民族舞山丹丹红艳艳:为何结核病如此难以治愈

微生物分裂时，大多数情况下你看到的情景是这样的：一个细胞分裂，产生两个一模一样的自身拷贝。但是新的研究发现造成人类结核病的分枝杆菌不是这样分裂的，这也解释了为何这种疾病如此难以治愈。分枝杆菌以不平衡的形式进行分裂，创造了大量以不同速度生长的细胞群，这些细胞拥有不同的体积，对抗生素也拥有不同程度的敏感性，这增加了一些细菌幸免于难的几率。研究者希望通过这些发现帮助他们研发新药，对付这种极其难以歼灭的细菌。

"It is incredible that we are finding such basic things out only now," says immunologist Sarah Fortune of at the Harvard School of Public Health in Boston, the paper's lead author. "But it reflects the fact that mycobacteria are relatively understudied." 

这份论文的第一作者，一名来自哈佛·波士顿公共卫生学院的免疫学家——萨拉·佛茜说：“目前我们发现的这一基本事实，真是不可思议。但这也表明对分枝杆菌的研究还是不充分的。”

More than a third of the world's population is estimated to be infected with Mycobacterium tuberculosis. Most people's immune system can keep the bacteria in check, but there is a lifetime chance of 1 in 10 that the dormant infection will progress to TB; the disease still kills 4000 people every day. Tuberculosis treatment is a combination of antibiotics taken for half a year or more—a major drawback, because patients often quit therapy prematurely, increasing the risk of drug-resistant strains emerging. Scientists have assumed that mycobacteria are so hard to kill because dormant cells exist even in patients with active disease and these cells are far less susceptible to antibiotics than metabolically active bacteria. 

全世界估计有三分之一的人口感染了分枝杆菌结核病。大多数人能够将此细菌控制住，但是在病人的一生中，这种“休眠的感染”有十分之一的几率发展为结核病，它每天仍然使4000人送命。我们对结核病采取半年左右的抗生素联合治疗，而这是该治疗的一个主要缺陷，因为病人常常过早停止抗生素治疗，致使抗药菌株出现的风险大为增加。科学家猜测分枝杆菌之所以如此难对付，是因为休眠的细菌即使在病情严重的病人体内也存在，而且它们远比新陈代谢活跃的细菌更能抵挡抗生素的攻击。1

But Fortune and her colleagues found a second, more surprising mechanism. They cultured M. smegmatis, which is closely related to M. tuberculosis but faster growing, in a tiny chamber with a constant flow of nutrients, allowing them to watch single live cells growing and replicating. Unlike other rod-shaped bacteria, such as E. coli, mycobacterial cells divided asymmetrically, creating a tapestry of cell types with widely different sizes and growth rates, the team reports online today in Science. 

但是佛茜和她的同事发现了第二种更为惊人的机制。他们在小室中培育了一种齿垢分枝杆菌，并不停地给它提供营养液，以便观察单个细胞群的生长和复制；这种细菌与分枝杆菌联系极密切，但它的生长速度更快。今天，此研究组在《科学》杂志网络期刊上报道说，与其他杆状细菌（像是E. coli细菌）不同，分枝杆菌的细胞分裂是不平衡的，它产生一系列不同的细胞类型，具有差别巨大的大小尺寸和生长速度。

By labeling the cell wall of the mycobacteria with a fluorescent dye and observing the new, unstained cell wall growing at the poles, the researchers found that daughter cells mainly grow at their "old" pole. As the new end, created by the cell division, grows older, it matures and the cell elongates faster. And as the cells go through numerous divisions, cells with poles of many different "ages" emerge, leading to the wide variety in growth rates. 

研究人员用荧光染料标记分枝杆菌的细胞壁，并且观察在细胞两极新生长的未标记细胞壁，他们发现子细胞主要聚在细胞“旧极”生长。细胞分裂产生的新端逐渐变老，同时也逐渐成熟，而细胞则愈加迅速地伸长。当细胞分裂无数次后，拥有不同“年龄”两极的细胞也就产生聚集了，因此导致了它们相差巨大的生长速度。

Importantly, the cells also differed in their susceptibility to antibiotics: While "older," fast-growing cells were more susceptible to the drugs isoniazid and cycloserine; younger, slower-growing cells were more susceptible to rifampicin. "When I started working on mycobacteria, the assumption was that all the bacteria are indistinguishable. This is the first mechanistic insight into why the cells are phenotypically different," says Fortune. The asymmetry is a way for mycobacteria to keep their population diverse, she says, just like viruses create diversity by mutating frenetically. 

细胞群对抗生素的敏感程度也不尽相同，这一点非常重要。“老的”、生长迅速的细胞更容易被抗生素异烟肼（isoniazid）、环丝氨酸（cycloserine）所杀灭；“年轻的”、生长缓慢的细胞则更易受利福平（rifampicin）影响。“开始研究分枝杆菌时，我猜想这些细菌都是不可辨别的。对为何这些细菌有不同表型，这是第一种机械观点。”萨拉如是说。她说，不平衡的（分裂）是分枝杆菌保持它们种族多样性的方式，就像病毒疯狂地变异一样。

"This is an important study, because it shows that our way of thinking that populations are the sum of equal organisms is incorrect," says immunologist Stefan Kaufmann of the Max Planck Institute for Infection Biology in Berlin. "As we look at individual microbes, we find diversity." Kaufmann cautions, however, that most of the experiments were done with M. smegmatis and need to be verified with M. tuberculosis. "But this could explain, at least in part, why tuberculosis is so hard to treat," he says. "And it could pave the way for a rational search for new combination therapies composed of drugs that attack the different types of bacteria."

斯蒂芬·考夫曼， 一位来自柏林的马克思·普朗克学院传染生物系的免疫学家说：“这项研究具有重大意义，因为它证明‘生物群体都是完全相同的有机体’这种思维的错误性。当我们仔细观察微生物时，我们发现它们是丰富多样的。” 当然，考夫曼提醒道，大部分实验都是以齿垢分枝杆菌为对象开展的，这需要通过结核分枝杆菌的实验来验证。他补充道：“这至少部分解释了为何结核病难以治愈，而且对于探索出一种消灭不同类型病菌的药物联合疗法奠定了理性的基础。”