Discovery of potential key to better drugs to fight Toxoplasmosis parasite
Discoveries by IU School of Medicine scientists have opened a promising door to new drugs for toxoplasmosis and other parasites that now can evade treatments by turning dormant in the body.
Their findings help explain how the parasite that causes toxoplasmosis transforms into a cyst form that resists drugs and the body\'s immune system, yet can emerge from its dormant state to strike when a patient\'s immune system is weakened.
Led by William J. Sullivan Jr., Ph.D., assistant professor of pharmacology and toxicology, and Ronald C. Wek, Ph.D., professor of biochemistry and molecular biology, the research team found a cellular signaling system that takes hold when the parasite is stressed, enabling it to transform into the cyst surrounded by a protective barrier.
The signaling system identified by the IU team could serve as a target to block the transformation into the cyst form or to attack the parasite while in the cyst form. Their report was published in the June 13 issue of the Journal of Biological Chemistry.
The Toxoplasma gondii parasite converts from an active state to the inactive cyst state when it is stressed, for example, by heat from fever. Stress response mechanisms have been well studied in yeast and other organisms, but the pathways used by the toxoplasmosis parasite had not been determined.
"We found a cellular signal that appears to put the parasite to sleep, which in turn tells us something new about how opportunistic pathogens such as Toxoplasma awaken to cause disease during immunosuppression," said Dr. Sullivan.
An estimated 60 million people in the United States are infected with the toxoplasmosis parasite, but for most infection produces flu-like symptoms or no symptoms at all. However, for people with immune system problems - such as those undergoing chemotherapy or people with AIDS - the disease can cause serious effects including lung problems, blurred vision and seizures. Also, infants born to mothers who are infected during or shortly before pregnancy are at risk for severe complications, miscarriages or stillbirths.
Medications to treat Toxoplasma gondii are effective but too toxic for extended use, and they don\'t affect the cyst form, said Dr. Sullivan.
"A healthy immune system can keep this parasite in the cyst state. Without a healthy immune system, this organism can run rampant," said Dr. Sullivan. "This can be a very serious problem for people with AIDS."
The discovery linking this stress-response mechanism to cyst formation and maintenance not only offers a possible target for new drugs, but it could also lead to a preventative vaccine - for animals.
The Toxoplasma gondii parasite can infect most animals and birds, but it reproduces in cats, which can shed the parasite in their feces. Humans can be infected through contact with the infected feces or litter. People can also become infected by consuming undercooked meat.
A vaccine to prevent infection in cats and livestock could prevent a significant proportion of human infections, Dr. Sullivan said.
The research of Drs. Sullivan and Wek is supported by the National Institutes of Health and the American Heart Association.
发现开发更有效抗弓形虫药物的钥匙印第安纳大学医学院的科学家们的发现给开发新的药物用于治疗弓形虫等寄生虫打开了一扇希望的大门，这些寄生虫目前在体内能以休眠状态逃避药物打击。他们的发现帮助解释了引起弓形虫病的寄生虫是如何转变成孢囊的形式来抵御药物和人体免疫系统，然后在免疫力下降的时候复苏攻击机体。该研究团队由William J. Sullivan Jr（博士，药理毒理学副教授）和Ronald C. Wek（博士，生物化学和分子生物学教授）领导，他们发现了一套细胞信号系统，当弓形虫处于应激状态时该系被激活，使它可以被一层防护屏障包围而成为孢囊。由印第安纳大学团队鉴别的这套信号系统可以作为阻断孢囊转化或攻击孢囊形式寄生虫的靶点。他们的报告发表在6月13号发行的生物化学杂志上。鼠弓形虫在应激情况如发烧受热时会从活化状态转化为非活化的孢囊状态。应激反应机制在酵母菌和其他生物体上已经研究得相当透彻，但弓形虫所使用的途径尚不明确。“我们发现了一个细胞信号，看起来它可以让寄生虫睡着，接着它让我们在条件致病菌如弓形虫如何在免疫抑制时复苏并致病方面了解了一些新的东西。” Dr. Sullivan说。据估计在美国有6千万人感染弓形虫，但多数仅表现为流感样症状或根本没有症状。但是，对于免疫系统异常者——如接受化疗的人或AIDS患者——这种感染能引起严重的问题如肺病、视力模糊和癫痫发作。同样，母亲在怀孕期间或孕前不久曾被感染，其婴儿将面临严重并发症、流产或死产的危险。“健康的免疫系统可以将这种寄生虫维持在孢囊状态，但没有了健康的免疫系统，这种生物将疯狂蔓延，” Dr. Sullivan说，“对于AIDS患者这是极其严重的问题。”这项将该应激反应机制和孢囊生成及维持联系起来的发现不仅为新药开发提供了可能的靶点，同时它可能引向动物预防性疫苗的研发。鼠弓形体可以感染大部分的兽类和鸟类，但它在猫体内增殖，并通过粪便排出。人类可以通过接触污染的粪便或垃圾而被感染。人们同样可以经由食用未煮熟的肉类而感染。一种能保护猫和家畜免受感染的疫苗可以防止很大一部分人群被传染，Dr. Sullivan说。
发布于 2008-06-25 17:49:15 修改
Discovery of potential key to better drugs to fight Toxoplasmosis parasite
Discoveries by IU School of Medicine scientists have opened a promising door to new drugs for toxoplasmosis and other parasites that now can evade treatments by turning dormant in the body.
Their findings help explain how the parasite that causes toxoplasmosis transforms into a cyst form that resists drugs and the body\'s immune system, yet can emerge from its dormant state to strike when a patient\'s immune system is weakened.
Led by William J. Sullivan Jr., Ph.D., assistant professor of pharmacology and toxicology, and Ronald C. Wek, Ph.D., professor of biochemistry and molecular biology, the research team found a cellular signaling system that takes hold when the parasite is stressed, enabling it to transform into the cyst surrounded by a protective barrier.
The signaling system identified by the IU team could serve as a target to block the transformation into the cyst form or to attack the parasite while in the cyst form. Their report was published in the June 13 issue of the Journal of Biological Chemistry.
The Toxoplasma gondii parasite converts from an active state to the inactive cyst state when it is stressed, for example, by heat from fever. Stress response mechanisms have been well studied in yeast and other organisms, but the pathways used by the toxoplasmosis parasite had not been determined.
"We found a cellular signal that appears to put the parasite to sleep, which in turn tells us something new about how opportunistic pathogens such as Toxoplasma awaken to cause disease during immunosuppression," said Dr. Sullivan.
An estimated 60 million people in the United States are infected with the toxoplasmosis parasite, but for most infection produces flu-like symptoms or no symptoms at all. However, for people with immune system problems - such as those undergoing chemotherapy or people with AIDS - the disease can cause serious effects including lung problems, blurred vision and seizures. Also, infants born to mothers who are infected during or shortly before pregnancy are at risk for severe complications, miscarriages or stillbirths.
Medications to treat Toxoplasma gondii are effective but too toxic for extended use, and they don\'t affect the cyst form, said Dr. Sullivan.
"A healthy immune system can keep this parasite in the cyst state. Without a healthy immune system, this organism can run rampant," said Dr. Sullivan. "This can be a very serious problem for people with AIDS."
The discovery linking this stress-response mechanism to cyst formation and maintenance not only offers a possible target for new drugs, but it could also lead to a preventative vaccine - for animals.
The Toxoplasma gondii parasite can infect most animals and birds, but it reproduces in cats, which can shed the parasite in their feces. Humans can be infected through contact with the infected feces or litter. People can also become infected by consuming undercooked meat.
A vaccine to prevent infection in cats and livestock could prevent a significant proportion of human infections, Dr. Sullivan said.
The research of Drs. Sullivan and Wek is supported by the National Institutes of Health and the American Heart Association.
发现开发更有效抗弓形虫药物的钥匙印第安纳大学医学院的科学家们的发现给开发新的药物用于治疗弓形虫等寄生虫打开了一扇希望的大门，这些寄生虫目前在体内能以休眠状态逃避药物打击。他们的发现帮助解释了引起弓形虫病的寄生虫是如何转变成孢囊的形式来抵御药物和人体免疫系统，然后在免疫力下降的时候复苏攻击机体。该研究团队由William J. Sullivan Jr（博士，药理毒理学副教授）和Ronald C. Wek（博士，生物化学和分子生物学教授）领导，他们发现了一套细胞信号系统，当弓形虫处于应激状态时该系被激活，使它可以被一层防护屏障包围而成为孢囊。由印第安纳大学团队鉴别的这套信号系统可以作为阻断孢囊转化或攻击孢囊形式寄生虫的靶点。他们的报告发表在6月13号发行的生物化学杂志上。鼠弓形虫在应激情况如发烧受热时会从活化状态转化为非活化的孢囊状态。应激反应机制在酵母菌和其他生物体上已经研究得相当透彻，但弓形虫所使用的途径尚不明确。“我们发现了一个细胞信号，看起来它可以让寄生虫睡着，接着它让我们在条件致病菌如弓形虫如何在免疫抑制时复苏并致病方面了解了一些新的东西。” Dr. Sullivan说。据估计在美国有6千万人感染弓形虫，但多数仅表现为流感样症状或根本没有症状。但是，对于免疫系统异常者——如接受化疗的人或AIDS患者——这种感染能引起严重的问题如肺病、视力模糊和癫痫发作。同样，母亲在怀孕期间或孕前不久曾被感染，其婴儿将面临严重并发症、流产或死产的危险。“健康的免疫系统可以将这种寄生虫维持在孢囊状态，但没有了健康的免疫系统，这种生物将疯狂蔓延，” Dr. Sullivan说，“对于AIDS患者这是极其严重的问题。”这项将该应激反应机制和孢囊生成及维持联系起来的发现不仅为新药开发提供了可能的靶点，同时它可能引向动物预防性疫苗的研发。鼠弓形体可以感染大部分的兽类和鸟类，但它在猫体内增殖，并通过粪便排出。人类可以通过接触污染的粪便或垃圾而被感染。人们同样可以经由食用未煮熟的肉类而感染。一种能保护猫和家畜免受感染的疫苗可以防止很大一部分人群被传染，Dr. Sullivan说。
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