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1.
mSphere ; 9(1): e0059723, 2024 Jan 30.
Article in English | MEDLINE | ID: mdl-38051073

ABSTRACT

Toxoplasma gondii is a protozoan parasite that infects a broad spectrum of hosts and can colonize many organs and cell types. The ability to reside within a wide range of different niches requires substantial adaptability to diverse microenvironments. Very little is known about how this parasite senses various milieus and adapts its metabolism to survive, replicate during the acute stage, and then differentiate to the chronic stage. T. gondii possesses a lysosome-like organelle known as the plant-like vacuolar compartment (PLVAC), which serves various functions, including digestion, ion storage and homeostasis, endocytosis, and autophagy. Lysosomes are critical for maintaining cellular health and function by degrading waste materials and recycling components. To supply the cell with the essential building blocks and energy sources required for the maintenance of its functions and structures, the digested solutes generated within the lysosome are transported into the cytosol by proteins embedded in the lysosomal membrane. Currently, a limited number of PLVAC transporters have been characterized, with TgCRT being the sole potential transporter of amino acids and small peptides identified thus far. To bridge this knowledge gap, we used lysosomal amino acid transporters from other organisms as queries to search the T. gondii proteome. This led to the identification of four potential amino acid transporters, which we have designated as TgAAT1-4. Assessing their expression and sub-cellular localization, we found that one of them, TgAAT1, localized to the PLVAC and is necessary for normal parasite extracellular survival and bradyzoite differentiation. Moreover, we present preliminary data showing the possible involvement of TgAAT1 in the PLVAC transport of arginine.IMPORTANCEToxoplasma gondii is a highly successful parasite infecting a broad range of warm-blooded organisms, including about one-third of all humans. Although Toxoplasma infections rarely result in symptomatic disease in individuals with a healthy immune system, the incredibly high number of persons infected, along with the risk of severe infection in immunocompromised patients and the potential link of chronic infection to mental disorders, makes this infection a significant public health concern. As a result, there is a pressing need for new treatment approaches that are both effective and well tolerated. The limitations in understanding how Toxoplasma gondii manages its metabolism to adapt to changing environments and triggers its transformation into bradyzoites have hindered the discovery of vulnerabilities in its metabolic pathways or nutrient acquisition mechanisms to identify new therapeutic targets. In this work, we have shown that the lysosome-like organelle plant-like vacuolar compartment (PLVAC), acting through the putative arginine transporter TgAAT1, plays a pivotal role in regulating the parasite's extracellular survival and differentiation into bradyzoites.


Subject(s)
Parasites , Toxoplasma , Animals , Humans , Toxoplasma/metabolism , Vacuoles/metabolism , Amino Acid Transport Systems/metabolism , Arginine/metabolism
2.
bioRxiv ; 2023 Sep 01.
Article in English | MEDLINE | ID: mdl-37693549

ABSTRACT

Toxoplasma gondii is a protozoan parasite that infects a broad spectrum of hosts and can colonize many organs and cell types. The ability to reside within a wide range of different niches requires substantial adaptability to diverse microenvironments. Very little is known about how this parasite senses various milieus and adapts its metabolism to survive, replicate during the acute stage, and then differentiate to the chronic stage. Most eukaryotes, from yeast to mammals, rely on a nutrient sensing machinery involving the TORC complex as master regulator of cell growth and cell cycle progression. The lysosome functions as a signaling hub where TORC complex assembles and is activated by transceptors, which both sense and transport amino acids, including the arginine transceptor SLC38A9. While most of the TORC components are lost in T. gondii , indicating the evolution of a distinct nutrient sensing mechanism, the parasite's lysosomal plant-like vacuolar compartment (PLVAC) may still serve as a sensory platform for controlling parasite growth and differentiation. Using SLC38A9 to query the T. gondii proteome, we identified four putative amino acid transporters, termed TgAAT1-4, that structurally resemble the SLC38A9 arginine transceptor. Assessing their expression and sub-cellular localization, we found that one of them, TgAAT1, localized to the PLVAC and is necessary for normal parasite extracellular survival and bradyzoite differentiation. Moreover, we show that TgAAT1 is involved in the PLVAC efflux of arginine, an amino acid playing a key role in T. gondii differentiation, further supporting the hypothesis that TgAAT1 might play a role in nutrient sensing. IMPORTANCE: T. gondii is a highly successful parasite infecting a broad range of warm-blood organisms including about one third of all humans. Although Toxoplasma infections rarely result in symptomatic disease in individuals with a healthy immune system, the incredibly high number of persons infected along with the risk of severe infection in immunocompromised patients and the potential link of chronic infection to mental disorders make this infection a significant public health concern. As a result, there is a pressing need for new treatment approaches that are both effective and well-tolerated. The limitations in understanding how Toxoplasma gondii manages its metabolism to adapt to changing environments and triggers its transformation into bradyzoites have hindered the discovery of vulnerabilities in its metabolic pathways or nutrient acquisition mechanisms to identify new therapeutic targets. In this work, we have shown that the lysosome-like organelle PLVAC, acting through the putative arginine transporter TgAAT1, plays a pivotal role in regulating the parasite's extracellular survival and differentiation into bradyzoites.

3.
Angew Chem Int Ed Engl ; 62(18): e202218421, 2023 Apr 24.
Article in English | MEDLINE | ID: mdl-36856155

ABSTRACT

The development of solid-state proton conductors with high proton conductivity at low temperatures is crucial for the implementation of hydrogen-based technologies for portable and automotive applications. Here, we report on the discovery of a new crystalline metal acid triphosphate, ZrH5 (PO4 )3 (ZP3), which exhibits record-high proton conductivity of 0.5-3.1×10-2  S cm-1 in the range 25-110 °C in anhydrous conditions. This is the highest anhydrous proton conductivity ever reported in a crystalline solid proton conductor in the range 25-110 °C. Superprotonic conductivity in ZP3 is enabled by extended defective frustrated hydrogen bond chains, where the protons are dynamically disordered over two oxygen centers. The high proton conductivity and stability in anhydrous conditions make ZP3 an excellent candidate for innovative applications in fuel cells without the need for complex water management systems, and in other energy technologies requiring fast proton transfer.

4.
Microorganisms ; 9(12)2021 Dec 15.
Article in English | MEDLINE | ID: mdl-34946193

ABSTRACT

Obligate intracellular parasites have evolved a remarkable assortment of strategies to scavenge nutrients from the host cells they parasitize. Most apicomplexans form a parasitophorous vacuole (PV) within the invaded cell, a replicative niche within which they survive and multiply. As well as providing a physical barrier against host cell defense mechanisms, the PV membrane (PVM) is also an important site of nutrient uptake that is essential for the parasites to sustain their metabolism. This means nutrients in the extracellular milieu are separated from parasite metabolic machinery by three different membranes, the host plasma membrane, the PVM, and the parasite plasma membrane (PPM). In order to facilitate nutrient transport from the extracellular environment into the parasite itself, transporters on the host cell membrane of invaded cells can be modified by secreted and exported parasite proteins to maximize uptake of key substrates to meet their metabolic demand. To overcome the second barrier, the PVM, apicomplexan parasites secrete proteins contained in the dense granules that remodel the vacuole and make the membrane permissive to important nutrients. This bulk flow of host nutrients is followed by a more selective uptake of substrates at the PPM that is operated by specific transporters of this third barrier. In this review, we recapitulate and compare the strategies developed by Apicomplexa to scavenge nutrients from their hosts, with particular emphasis on transporters at the parasite plasma membrane and vacuolar solute transporters on the parasite intracellular digestive organelle.

5.
Inorg Chem ; 43(1): 368-74, 2004 Jan 12.
Article in English | MEDLINE | ID: mdl-14704089

ABSTRACT

This paper reports the preparation and characterization of a series of organic derivatives of ZrPO(4)Cl(CH(3))(2)SO obtained by topotactic anion exchange of chloride ligands with several n-alkoxide (RO) and carboxylate groups (RCOO). Exchange with alkoxides, with an alkyl chain length from 2 to 8 carbon atoms, gave products of general formula ZrPO(4)RO(CH(3))(2)SO. In these derivatives alkoxide groups, covalently bonded to zirconium atoms via Zr-O bonds, point toward the interlayer region. Carboxylate derivatives, of general formula ZrPO(4)[(RCOO)(CH(3))(2)SO](1)(-)(x)(OH H(2)O)(x), were obtained using benzoate (x = 0), nitrobenzoate (x = 0.3), and phenylacetate (x = 0.2) groups. The thermal behavior of these organic derivatives is discussed. Due to this reactivity, ZrPO(4)Cl(CH(3))(2)SO is an attractive precursor for materials chemistry.

6.
Inorg Chem ; 41(7): 1913-9, 2002 Apr 08.
Article in English | MEDLINE | ID: mdl-11925188

ABSTRACT

Crystalline ZrPO(4)Cl(CH(3))(2)SO was prepared by direct precipitation in the presence of oxalic acid as a zirconium complexing agent. The structure of ZrPO(4)Cl(CH(3))(2)SO, refined with the Rietveld method using X-ray powder diffraction data, was confirmed to be close to that of the compound prepared using gamma-zirconium phosphate as a precursor. Chloride anions directly bonded to zirconium were found to act as weak ligands; this made possible their replacement with other monodentate anionic ligands. The preparation and a preliminary characterization of a series of inorganic derivatives obtained by topotactic replacement of Cl with OH, Br, MSO(4) (M = H, NH(4), Na), NaMoO(4), and HCrO(4) anions is reported. The possibility of replacement of chloride also with organic anions, such as alkoxides and carboxylates, and the possibility of substituting also dimethyl sulfoxide with other neutral ligands, as shown by preliminary study, makes ZrPO(4)Cl(CH(3))(2)SO a useful and very flexible precursor for materials chemistry.

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