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Immune System Protein Starves 'Staph' Bacteria, Could Lead To New Treatments
ScienceDaily (Feb. 19, 2008) — One of the ways we defend ourselves against bacterial foes is to \"hide\" their food, particularly the metals they crave. A multi-disciplinary team led by Vanderbilt University investigators has now discovered that a protein inside certain immune system cells blocks the growth of \"staph\" bacteria by sopping up manganese and zinc.
The findings, reported Feb. 15 in Science, support the notion that binding metals -- to starve bacteria -- is a viable therapeutic option for treating localized bacterial infections. New treatment strategies are urgently needed to combat the surging number of infections and deaths caused by antibiotic-resistant forms of Staphylococcus aureus (staph), such as MRSA.
If recent estimates are accurate, the number of deaths caused by MRSA exceeds the number of deaths attributable to HIV/AIDS in the United States. \"Staph is arguably the most important bacterial pathogen impacting the public health of Americans,\" said Eric Skaar, Ph.D., assistant professor of Microbiology and Immunology and senior author of the study.
Staph is the leading cause of pus-forming skin and soft tissue infections, the leading cause of infectious heart disease, the number one hospital-acquired infection, and one of four leading causes of food-borne illness. \"And it seems as if complete and total antibiotic resistance of the organism is inevitable at this point,\" Skaar said.
The dire outlook motivates Skaar and his colleagues in their search for new antibiotic targets.
Skaar and Brian Corbin, Ph.D., postdoctoral fellow and lead author of the report in Science, reasoned that proteins present at the site of a staph infection might be important to the battle between the bug and the immune system, and might therefore make good targets for therapeutics. They took advantage of the fact that staph forms abscesses -- pimple-like infected areas -- in internal organs like the liver.
\"Because we can tell exactly where the infection is, we can look for proteins that are present only at the site of infection,\" Skaar said.
Using sophisticated technology called \"imaging mass spectrometry,\" the investigators identified dozens of proteins specifically expressed in staph abscesses in mice. They decided to focus on one that was particularly abundant.
The protein turned out to be calprotectin, which was discovered as a calcium-binding protein about 20 years ago and is known to inhibit bacterial and fungal growth in test tubes. But how it kills bugs was unclear.
The team demonstrated in a series of in vitro and in vivo experiments that calprotectin inhibits staph growth and that it does this by binding -- chelating -- nutrient metals, specifically manganese and zinc.
\"It basically starves the bacteria by stealing its food,\" Skaar said.
Calprotectin makes up about half of the internal content of neutrophils, the primary immune cells that respond to a staph infection. The investigators propose that calprotectin is a second weapon neutrophils employ as they wage battle in the abscess. First, neutrophils try to \"gobble up\" the bacteria. If they fail and die (staph is expert at secreting toxins that kill neutrophils), then they spill their guts, which are filled with metal-binding calprotectin sponges that soak up the metals.
\"The neutrophil gets the last laugh,\" Skaar quipped.
\"The work is a phenomenal merger of several cutting edge technologies, which collectively allow an unprecedented view of the host-pathogen interface,\" said Paul Dunman, Ph.D., assistant professor of Pathology and Microbiology at the University of Nebraska Medical Center, and a co-author of the Science paper. \"This discovery could lead to a new way to treat staph infections.\"
The findings suggest that drugs that bind metals -- like calprotectin does -- would make good antibiotics.
\"If we can figure out how to make a molecule that transiently binds metals, and that can be targeted to abscesses, I think that would be a great drug,\" Skaar said.
Walter Chazin, Ph.D., Richard Caprioli, Ph.D., and members of their teams at Vanderbilt were key to the studies, as were collaborators at the University of Aberdeen, Scotland, the University of Nebraska Medical Center, the University of Muenster, Germany, and Applied Speciation and Consulting in Washington. The research was supported by the Searle Scholars Program, the Burroughs Wellcome Fund, the National Institutes of Health, and the Department of Defense.
http://www.sciencedaily.com/releases/2008/02/080214144506.htm
ScienceDaily(2008年2月19日) 我们对抗细菌的方法之一是阻断它们的”食物”来源,尤其是它们所渴求的金属.范德堡大学的一个多学科综合研究小组的研究者们现在发现存在于特定的免疫细胞中的一种蛋白可以阻断葡萄球菌属细菌的生长所需要的微量元素锰和锌.
由2月15日Science报道的这项发现,进一步支持了在抵抗局部细菌感染的时,阻止金属生长需要的微量元素的吸收是一种有效的治疗方法.这种新的治疗策略对于那些由于诸如甲氧西林耐药性的金黄色葡萄球属所引起的感染和死亡的人们来说是迫切需要的.
如果最近的估计是准确的,在美国,由于MRSA(甲氧西林耐药金黄色葡萄球菌)引起的死亡人数超过了由于HIV/AIDS造成的死亡人数.这项研究的主要负责人、微生物与免疫学助理教授 Eric Skaar博士说:”葡萄球菌属可能是威胁美国公共卫生的最为重要的细菌性病原体.”
葡萄球菌属是皮肤和软组织化脓和感染性心脏病的最主要原因,处于医院内获得性感染病因的第一位,占食物传染疾病病因的四分之一. Skaar说,”而且,在这一点上机体的抗生素耐药性似乎是不可避免的.
这种令人恐惧的形势使Skaar和他的同事们去努力寻找抗生素的新靶位.
Skaar和这份报道首要负责人,博士后研究员Brian Corbin博士详细论述了这种在葡萄球菌属感染时出现的蛋白可能在病原和免疫系统的”战争”中是重要的,并且可能在治疗上提供了一个很好的的靶点.他们利用了葡萄球菌属感染脓肿时的形式在如肝脏等内脏器官小脓疱样的感染区域的事实.
“由于可以确定感染灶在哪里,我们因此能够寻找只有在感染的位置才存在的特定蛋白.” Skaar说.
利用叫做” 质谱分析成像”的精密技术,研究人员可以鉴别数十种在小鼠脓肿上特异表达蛋白.他们决定把目标锁定为含量特别丰富的一种蛋白.
这种蛋白被证明是钙卫蛋白.钙卫蛋白是一种20年前发现的,能够在试管中抑制细菌和真菌生长的钙结合蛋白.但是它是怎样杀死病原菌一直不得而知.
这个研究小组通过一系列的体外和体内试验证明钙卫蛋白能够抑制葡萄球菌属的生长,并且是通过黏合和螯合(细菌的需要的)营养微量元素,特别是锰和锌.
\"It basically starves the bacteria by stealing its food,\" Skaar said.
Skaar说,它主要是通过”偷窃”营养物质来把细菌”饿死”.
钙卫蛋白能够弥补体内大约一半的在葡萄球菌属感染时产生的初级免疫细胞——中性粒细胞(的作用).研究人员认为钙卫蛋白是中性粒细胞所雇用的第二种武器.首先,中性粒细胞试图去杀死细菌.一旦它们失败或者死亡(葡萄糖球菌属擅长分泌能够杀死中性粒细胞的毒素),它们(中性粒细胞)的胞液释放,胞液中充满了能够像海绵一样大量粘附金属微量元素的钙卫蛋白,从而粘附大量的微量元素.
Skaar开玩笑说:”中性粒细胞笑到了最后.”
此篇论文的合作者,内布拉斯加州大学医学中心病理学和微生物学助理教授Paul Dunman博士说:” 这项工作合并了若干反而前沿技术，它们共同允许在一个前所未有的界面来研究宿主和病原体.
这项发现说明如钙卫蛋白那样吸附微量元素的药物将产生很好的抗菌性.
如果我们能制备短暂吸附微量元素的分子,并且将它们定向的注入脓肿中,我想,这将是一个伟大的药物,” Skaar说.
Walter Chazin博士、Richard Caprioli 博士和他们在范德堡大学的同事是这项研究的核心成员,另外还有苏格兰阿伯丁大学、内布拉斯加大学医学中心、德国Muenster大学、华盛顿应用形态和咨询中心的研究人员。这项研究是由”西尔学者计划” 、 Burroughs Wellcome基金会、国立卫生研究院和国防部共同资助的。 |
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发表于 2008-3-11 07:47:50