Recent Advances in the Roles of Autophagy and Autophagy Proteins in Host Cells During Toxoplasma gondii Infection and Potential Therapeutic Implications

Subauste, Carlos S.

doi:10.3389/fcell.2021.673813

Cited by 11 publications

(11 citation statements)

References 62 publications

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“…Toxoplasma gondii , the causative agent of toxoplasmosis, is known to cause encephalitis, retinitis and miscarriage [ 181 ] Data reported an increase of mitochondria fragmentation of human fibroblasts cells infected with the T. gondii and these mitochondria were recruited to the parasitophorous vacuole [ 158 , 182 ]. In addition, infected cells had metabolic perturbations of mitochondrial glycolysis [ 160 ] and OXPHOS complex [ 161 ], as well as increase of mitochondrial ROS, changes the amount of OXPHOS components and many other mitochondrial-related proteins [ 158 , 183 ].…”

Section: Mitochondrial Bioenergetics and Dynamics In Infectious Diseasesmentioning

confidence: 99%

Mitochondria as a Cellular Hub in Infection and Inflammation

Andrieux

Chevillard

Cunha‐Neto

et al. 2021

IJMS

173

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Mitochondria are the energy center of the cell. They are found in the cell cytoplasm as dynamic networks where they adapt energy production based on the cell’s needs. They are also at the center of the proinflammatory response and have essential roles in the response against pathogenic infections. Mitochondria are a major site for production of Reactive Oxygen Species (ROS; or free radicals), which are essential to fight infection. However, excessive and uncontrolled production can become deleterious to the cell, leading to mitochondrial and tissue damage. Pathogens exploit the role of mitochondria during infection by affecting the oxidative phosphorylation mechanism (OXPHOS), mitochondrial network and disrupting the communication between the nucleus and the mitochondria. The role of mitochondria in these biological processes makes these organelle good targets for the development of therapeutic strategies. In this review, we presented a summary of the endosymbiotic origin of mitochondria and their involvement in the pathogen response, as well as the potential promising mitochondrial targets for the fight against infectious diseases and chronic inflammatory diseases.

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Section: Mitochondrial Bioenergetics and Dynamics In Infectious Diseasesmentioning

confidence: 99%

Mitochondria as a Cellular Hub in Infection and Inflammation

Andrieux

Chevillard

Cunha‐Neto

et al. 2021

IJMS

173

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“…argued that this process occurs under the regulation of IFN-stimulated genes ( Bhushan et al., 2020 ). Nevertheless, in human endothelial cells infected by type II strains, ubiquitinated K63 is recruited by IFN-γ to induce the fusion of lysosomes and PVM to T. gondii ( Clough et al., 2016 ; Subauste, 2021 ). NDP52 and p62 are subsequently recruited around PV in the absence of LC3 and ATG16L ( Figure 2C ).…”

Section: The Interplay Of T Gondii and Host Cell A...mentioning

confidence: 99%

Modulation of autophagy as a therapeutic strategy for Toxoplasma gondii infection

Cheng

Zhang

Chen

et al. 2022

Front. Cell. Infect. Microbiol.

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Toxoplasma gondii infection is a severe health threat that endangers billions of people worldwide. T. gondii utilizes the host cell membrane to form a parasitophorous vacuole (PV), thereby fully isolating itself from the host cell cytoplasm and making intracellular clearance difficult. PV can be targeted and destroyed by autophagy. Autophagic targeting results in T. gondii killing via the fusion of autophagosomes and lysosomes. However, T. gondii has developed many strategies to suppress autophagic targeting. Accordingly, the interplay between host cell autophagy and T. gondii is an emerging area with important practical implications. By promoting the canonical autophagy pathway or attenuating the suppression of autophagic targeting, autophagy can be effectively utilized in the development of novel therapeutic strategies against T gondii. Here, we have illustrated the complex interplay between host cell mediated autophagy and T. gondii. Different strategies to promote autophagy in order to target the parasite have been elucidated. Besides, we have analyzed some potential new drug molecules from the DrugBank database using bioinformatics tools, which can modulate autophagy. Various challenges and opportunities focusing autophagy mediated T. gondii clearance have been discussed, which will provide new insights for the development of novel drugs against the parasite.

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“…Studies on T. gondii have shown that autophagosomes cannot directly kill T. gondii in parasitophorous vacuoles, but autophagy and autophagy-related proteins can promote the killing effect of the non-canonical IFN-γ-dependent autophagy pathway against T. gondii ( Sasai et al, 2018 ; Zhu et al, 2019 ; Subauste, 2021 ). Next, we tried to research the effect of C3 on killing T. gondii by IFN-γ-activated macrophages.…”

Section: Resultsmentioning

confidence: 99%

“…It mainly affects the central nervous system (CNS) ( Schluter and Barragan, 2019 ). T. gondii are targeted by a non-canonical autophagy pathway in IFN-γ-activated cells to restrict parasite growth ( Selleck et al, 2015 ; Subauste, 2021 ). T. gondii is an important model for studying infection and immunity and is a relatively mature in vivo and in vitro infection model.…”

Section: Introductionmentioning

confidence: 99%

Locally generated C3 regulates the clearance of Toxoplasma gondii by IFN-γ-primed macrophage through regulation of xenophagy

et al. 2022

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Exogenous pathogen infection can induce autophagy in cells. Autophagy is essential for cell survival, development, and homeostasis. It not only regulates cell defense and stress, but also has a close relationship with innate and adaptive immunity. Complement is an important part of innate immunity, which could be activated by three approaches, including classic, alternative, and lectin pathways. All the three pathways result in the activation of C3, and generate anaphylatoxin fragments C3a and C5a, and formation of the membrane attack complex. Either C3a or C5a induces the inflammatory cytokines through binding to C3aR or C5aR, respectively. However, it is still unknown whether the complement could regulate the autophagy of intracellular microorganisms or not. In this study, we constructed a Toxoplasma gondii (T. gondii) and macrophages co-culture experimental model using T. gondii expressing enhanced green fluorescence protein (EGFP) fluorescence and C3−/-C57BL/6 J mice for that T. gondii invaded peritoneal macrophages in mice. Western blot, laser confocal microscopy (LCM), and transmission electron microscopy (TEM) were used to observe the changes of autophagy between the macrophages from wild-type (WT) and C3−/− mice. Flow cytometry and LCM were used to investigate the effect of autophagy on the killing ability of macrophages against T. gondii. Here, we found that local C3 could suppress not only the canonical autophagy of macrophage, but also the xenophagy to T. gondii. Interestingly, the inhibition of C3 on host cell autophagy could significantly suppress the clearance of T. gondii by the IFN-γ-primed macrophage. Finally, we investigated the mechanism of the autophagy regulation of C3 that the effect of C3 on the macrophage-specific autophagy against T. gondii depends on mTOR. And, there is C3a but not C5a/C5aR involved in regulating macrophage xenophagy against T. gondii. Collectively, our findings suggest locally generated C3 regulates the clearance of T. gondii by Macrophage through the regulation of the non-canonical IFN-γ-dependent autophagy pathway, and paint a clearer picture in the regulation of autophagy by innate immune components.

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Recent Advances in the Roles of Autophagy and Autophagy Proteins in Host Cells During Toxoplasma gondii Infection and Potential Therapeutic Implications

Cited by 11 publications

References 62 publications

Mitochondria as a Cellular Hub in Infection and Inflammation

Mitochondria as a Cellular Hub in Infection and Inflammation

Modulation of autophagy as a therapeutic strategy for Toxoplasma gondii infection

Locally generated C3 regulates the clearance of Toxoplasma gondii by IFN-γ-primed macrophage through regulation of xenophagy

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