefferkorn et al , ; Niedelman et al , ; Qin et al , ; Bando et al , ).…”

Section: Introductionmentioning

confidence: 99%

Toxoplasma GRA 15 limits parasite growth in IFN γ‐activated fibroblasts through TRAF ubiquitin ligases

et al. 2020

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The protozoan parasite Toxoplasma gondii lives inside a vacuole in the host cytosol where it is protected from host cytoplasmic innate immune responses. However, IFNc-dependent cell-autonomous immunity can destroy the vacuole and the parasite inside. Toxoplasma strain differences in susceptibility to human IFNc exist, but the Toxoplasma effector(s) that determine these differences are unknown. We show that in human primary fibroblasts, the polymorphic Toxoplasma-secreted effector GRA15 mediates the recruitment of ubiquitin ligases, including TRAF2 and TRAF6, to the vacuole membrane, which enhances recruitment of ubiquitin receptors (p62/NDP52) and ubiquitin-like molecules (LC3B, GABARAP). This ultimately leads to lysosomal degradation of the vacuole. In murine fibroblasts, GRA15-mediated TRAF6 recruitment mediates the recruitment of immunity-related GTPases and destruction of the vacuole. Thus, we have identified how the Toxoplasma effector GRA15 affects cell-autonomous immunity in human and murine cells.

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The human immune response to Toxoplasma: Autophagy versus cell death

Cited by 33 publications

References 23 publications

Inducible Nitric Oxide Synthase Is a Key Host Factor forToxoplasmaGRA15-Dependent Disruption of the Gamma Interferon-Induced Antiparasitic Human Response

Inducible Nitric Oxide Synthase Is a Key Host Factor forToxoplasmaGRA15-Dependent Disruption of the Gamma Interferon-Induced Antiparasitic Human Response

Human GBP 1 is a microbe‐specific gatekeeper of macrophage apoptosis and pyroptosis

Toxoplasma GRA 15 limits parasite growth in IFN γ‐activated fibroblasts through TRAF ubiquitin ligases

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