The heat shock protein 90 of <i>Toxoplasma gondii</i> is essential for invasion of host cells and tachyzoite growth

Sun, Hongchao; Zhuo, Xunhui; Zhao, Xianfeng; Yang, Yi; Chen, Xueqiu; Yao, Chaoqun; Du, Aifang

doi:10.1051/parasite/2017023

Cited by 27 publications

(15 citation statements)

References 55 publications

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“…Another cytoplasmic heat shock protein, TgHsp90, has increased expression under alkaline conditions and localizes to the nucleus and cytoplasm in bradyzoites [69]. Deletion of TgHsp90 reduces the expression of BAG1 and MAG1 (tested in a type I strain which typically do not differentiate well to bradyzoites) [70]. DnaK-tetratricopeptide repeat (TgDnaK-TPR), another heat shock protein, has been shown to be upregulated within Type II strains, though its function has yet to be characterized [71].…”

Section: Bradyzoite Developmentmentioning

confidence: 99%

Observations on bradyzoite biology

Yakubu

Weiss

2018

Microbes and Infection

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Tachyzoites of the Apicomplexan Toxoplasma gondii cause acute infection, disseminate widely in their host, and eventually differentiate into a latent encysted form called bradyzoites that are found within tissue cysts. During latent infection, whenever transformation to tachyzoites occurs, any tachyzoites that develop are removed by the immune system. In contrast, cysts containing bradyzoites are sequestered from the immune system. In the absence of an effective immune response released organisms that differentiate into tachyzoites cause acute infection. Tissue cysts, therefore, serve as a reservoir for the reactivation of toxoplasmosis when the host becomes immunocompromised by conditions such as HIV infection, organ transplantation, or due to the impaired immune response that occurs when pathogens are acquired in utero. While tachyzoites and bradyzoites are well defined morphologically, there is no clear consensus on how interconversion occurs or what exact signal(s) mediate this transformation. Advances in research methods have facilitated studies on T. gondii bradyzoites providing important new insights into the biology of latent infection.

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Section: Bradyzoite Developmentmentioning

confidence: 99%

Observations on bradyzoite biology

Yakubu

Weiss

2018

Microbes and Infection

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“…Another important heat shock protein for protozoa is HSP90, which has already been associated with the process of differentiation and invasion of host cells, and is modulated by posttranslational modifications (Roy et al 2012;Schopf et al 2017). In Toxoplasma gondii, HSP90 is associated with bradyzoite differentiation, host-cell invasion, and growth and virulence (Sun et al 2017). The inactivation of HSP90 for drug geldanamycin or radicicol in Leishmania donovani leads to the differentiation of the promastigote form into the amastigote (Wiesgigl and Clos 2001).…”

Section: Discussionmentioning

confidence: 99%

Quantitative phosphoproteome and proteome analyses emphasize the influence of phosphorylation events during the nutritional stress of Trypanosoma cruzi: the initial moments of in vitro metacyclogenesis

Lucena

Amorim

Lima

et al. 2019

Cell Stress and Chaperones

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Phosphorylation is an important event in cell signaling that is modulated by kinases and phosphatases. In Trypanosoma cruzi, the etiological agent of Chagas disease, approximately 2% of the protein-coding genes encode for protein kinases. This parasite has a heteroxenic life cycle with four different development stages. In the midgut of invertebrate vector, epimastigotes differentiate into metacyclic trypomastigotes in a process known as metacyclogenesis. This process can be reproduced in vitro by submitting parasites to nutritional stress (NS). Aiming to contribute to the elucidation of mechanisms that trigger metacyclogenesis, we applied super-SILAC (super-stable isotope labeling by amino acids in cell culture) and LC-MS/MS to analyze different points during NS. This analysis resulted in the identification of 4205 protein groups and 3643 phosphopeptides with the location of 4846 phosphorylation sites. Several phosphosites were considered modulated along NS and are present in proteins associated with various functions, such as fatty acid synthesis and the regulation of protein expression, reinforcing the importance of phosphorylation and signaling events to the parasite. These modulated sites may be triggers of metacyclogenesis.

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“…T. gondii Hsp90 (TgHsp90) is an essential molecule, that plays an important role during the transition from tachyzoite to bradyzoite stages [82]. As a consequence, the application of GA to inhibit TgHsp90 resulted in growth stage arrest of the parasite [82,83]. In addition, treatment of the parasite using GA compromised its virulence [82].…”

Section: Hsp90 Familymentioning

confidence: 99%

“…As a consequence, the application of GA to inhibit TgHsp90 resulted in growth stage arrest of the parasite [82,83]. In addition, treatment of the parasite using GA compromised its virulence [82]. Despite TgHsp90 being an attractive drug target, the unavailability of a three-dimensional image of the protein hampers the design of novel inhibitors targeting this protein.…”

Section: Hsp90 Familymentioning

confidence: 99%

Small Molecule Inhibitors Targeting the Heat Shock Protein System of Human Obligate Protozoan Parasites

Zininga

Shonhai

2019

IJMS

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Obligate protozoan parasites of the kinetoplastids and apicomplexa infect human cells to complete their life cycles. Some of the members of these groups of parasites develop in at least two systems, the human host and the insect vector. Survival under the varied physiological conditions associated with the human host and in the arthropod vectors requires the parasites to modulate their metabolic complement in order to meet the prevailing conditions. One of the key features of these parasites essential for their survival and host infectivity is timely expression of various proteins. Even more importantly is the need to keep their proteome functional by maintaining its functional capabilities in the wake of physiological changes and host immune responses. For this reason, molecular chaperones (also called heat shock proteins)—whose role is to facilitate proteostasis—play an important role in the survival of these parasites. Heat shock protein 90 (Hsp90) and Hsp70 are prominent molecular chaperones that are generally induced in response to physiological stress. Both Hsp90 and Hsp70 members are functionally regulated by nucleotides. In addition, Hsp70 and Hsp90 cooperate to facilitate folding of some key proteins implicated in cellular development. In addition, Hsp90 and Hsp70 individually interact with other accessory proteins (co-chaperones) that regulate their functions. The dependency of these proteins on nucleotide for their chaperone function presents an Achille’s heel, as inhibitors that mimic ATP are amongst potential therapeutic agents targeting their function in obligate intracellular human parasites. Most of the promising small molecule inhibitors of parasitic heat shock proteins are either antibiotics or anticancer agents, whose repurposing against parasitic infections holds prospects. Both cancer cells and obligate human parasites depend upon a robust protein quality control system to ensure their survival, and hence, both employ a competent heat shock machinery to this end. Furthermore, some inhibitors that target chaperone and co-chaperone networks also offer promising prospects as antiparasitic agents. The current review highlights the progress made so far in design and application of small molecule inhibitors against obligate intracellular human parasites of the kinetoplastida and apicomplexan kingdoms.

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The heat shock protein 90 of Toxoplasma gondii is essential for invasion of host cells and tachyzoite growth

Cited by 27 publications

References 55 publications

Observations on bradyzoite biology

Observations on bradyzoite biology

Quantitative phosphoproteome and proteome analyses emphasize the influence of phosphorylation events during the nutritional stress of Trypanosoma cruzi: the initial moments of in vitro metacyclogenesis

Small Molecule Inhibitors Targeting the Heat Shock Protein System of Human Obligate Protozoan Parasites

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