The kinetic properties and sensitivities to inhibitors of lactate dehydrogenases (LDH1 and LDH2) from Toxoplasma gondii: comparisons with pLDH from Plasmodium falciparum

Dando, Caroline; Schroeder, Eric R; Hunsaker, Lucy A.; Deck, Lorraine M.; Royer, Robert E.; Zhou, Xiulan; Parmley, Stephen; Jagt, David L. Vander

doi:10.1016/s0166-6851(01)00360-7

Cited by 65 publications

(80 citation statements)

References 28 publications

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“…The doubling time of TL1T tachyzoites was twice that of the parental tachyzoites. It was recently reported that upon inhibiting LDH1 enzymatic activity by gossypol, the tachyzoite growth was reduced in cultured fibroblasts (14,15). Therefore, the TL1T phenotype is in concordance with these previous enzymatic and inhibition studies.…”

Section: Discussionsupporting

confidence: 85%

“…The activity of LDHs is generally inhibited by an excess of pyruvate. However, this property is greatly reduced in the LDHs from Plasmodium and Toxoplasma (15,16).…”

mentioning

confidence: 99%

“…During differentiation, T. gondii modifies its morphology and energy metabolism to adapt to its surrounding environment. Aerobic respiration and glycolysis are functional in tachyzoites, whereas glycolysis is the only energy source in bradyzoites (15,18). Therefore, LDH, which is important for anaerobic respiration, might be a promising target for developing drugs for chronic toxoplasmosis.…”

mentioning

confidence: 99%

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The Expression of Lactate Dehydrogenase Is Important for the Cell Cycle of Toxoplasma gondii

Anouti

Tomavo

Parmley

et al. 2004

Journal of Biological Chemistry

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In Toxoplasma gondii, lactate dehydrogenase is encoded by two independent and developmentally regulated genes LDH1 and LDH2. These genes and their products have been implicated in the control of a metabolic flux during parasite differentiation. To investigate the significance of LDH1 and LDH2 in this process, we generated stable transgenic parasite lines in which the expression of these two expressed isoforms of lactate dehydrogenase was knocked down in a stage-specific manner. These LDH knockdown parasites exhibited variable growth rates in either the tachyzoite or the bradyzoite stage, as compared with the parental parasites. Their differentiation processes were impaired when the parasites were grown under in vitro conditions. In vivo studies in a murine model system revealed that tachyzoites of these parasite lines were unable to form significant numbers of tissue cysts and to establish a chronic infection. Most importantly, all mice that were initially infected with tachyzoites of either of the four LDH knockdown lines survived a subsequent challenge with tachyzoites of the parental parasites (10 4 ), a dose that usually causes 100% mortality, suggesting that live vaccination of mice with the LDH knockdown tachyzoites can confer protection against T. gondii. Thus, we conclude that LDH expression is essential for parasite differentiation. The knockdown of LDH1 and LDH2 expression gave rise to virulence-attenuated parasites that were unable to exhibit a significant brain cyst burden in a murine model of chronic infection.

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Section: Discussionsupporting

confidence: 85%

“…The activity of LDHs is generally inhibited by an excess of pyruvate. However, this property is greatly reduced in the LDHs from Plasmodium and Toxoplasma (15,16).…”

mentioning

confidence: 99%

mentioning

confidence: 99%

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The Expression of Lactate Dehydrogenase Is Important for the Cell Cycle of Toxoplasma gondii

Anouti

Tomavo

Parmley

et al. 2004

Journal of Biological Chemistry

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“…This may suggest that NAD(P)H oxidase may participate in a mechanism by which INF-γ-activated HUVEC inhibit T. gondii multiplication [771]. This suggestion and the fact that diabetic patients had increased NAD(P)H oxidase activity [749] are consistent with the finding that two forms of lactate dehydrogenase LDH1 and LDH2 from T. gondii were inhibited competitively by gossypol and gossylic iminolactone, and this correlated with specific inhibition of tachyzoites growth in human foreskin fibroblast cultures [772]. Since the bradyzoite LDH2 was more sensitive in vitro to these compounds than the tachyzoite LDH1, it is likely that the growth of bradyzoites in cysts would be inhibited by gossypol and gossylic iminolactone as well [772].…”

Section: T Gondii Infectionsupporting

confidence: 70%

T. gondii Infection Acquired during Pregnancy and/or after Birth may be Responsible for Development of both Type 1 and 2 Diabetes Mellitus

Pr¹,

ota²

2013

J Diabetes Metab

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Recently, it was suggested that maternal T and potentially B cells transferred during pregnancy and/or the breast milk feeding and their encounter with the antigen in mesenteric lymph nodes might play a role in development of type 1 diabetes mellitus (T1DM). T. gondii infection during gestation and/or after birth may be responsible for development of both T1DM and T2DM in children, adolescents and adults because: a) maternal microchimerism in peripheral blood was demonstrated to be significantly higher in patients with T1DM compared to unaffected siblings and healthy subjects, b) transmission of T. gondii as a Trojan horse in various types of eukaryotic cells, including T and B lymphocytes, c) swallowing by the fetus of amniotic fluid containing infected leukocytes and other cells, d) elimination of T. gondii in the breast milk during lactation, e) involvement of mesenteric lymph nodes after oral infection with the parasite, and f) damage of the myenteric neurons during infection with the parasite in both the animals with streptozotocin-induced diabetes and diabetic patients. Moreover, a significantly lower occurrence of antibodies against T. gondii found in the sera of patients with T1DM compared with their first-degree family members or healthy controls may be due to their T and/or B cell exhaustion perspective caused by chronic infection with the parasite. This suggestion may be supported by the finding that latent toxoplasmosis was associated with markedly reduced lymphocyte B-cell counts responsible for production of antibodies, markedly lower serum IgG, IgM, and IgA levels, and a significant suppression of IL-2. On the other hand, patients with T2DM had increased anti-T. gondii antibodies significantly more frequently than respective controls. Impaired vascular endothelial function characteristic for the patients with diabetes mellitus may be at least in part due to the preferential T. gondii infection of endothelial cells. Vitamin D and minocycline exerted beneficial effects on development and clinical course of diabetes mellitus probably because of their immunomodulatory and antitoxoplasmatic activities. These data strongly suggest that the parasite play an important role in development of both types of diabetes mellitus.

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“…LDH1 is expressed mainly in the tachyzoite stage, while LDH2 is expressed during the bradyzoite stage; both are substantially different from the mammalian LDH (83). The cotton plant-derived gossypol and its derivatives (exemplified by compound 37) have been shown to be potent LDH2 inhibitors (enzyme K i , 1.1 M) and are somewhat active against LDH1 (enzyme K i , 6.1 M), with an IC 50 of 5 to 10 M against intracellular tachyzoites (84). However, these compounds have not been tested against the bradyzoite form.…”

Section: Inhibition Of Transcriptionmentioning

confidence: 99%

Review of Experimental Compounds Demonstrating Anti-Toxoplasma Activity

McFarland

Zach

Wang

et al. 2016

Antimicrob Agents Chemother

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Toxoplasma gondii is a ubiquitous apicomplexan parasite capable of infecting humans and other animals. Current treatment options for T. gondii infection are limited and most have drawbacks, including high toxicity and low tolerability. Additionally, no FDA-approved treatments are available for pregnant women, a high-risk population due to transplacental infection. Therefore, the development of novel treatment options is needed. To aid this effort, this review highlights experimental compounds that, at a minimum, demonstrate inhibition of in vitro growth of T. gondii. When available, host cell toxicity and in vivo data are also discussed. The purpose of this review is to facilitate additional development of anti-Toxoplasma compounds and potentially to extend our knowledge of the parasite.

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The kinetic properties and sensitivities to inhibitors of lactate dehydrogenases (LDH1 and LDH2) from Toxoplasma gondii: comparisons with pLDH from Plasmodium falciparum

Cited by 65 publications

References 28 publications

The Expression of Lactate Dehydrogenase Is Important for the Cell Cycle of Toxoplasma gondii

The Expression of Lactate Dehydrogenase Is Important for the Cell Cycle of Toxoplasma gondii

T. gondii Infection Acquired during Pregnancy and/or after Birth may be Responsible for Development of both Type 1 and 2 Diabetes Mellitus

Review of Experimental Compounds Demonstrating Anti-Toxoplasma Activity

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