Toxoplasma Research Community

Published by wjsullivan on 28 November 2006 - 3:21pm

Welcome, I am Bill Sullivan, the online leader for The Synaptic Leap's Toxoplasma research community. You can find out more about my work at the laboratory web site.

Why Toxoplasma is important

Toxoplasma gondii is a protozoan (single-celled) parasite that has permanently infected tens of millions of people in the world.  A normal immune response typically controls infection promptly, but the parasite persists as a latent cyst within host tissues.  Tissue cysts can form in brain, heart, and skeletal muscle tissue.  If immunity should become compromised due to disease (such as AIDS) or immunosuppressive therapies (e.g., cancer chemotherapy or organ transplantation), the acute stage of infection may recrudesce.  Thus, Toxoplasma is a significant opportunisitc pathogen.  However, there are instances when Toxoplasma threatens normal, healthy individuals as well.  For example, Toxoplasma can cause abortion or congenital birth defects; this may occur if a woman becomes infected for the first time during pregnancy.  Additionally, emerging studies have demonstrated intriguing alterations in host organism behavior upon infection, or correlations with neurological disorders such as schizophrenia.

Toxoplasma infection may be picked up from cats (the definitive host) or contaminated food/water.  People at significant risk (HIV+ or pregnant individuals) should cook meat thoroughly, wash vegetables, and avoid cat litter boxes and gardening.

Get Involved With an Open Research Project

If you're studying Toxoplasma, I encourage you to make all or portions of your project open. Invite others to help or add their thoughts to your project. Simply create a "child page" to our current project page to begin. Or if you're still in the brainstorming phase, post a blog and invite others you know working in the field to participate online. 

Comments

jcbradley's picture

Bill,

This looks like a great application.  Have you defined what you are making open from your lab?  What kind of contributions are you asking for? 

 

JC - thanks for writing...this is all pretty new and in progress, but more details are to come.  For time being, the link to my faculty page and lab web site should be informative.  I noticed the link to the lab web site is broken...we will fix that!  It should be:  www.sullivanlab.com.  In short, we are examing histone acetyltransferases (HATs) in Toxo as potential new drug targets.  So we'd be very interested if anyone had inhibitors against HATs or could help us express them functionally in heterologous systems for high-throughput screening, etc.  Cheers --Bill

MatTodd's picture

Bill,

This sounds interesting. For the chemists here, do you have any lead references for structures we should be looking at? It would be good if someone could post some structures of promising inhibitors to get the mental gears in motion.

Cheers,

Mat

 

jcbradley's picture

Bill,

Thanks for the link.  I've subscribed to your blog as well.  I'll be looking there as well as on SL for updates on the data you make open.  Following up on Mat's thoughts, we are also synthetic organic chemists and would be interested in allocating some of our resources towards the synthesis of inhibitors if it makes sense, like we have been doing for malaria here:

http://usefulchem.wikispaces.com 

 

Thanks for the replies and interest.  I will try to post some here today, along with proper references.  Shouldn't take long as there is a paucity of HAT inhibitors.  Quite surprising given how many people study HATs and the fact that HDAC (histone deacetylases) inhibitors are now in clinical trials against cancer (and also show anti-parasite activity).  Bottom line - there is substantial interest in HAT inhibitors for many folks studying eukaryotic cell biology, and they could have multi-fold clinical relevance.  Cheers --Bill

rayonsoleil's picture

Sodium butyrate is an HDAC inhibitor -- very early & very recent cites --

J Biol Chem. 2007 Mar 30;282(13):9797-804. Epub 2007 Jan 24.Essential role of the JAK/STAT1 signaling pathway in the expression of inducible nitric-oxide synthase in intestinal epithelial cells and its regulation by butyrate.
Stempelj M, Kedinger M, Augenlicht L, Klampfer L.

 

Cell. 1978 May;14(1):105-13. Sodium butyrate inhibits histone deacetylation in cultured cells. Candido EP, Reeves R, Davie JR.

 

At Sullivan Lab, have you tried it and rejected it? Not yet tried it? Have reasons why it would not be suitable? Etc . . .

rayonsoleil's picture

Have you tried valproic acid? If so, what sorts of results?

J. Endocrinol., November 1, 2006; 191(2): 465 - 472. Valproic acid, a histone deacetylase inhibitor, enhances sensitivity todoxorubicin in anaplastic thyroid cancer cells. M. G Catalano, N. Fortunati, M. Pugliese, R. Poli, O. Bosco, R.Mastrocola, M. Aragno, and G. Boccuzzi

bill:

    however,most of the paper before conclude that p300 act as tumor repressor.how ever there still some report assert that p300 also can promter cancer cell growth.yet,i think we should consider the balance of HAT activity of p300 in cancer cell.low level or high level of p300 both contribut to cancer prolification. and so could we imagine that the histone acetyalase inhibitor may be a durg to cure cancer or to inhibitor cancer deterioration?

Thanks for the comments. There are reports that certain HDAC inhibitors are indeed effective against the parasites (e.g. apicidin). There is concern about the selective toxicity, but more studies are warranted to examine other HDACs in turn. We've not focused on this area, but rather the HATs.

rayonsoleil's picture

What I should have asked would be something more like this. Even though Because sodium butyrateinhibits and also hyperacetylates, doesboth, have you considered it or tried it?

As to substances which blow hot and cold -- i.e., de-acetylate and hyper-acetylate -- perhaps an analogy would be vitamin C, which can be a pro-oxidant or an anti-oxidant. It alldepends on the circumstances.

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J Nutr. 2003 Jul;133(7 Suppl):2485S-2493S. Inhibition of histone deacetylase activity by butyrate. Davie JR.

This article reviews the effects of the short-chain fatty acid butyrate on histone deacetylase (HDAC) activity. Sodium butyrate has multiple effects on cultured mammalian cells that include inhibition of proliferation, induction of differentiation and induction or repression of gene expression.

The observation that butyrate treatment of cells results in histone hyperacetylation initiated a flurry of activity that led to the discovery that butyrate inhibits HDAC activity.

Butyrate has been an essential agent for determining the role of histone acetylation in chromatin structure and function. Interestingly, inhibition of HDAC activity affects the expression of only 2% of mammalian genes.

Promoters of butyrate-responsive genes have butyrate response elements, and the action of butyrate is often mediated through Sp1/Sp3 binding sites (e.g., p21(Waf1/Cip1)).

We demonstrated that Sp1 and Sp3 recruit HDAC1 and HDAC2, with the latter being phosphorylated by protein kinase CK2.

A model is proposed in which inhibition of Sp1/Sp3-associated HDAC activity leads to histone hyperacetylation and transcriptional activation of the p21(Waf1/Cip1) gene; p21(Waf1/Cip1) inhibits cyclin-dependent kinase 2 activity and thereby arrests cell cycling.

Pending the cell background, the nonproliferating cells may enter differentiation or apoptotic pathways. The potential of butyrate and HDAC inhibitors in the prevention and treatment of cancer is presented.

PMID: 12840228

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and valproate -- Le Centre National de la Recherche Scientifique has this available,from the journal Cancer, some time in 2006. It describes valproate as a deacetylase inhibitor --

Valproate enhances imatinib-lnduced growth arrest and apoptosis in chronic myeloid leukemia cells. MOROTTI, et al.

Résumé / Abstract: The objective of this study was to evaluate the ability of the clinically available histone deacetylase (HDAC) inhibitor valproate to < snip >