Do you love cats? There may be a reason, quite beyond their noble indifference to your affection. Toxoplasma gondii is a parasitic microbe that passes from cats to other animals in their environment, including humans, and is notorious for causing mental disturbances in them. For example, rats infected with Toxoplasma switch from avoiding cat urine to being attracted by it. The evolutionary logic of this phenomenon is as obvious as it is macabre, but how does it happen? A recent paper presented a small step towards understanding this pathogen, by finding one transcription factor that runs a large portion of its program of differentiation into the brain-cyst form, the bradyzoite.
Toxoplasma is a complex one-celled eukaryote, in the same family as the malaria parasite, plasmodium vivax. These pathogens lead far more interesting lives than your average bacterium and come with larger genetic repertoires. Toxoplasma generates several different cell types, starting with sperm and egg cells, which form in the cat hosts. These mate and form oocysts which are incredibly tough- they survive defecation by the cat and survive thereafter in the environment for months. When picked up by another unsuspecting mammal, (we can ingest them either as contaminating oocysts from the environment, or from undercooked pork that was infected), they proliferate in an asexual stage, and can invade any cell or tissue, causing toxoplasmosis, which can be fatal. But usually it isn't, and the immune system fights these tiny cells to a draw, prompting some to hunker down in a specially dormant form, the bradyzoite, that forms cysts full of toxoplasma cells in muscle and brain tissue. These cysts are completely impervious, not only to immune system attack, but to any drug or vaccine yet devised.
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| A Toxoplasma cyst in a brain, full of pathogen cells, courtesy of the USDA. |
Somewhere between a quarter and half of the US population is chronically infected with this pathogen, and it would be nice to know what effects it is having. Chronic toxoplasma infection is known to positively associate with schizophrenia, pose special dangers to pregnant women, and even contribute to traffic accidents, not to mention to the proliferation of cats. While we do not yet know quite what the bradyzoites are doing in our brains, their formation is more amenable to scientific study. It is stress factors from immune pressure, specifically chemical attack from cells like neutrophils and macrophages that cause Toxoplasma to respond by differentiating, in a program that involves hundreds of genes, (of its genome of roughly 8,000 genes), to the bradyzoite cell type, which is slow-growing and communal, with special protective surface features. The current authors have finally found one gene that, when knocked out, completely abolishes differentiation into the bradyzoite state, and also, they show, is a critical part of the normal program that generates it. They call this gene BFD1, for bradyzoite formation deficient.
BFD1 is a transcription regulator, from a well-known (Myb) family, which bind DNA and frequently participate in development and proliferation, some of which are also oncogenes. In this case, not only is BFD1 itself induced during such stress and able to completely block differentiation when absent, but it can also drive differentiation all by itself, in the absence of stress. This is shown by arranging overexpression under control of the experimenter rather than by the normal stresses, which leads to cell differentiation and formation of the characteristic bradyzoite cysts. It is a rare demonstration of a true master controller of a developmental process.
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| Toxoplasma gene BFD1 is driven by the experimenters by adding a chemical (called Shield-1, lower panels) that releases a destruction system over an engineered and over-expressed BFD1, and leads, after 6 days, to cyst formation. The control infection (upper panels) leads instead to the obliteration of the infected cells. This demonstrates that even in the absence of normal differentiating signals, BFD1 will initiate the full differentiation program all by itself. |
This is a landmark achievement in the study of this pathogen, and will open up a lot of future work on its encystment differentiation program, on how these cells defend themselves in a hostile environment, and what they are doing in our and to our brains. For example, these researchers found 509 genes to which BFD1 binds, among which are itself (for a positive feedback loop), and other genes known as markers for the bradyzoite state. Is some unusual chemical or protein being expressed that causes neural alterations, or is it the locations the bradyzoites choose for their cyst formation? Or is it the occasional release from encystement, and the ensuing immune reaction, that generates these effects? It is an area of some public health concern, and another area slowly yielding to the advance of scientific inquiry.
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