CD40, autophagy and Toxoplasma gondii

Subauste, Carlos S.

doi:10.1590/s0074-02762009000200020

Cited by 9 publications

(11 citation statements)

References 73 publications

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“…Although some bacteria, such as Mycobacterium tuberculosis , Chlamydia trachomatis , and adherent invasive Escherichia coli , are able to manipulate this pathway to reduce their fusion with and/or acidification of lysosomes ( 35 , 44 – 47 ), they have all been reported to acquire LAMP-1 on the autophagosome to a substantial degree ( 48 ). Similarly, activation of CD40 on mouse and human cells leads to recruitment of autophagy adaptors and delivery of T. gondii to lysosomes, where they are destroyed by a process that is independent of IFN-γ ( 25 – 27 ). In contrast, we demonstrate that, in human cells, LAMP-1 does not accumulate on PVs targeted by autophagy, nor are susceptible parasites cleared from IFN-γ-activated HeLa cells.…”

Section: Discussionmentioning

confidence: 99%

“…However, neither of these mechanisms operates in all cell types, suggesting the presence of multiple overlapping pathways for IFN-γ-mediated control of T. gondii in human cells. Additionally, it has been shown that the ligation of CD40 on the surface of hematopoietic and nonhematopoietic cells is able to eliminate intracellular T. gondii in an autophagy-dependent manner ( 25 , 26 ), although this mechanism is not dependent on activation by IFN-γ ( 27 ).…”

Section: Introductionmentioning

confidence: 99%

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A Noncanonical Autophagy Pathway Restricts Toxoplasma gondii Growth in a Strain-Specific Manner in IFN-γ-Activated Human Cells

Selleck

Orchard

Beatty

et al. 2015

mBio

134

230

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A core set of autophagy proteins is required for gamma interferon (IFN-γ)-mediated clearance of Toxoplasma gondii in the mouse because of their control of several downstream effectors, including immunity-related GTPases (IRGs) and guanylate-binding proteins (GBPs). However, these effectors are absent (i.e., IRGs) from or nonessential (i.e., GBPs) in IFN-γ-activated human cells, raising the question of how these cells control parasite replication. Here, we define a novel role for ubiquitination and recruitment of autophagy adaptors in the strain-specific control of T. gondii replication in IFN-γ-activated human cells. Vacuoles containing susceptible strains of T. gondii became ubiquitinated, recruited the adaptors p62 and NDP52, and were decorated with LC3. Parasites within LC3-positive vacuoles became enclosed in multiple layers of host membranes, resulting in stunting of parasite replication. However, LC3-positive T. gondii-containing vacuoles did not fuse with endosomes and lysosomes, indicating that this process is fundamentally different from xenophagy, a form of autophagy involved in the control of intracellular bacterial pathogens. Genetic knockout of ATG16L or ATG7 reverted the membrane encapsulation and restored parasite replication, indicating that core autophagy proteins involved in LC3 conjugation are important in the control of parasite growth. Despite a role for the core autophagy machinery in this process, upstream activation through Beclin 1 was not sufficient to enhance the ubiquitination of T. gondii-containing vacuoles, suggesting a lack of reliance on canonical autophagy. These findings demonstrate a new mechanism for IFN-γ-dependent control of T. gondii in human cells that depends on ubiquitination and core autophagy proteins that mediate membrane engulfment and restricted growth.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

A Noncanonical Autophagy Pathway Restricts Toxoplasma gondii Growth in a Strain-Specific Manner in IFN-γ-Activated Human Cells

Selleck

Orchard

Beatty

et al. 2015

mBio

134

230

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“…177 The level of Autophagy plays an important role in such an innate, cell-mediated immune defense mechanism. 167,168 When CD40 of human or mouse macrophages infected with T. gondii is stimulated with (CD154 + )CD4 + T cells or exposed to anti-CD4 antibodies, the nonfusogenic nature of the PV is reversed and the vacuole fuses with late endosomes and lysosomes. This fusion is dependent on autophagy, as indicated by observations that it is impaired by knockdown of Beclin 1 and treatment with 3-MA, an inhibitor of phagophore formation, whereas it is stimulated by rapamycin.…”

Section: O N O T D I S T R I B U T Ementioning

confidence: 99%

“…Moreover, CD40 activation stimulates expression of LC3/ Atg8 that localizes to the PV. 168 Furthermore, bafilomycin A 1 and LY294002, drugs that inhibit autophagosome formation and degradation of the content of autolysosomes, inhibit the fusion of the PV with lysosomes.…”

Section: O N O T D I S T R I B U T Ementioning

confidence: 99%

Autophagy in protists

et al. 2011

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Autophagy is the degradative process by which eukaryotic cells digest their own components using acid hydrolases within the lysosome. Originally thought to function almost exclusively in providing starving cells with nutrients taken from their own cellular constituents, autophagy is in fact involved in numerous cellular events including differentiation, turnover of macromolecules and organelles, and defense against parasitic invaders. During the last 10-20 years, molecular components of the autophagic machinery have been discovered, revealing a complex interactome of proteins and lipids, which, in a concerted way, induce membrane formation to engulf cellular material and target it for lysosomal degradation. Here, our emphasis is autophagy in protists. We discuss experimental and genomic data indicating that the canonical autophagy machinery characterized in animals and fungi appeared prior to the radiation of major eukaryotic lineages. Moreover, we describe how comparative bioinformatics revealed that this canonical machinery has been subject to moderation, outright loss or elaboration on multiple occasions in protist lineages, most probably as a consequence of diverse lifestyle adaptations. We also review experimental studies illustrating how several pathogenic protists either utilize autophagy mechanisms or manipulate host-cell autophagy in order to establish or maintain infection within a host. The essentiality of autophagy for the pathogenicity of many parasites, and the unique features of some of the autophagy-related proteins involved, suggest possible new targets for drug discovery. Further studies of the molecular details of autophagy in protists will undoubtedly enhance our understanding of the diversity and complexity of this cellular phenomenon and the opportunities it offers as a drug target

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“…This autophagic-mediated parasite killing is mediated by the immunity-related GTPases (IRGs) which are stimulated by IFN-γ. Engagement of CD40 also has been found to induce killing of T. gondii via autophagy in many nonhematopoetic cells including endothelial cells lines, human and mouse retinal pigment epithelial cells as well as in hemopoietic cells such as macrophages [44,45].…”

Section: Autophagymentioning

confidence: 99%

Modulation of Host Programmed Cell Death Pathways by the Intracellular Protozoan Parasite, Toxoplasma gondii — Implications for Maintenance of Chronic Infection and Potential Therapeutic Applications

Halonen¹

2015

Cell Death - Autophagy, Apoptosis and Necrosis

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Programmed cell death PCD pathways are genetically programmed mechanisms that can trigger the cell to die or commit cell suicide . There are three major forms of programmed cell death that are now recognized apoptosis type I , autophagy type II and necrotic cell death or necroptosis type III . While these cell death processes were once thought to occupy discrete cell states, evidence suggests that apoptosis, autophagy and necrosis are often regulated by similar pathways and share initiator and effector molecules and some subcellular compartments indicating that crosstalk exists between these three main forms of cell death pathways, resulting in a balanced interplay by which the cell decides its fate. PCD pathways have important roles in many cellular processes such as development and oncogenic transformation, but PCD pathways also play important roles in host defense and elimination of pathogens. Toxoplasma gondii is a microbial pathogen for which programmed cell death pathways are a key part of the host defense. T. gondii is an obligate intracellular protozoan parasite that infects approximately one-third of the world s population. In most immunocompetant individuals, the chronic infection is asymptomatic due to an effective immune response that eliminates active parasite replication. The parasite has evolved immune evasion strategies that enable it to survive and persist long enough in the host however to establish a chronic infection in which the cyst stage persists within neurons in the brain and skeletal muscle in the periphery. T. gondii has evolved multiple mechanisms to resist killing by apoptotic, autophagic and necrotic cell death pathways, and the parasite s manipulation of host PCD pathways plays a crucial role in host-parasite interactions and maintenance of the chronic infection. While most individuals chronically infected with T. gondii are asymptomatic, severe disease can occur in immunocompromised individuals where the infection reactivates from the brain causing severe necrotizing encephalitis, and increasing evidence indicates chronic cerebral toxoplasmosis in some individuals may lead to neuropsychiatric disorders such as schizophrenia and suicidal behavior. This review will focus on the role of PCD pathways in host defense of T. gondii and the parasite manipulation of these PCD pathways. " bet-

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CD40, autophagy and Toxoplasma gondii

Cited by 9 publications

References 73 publications

A Noncanonical Autophagy Pathway Restricts Toxoplasma gondii Growth in a Strain-Specific Manner in IFN-γ-Activated Human Cells

A Noncanonical Autophagy Pathway Restricts Toxoplasma gondii Growth in a Strain-Specific Manner in IFN-γ-Activated Human Cells

Autophagy in protists

Modulation of Host Programmed Cell Death Pathways by the Intracellular Protozoan Parasite, Toxoplasma gondii — Implications for Maintenance of Chronic Infection and Potential Therapeutic Applications

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