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Annual Review of Microbiology Sep 2020Many intracellular pathogens, including the protozoan parasite , live inside a vacuole that resides in the host cytosol. Vacuolar residence provides these pathogens with... (Review)
Review
Many intracellular pathogens, including the protozoan parasite , live inside a vacuole that resides in the host cytosol. Vacuolar residence provides these pathogens with a defined niche for replication and protection from detection by host cytosolic pattern recognition receptors. However, the limiting membrane of the vacuole, which constitutes the host-pathogen interface, is also a barrier for pathogen effectors to reach the host cytosol and for the acquisition of host-derived nutrients. This review provides an update on the specialized secretion and trafficking systems used by to overcome the barrier of the parasitophorous vacuole membrane and thereby allow the delivery of proteins into the host cell and the acquisition of host-derived nutrients.
Topics: Cytosol; Host-Parasite Interactions; Humans; Metabolic Networks and Pathways; Nutrients; Protein Transport; Protozoan Proteins; Toxoplasma; Vacuoles; Virulence Factors
PubMed: 32680452
DOI: 10.1146/annurev-micro-011720-122318 -
Nature Communications Jun 2023Iron is essential to cells as a cofactor in enzymes of respiration and replication, however without correct storage, iron leads to the formation of dangerous oxygen...
Iron is essential to cells as a cofactor in enzymes of respiration and replication, however without correct storage, iron leads to the formation of dangerous oxygen radicals. In yeast and plants, iron is transported into a membrane-bound vacuole by the vacuolar iron transporter (VIT). This transporter is conserved in the apicomplexan family of obligate intracellular parasites, including in Toxoplasma gondii. Here, we assess the role of VIT and iron storage in T. gondii. By deleting VIT, we find a slight growth defect in vitro, and iron hypersensitivity, confirming its essential role in parasite iron detoxification, which can be rescued by scavenging of oxygen radicals. We show VIT expression is regulated by iron at transcript and protein levels, and by altering VIT localization. In the absence of VIT, T. gondii responds by altering expression of iron metabolism genes and by increasing antioxidant protein catalase activity. We also show that iron detoxification has an important role both in parasite survival within macrophages and in virulence in a mouse model. Together, by demonstrating a critical role for VIT during iron detoxification in T. gondii, we reveal the importance of iron storage in the parasite and provide the first insight into the machinery involved.
Topics: Animals; Mice; Toxoplasma; Vacuoles; Reactive Oxygen Species; Membrane Transport Proteins; Parasites; Protozoan Proteins
PubMed: 37339985
DOI: 10.1038/s41467-023-39436-y -
Current Opinion in Microbiology Oct 2021During the vertebrate stage of the Plasmodium life cycle, obligate intracellular malaria parasites establish a vacuolar niche for replication, first within host... (Review)
Review
During the vertebrate stage of the Plasmodium life cycle, obligate intracellular malaria parasites establish a vacuolar niche for replication, first within host hepatocytes at the pre-patent liver-stage and subsequently in erythrocytes during the pathogenic blood-stage. Survival in this protective microenvironment requires diverse transport mechanisms that enable the parasite to transcend the vacuolar barrier. Effector proteins exported out of the vacuole modify the erythrocyte membrane, increasing access to serum nutrients which then cross the vacuole membrane through a nutrient-permeable channel, supporting rapid parasite growth. This review highlights the most recent insights into the organization of the parasite vacuole to facilitate the solute, lipid and effector protein trafficking that establishes a nutrition pipeline in the terminally differentiated, organelle-free red blood cell.
Topics: Erythrocytes; Host-Parasite Interactions; Humans; Malaria; Plasmodium; Plasmodium falciparum; Protein Transport; Protozoan Proteins; Vacuoles
PubMed: 34375857
DOI: 10.1016/j.mib.2021.07.010 -
Cell Host & Microbe Feb 2022Intracellular pathogens commonly reside within macrophages to find shelter from humoral defenses, but host cell death can expose them to the extracellular milieu. We...
Intracellular pathogens commonly reside within macrophages to find shelter from humoral defenses, but host cell death can expose them to the extracellular milieu. We find intracellular pathogens solve this dilemma by using virulence factors to generate a complement-dependent find-me signal that initiates uptake by a new phagocyte through efferocytosis. During macrophage death, Salmonella uses a type III secretion system to perforate the membrane of the pathogen-containing vacuole (PCV), thereby triggering complement deposition on bacteria entrapped in pore-induced intracellular traps (PITs). In turn, complement activation signals neutrophil efferocytosis, a process that shelters intracellular bacteria from the respiratory burst. Similarly, Brucella employs its type IV secretion system to perforate the PCV membrane, which induces complement deposition on bacteria entrapped in PITs. Collectively, this work identifies virulence factor-induced perforation of the PCV as a strategy of intracellular pathogens to generate a find-me signal for efferocytosis.
Topics: Phagocytosis; Type III Secretion Systems; Type IV Secretion Systems; Vacuoles; Virulence Factors
PubMed: 34951948
DOI: 10.1016/j.chom.2021.12.001 -
ELife Mar 2024Membrane contact sites (MCSs) are junctures that perform important roles including coordinating lipid metabolism. Previous studies have indicated that vacuolar...
Membrane contact sites (MCSs) are junctures that perform important roles including coordinating lipid metabolism. Previous studies have indicated that vacuolar fission/fusion processes are coupled with modifications in the membrane lipid composition. However, it has been still unclear whether MCS-mediated lipid metabolism controls the vacuolar morphology. Here, we report that deletion of tricalbins (Tcb1, Tcb2, and Tcb3), tethering proteins at endoplasmic reticulum (ER)-plasma membrane (PM) and ER-Golgi contact sites, alters fusion/fission dynamics and causes vacuolar fragmentation in the yeast . In addition, we show that the sphingolipid precursor phytosphingosine (PHS) accumulates in tricalbin-deleted cells, triggering the vacuolar division. Detachment of the nucleus-vacuole junction (NVJ), an important contact site between the vacuole and the perinuclear ER, restored vacuolar morphology in both cells subjected to high exogenous PHS and Tcb3-deleted cells, supporting that PHS transport across the NVJ induces vacuole division. Thus, our results suggest that vacuolar morphology is maintained by MCSs through the metabolism of sphingolipids.
Topics: Mitochondrial Membranes; Saccharomyces cerevisiae; Saccharomyces cerevisiae Proteins; Vacuoles; Sphingolipids; Lipid Metabolism; Cell Membrane
PubMed: 38536872
DOI: 10.7554/eLife.89938 -
ELife May 2023The amoeba-resistant bacterium causes Legionnaires' disease and employs a type IV secretion system (T4SS) to replicate in the unique, ER-associated -containing vacuole...
The amoeba-resistant bacterium causes Legionnaires' disease and employs a type IV secretion system (T4SS) to replicate in the unique, ER-associated -containing vacuole (LCV). The large fusion GTPase Sey1/atlastin is implicated in ER dynamics, ER-derived lipid droplet (LD) formation, and LCV maturation. Here, we employ cryo-electron tomography, confocal microscopy, proteomics, and isotopologue profiling to analyze LCV-LD interactions in the genetically tractable amoeba . Dually fluorescence-labeled producing LCV and LD markers revealed that Sey1 as well as the T4SS and the Ran GTPase activator LegG1 promote LCV-LD interactions. In vitro reconstitution using purified LCVs and LDs from parental or Δ mutant indicated that Sey1 and GTP promote this process. Sey1 and the fatty acid transporter FadL were implicated in palmitate catabolism and palmitate-dependent intracellular growth. Taken together, our results reveal that Sey1 and LegG1 mediate LD- and FadL-dependent fatty acid metabolism of intracellular .
Topics: Humans; Legionella pneumophila; GTP Phosphohydrolases; Macrophages; Dictyostelium; Lipid Droplets; Vacuoles; Legionella; Legionnaires' Disease; Bacterial Proteins
PubMed: 37158597
DOI: 10.7554/eLife.85142 -
Trends in Parasitology Feb 2020When a malaria parasite invades a host erythrocyte it pushes itself in and invaginates a portion of the host membrane, thereby sealing itself inside and establishing... (Review)
Review
When a malaria parasite invades a host erythrocyte it pushes itself in and invaginates a portion of the host membrane, thereby sealing itself inside and establishing itself in the resulting vacuole. The parasitophorous vacuolar membrane (PVM) that surrounds the parasite is modified by the parasite, using its secretory organelles. To survive within this enveloping membrane, the organism must take in nutrients, secrete wastes, export proteins into the host cell, and eventually egress. Here, we review current understanding of the unique solutions Plasmodium has evolved to these challenges and discuss the remaining questions.
Topics: Erythrocytes; Host-Parasite Interactions; Humans; Malaria; Plasmodium; Vacuoles
PubMed: 31866184
DOI: 10.1016/j.pt.2019.11.006 -
Current Opinion in Microbiology Apr 2020Intravacuolar bacterial pathogens establish intracellular niches by constructing membrane-encompassed compartments. The vacuoles surrounding the bacteria are remarkably... (Review)
Review
Intravacuolar bacterial pathogens establish intracellular niches by constructing membrane-encompassed compartments. The vacuoles surrounding the bacteria are remarkably stable, facilitating microbial replication and preventing exposure to host cytoplasmically localized innate immune sensing mechanisms. To maintain integrity of the membrane compartment, the pathogen is armed with defensive weapons that prevent loss of vacuole integrity and potential exposure to host innate signaling. In some cases, the microbial components that maintain vacuolar integrity have been identified, but the basis for why the compartment degrades in their absence is unclear. In this review, we point out that lessons from the microbial-programmed degradation of the vacuole by the cytoplasmically localized Shigella flexneri provide crucial insights into how degradation of pathogen vacuoles occurs. We propose that in the absence of bacterial-encoded guard proteins, aberrant trafficking of host membrane-associated components results in a dysfunctional pathogen compartment. As a consequence, the vacuole is poisoned and replication is terminated.
Topics: Autophagy; Bacterial Proteins; Chlamydia trachomatis; Gram-Negative Bacteria; Host-Pathogen Interactions; Humans; Legionella pneumophila; Multiprotein Complexes; Shigella flexneri; Sorting Nexins; Vacuoles; Virulence Factors
PubMed: 32044688
DOI: 10.1016/j.mib.2020.01.008 -
Archives of Razi Institute Jun 2023(), the etiological agent of the Q fever disease, ranks among the most sporadic and persistent global public health concerns. Ruminants are the principal source of... (Review)
Review
(), the etiological agent of the Q fever disease, ranks among the most sporadic and persistent global public health concerns. Ruminants are the principal source of human infections and diseases present in both acute and chronic forms. This bacterium is an intracellular pathogen that can survive and reproduce under acidic (pH 4 to 5) and harsh circumstances that contain -containing vacuoles. By undermining the autophagy defense system of the host cell, is able to take advantage of the autophagy pathway, which allows it to improve the movement of nutrients and the membrane, thereby extending the vacuole of the reproducing bacteria. For this method to work, it requires the participation of many bacterial effector proteins. In addition, the precise and prompt identification of the causative agent of an acute disease has the potential to delay the onset of its chronic form. Moreover, to make accurate and rapid diagnoses, it is necessary to create diagnostic devices. This review summarizes the most recent research on the epidemiology, pathogenesis, and diagnosis approaches of . This study also explored the complicated relationships between and the autophagic pathway, which are essential for intracellular reproduction and survival in host cells for the infection to be effective.
Topics: Humans; Coxiella burnetii; Q Fever; Vacuoles; Autophagy
PubMed: 38028822
DOI: 10.22092/ARI.2023.361161.2636 -
Molecular Biology of the Cell Mar 2023The conserved catalysts of intracellular membrane fusion are Rab-family GTPases, effector complexes that bind Rabs for membrane tethering, SNARE proteins of the R, Qa,...
The conserved catalysts of intracellular membrane fusion are Rab-family GTPases, effector complexes that bind Rabs for membrane tethering, SNARE proteins of the R, Qa, Qb, and Qc families, and SNARE chaperones of the SM, Sec17/SNAP, and Sec18/NSF families. Yeast vacuole fusion is regulated by phosphatidylinositol-3-phosphate (PI3P). PI3P binds directly to the vacuolar Qc-SNARE and to HOPS, the vacuolar tethering/SM complex. We now report several distinct functions of PI3P in fusion. PI3P binds the N-terminal PX domain of the Qc-SNARE to enhance its engagement for fusion. Even when Qc has been preassembled with the Qa- and Qb-SNAREs, PI3P still promotes -SNARE assembly and fusion between these 3Q proteoliposomes and those with R-SNARE, whether with the natural HOPS tether or with a synthetic tether. With HOPS, efficient -SNARE complex formation needs PI3P on the 3Q-SNARE proteoliposomes, in to the Qc. PI3P is also needed for HOPS to confer resistance to Sec17/Sec18. With a synthetic tether, fusion is supported by PI3P on either fusion partner membrane, but this fusion is blocked by Sec17/Sec18. PI3P thus supports multiple stages of fusion: the engagement of the Qc-SNARE, -SNARE complex formation with preassembled Q-SNAREs, HOPS protection of SNARE complexes from Sec17/Sec18, and fusion per se after tethering and Q-SNARE assembly.
Topics: Humans; Adenosine Triphosphatases; Membrane Fusion; Qc-SNARE Proteins; Saccharomyces cerevisiae; Saccharomyces cerevisiae Proteins; SNARE Proteins; Vacuoles; Vesicular Transport Proteins; Phosphatidylinositol Phosphates
PubMed: 36735517
DOI: 10.1091/mbc.E22-10-0486