官微已推送--新研究解释了为什么常见的细菌能产生严重的疾病

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新研究解释了为什么常见的细菌能产生严重的疾病

翻译：莫延花    审核：陈志锦

尽管我们不断地尽量避免与周围的人“共享”细菌，但即使两个人感染了相同的细菌，所造成的疾病也可能会有很大的不同——对于一个人来说只是轻微的感染，而另一个则可能是危及生命的严重感染。

现在，洛克菲勒大学的新研究提供了对这些差异发生的解析。传染病人类遗传学圣吉尔斯实验室负责人兼霍华德·休斯医学研究所研究员——Jean-Laurent Casanova领导的研究小组发现了有两个不同的条件：遗传免疫缺陷和延迟获得性免疫，二者结合可以产生危及生命的感染。

2月23日，卡萨诺瓦和他的团队在《细胞》在线发表的研究中，专门研究了一个身体健康年轻女孩因常见菌引发的致命感染病例。我们大多数人身上定植着这种名为金黄色葡萄球菌的细菌，主要存在于我们的皮肤和鼻孔中。它可以导致轻微感染，通常称为“葡萄球菌感染”，但在某些人中，会导致严重的疾病。

这位年轻女孩的病情很不可思议：她没有任何已知的危险因素会导致急性感染的发生，并且她的家人都没有任何感染。因此，Casanova和他的团队只能通过调查可能导致更容易受到金黄色葡萄球菌影响的DNA突变，才能确定其疾病的根本原因。

很快，他们发现了一个可能的罪魁祸首——两个被称为TIRAP的基因中，其阿红一个编码字母被替换了，因而被特定的免疫细胞标记为入侵细菌。

在实验室试验中，研究人员发现，TIRAP对细胞免疫系统防御入侵者的第一道防线来说至关重要。这些细胞在我们出生之前发育的细胞,往往存在于入侵者表面，充当着内置识别系统的角色。

Casanova说：“我们确信这是对葡萄球菌疾病严重程度的解释，我们认为我们确实已经找到了。”

但事情变得更加复杂。为了验证他的假设, Casanova决定分析病人其他家庭成员的DNA。他们没有受到严重的葡萄球菌感染,所以他们应该有正常的TIRAP基因。然而,他的发现却相反,她的七名家庭成员均与她一样，存在相同的基因突变。

研究人员现在有两个问题，而不是只有一个：为什么这个孩子得了侵袭性疾病？为什么她的家人尽管均存在免疫妥协突变，但免疫系统表面上看起来仍然正常？

答案在于免疫防御的第二道防线，在出生时并没有在我们的DNA编码中。这些二级防御依赖于细胞对抗外来化合物时产生的抗体。卡萨诺瓦解释道：“这不是与生俱来的,而是我们接触到新的病原体时,获得的永久性的抵抗力。”

研究人员还发现,患者缺乏针对单个分子的抗体，被称为LTA，但她所有家庭成员的LTA水平是正常的。LTA存在于葡萄球菌的细菌表面，通常能被两道防线的免疫细胞所辩别。

针对LTA的抗体能够恢复培养系统中患者免疫细胞的功能，研究人员将继续使用该病的小鼠模型确认他们的假设。

这个结果解析了为什么该患者出现了致命感染，但其家人却没有。Casanova解释说：“她的病可能是由于两种免疫系统的失败造成的。对于她的家人来说，第二层防线弥补了第一道防线的遗传缺陷。更广泛的一点，这也解析了两个人感染细菌相同，甚至有同样的免疫DNA，也可能发展为完全不同的疾病。”

※原文：

New Research Explains Why a Common Bacterium Can Produce Severe Illness

As much as we try to avoid it,  we are constantly sharing germs with those around us. But even when two people have the same infection, the resulting illnesses can be dramatically different -- mild for one person, severe or even life-threatening for the other. Now, new research from Rockefeller  University offers insights into how these differences arise. Jean-Laurent Casanova, head of St. Giles Laboratory of Human Genetics of Infectious Diseases and Howard Hughes Medical Institute Investigator, led a team of researchers to uncover how two different conditions--a genetic immunodeficiency and delayed acquired immunity--can combine to produce a life-threatening infection.

In the research, published online on February 23 in Cell, Casanova and his team focused on the case of an otherwise healthy young girl who developed a life-threatening infection from a very common strain of bacterium. Most of us carry this microbe, known as Staphylococcus aureus, on our skin and in our nostrils. It can cause minor infections (often referred to as "staph infections"), but in some people, it results in severe disease.

The young girl's illness was mysterious: she had no known risk factors that would lead her to develop the acute form of the disease, and none of her family members had contracted it. So Casanova and his team set out to define the underlying cause of her disease by searching her DNA for mutations that might make her more susceptible to staph disease.

They quickly identified a likely culprit--a single letter substitution in the two copies of a gene that encodes for a protein known as TIRAP, used by specific immune cells to flag invading bacteria.

In laboratory experiments, the researchers found that TIRAP is critical for cells in the immune system's first line of defense against invaders. These are cells that develop before we are born, with built-in recognition systems for a host of molecules that are frequently present on the surface of invaders.

"We were sure this was the explanation for the severity of her staphylococcal disease," says Casanova. "We thought we had it all figured out."

But things turned out to be more complicated. To test his hypothesis, Casanova decided to analyze the DNA of other members of the patient's family. They hadn't suffered from severe staph infections, so they should have had normal TIRAP genes. However, he found the opposite--all seven members of her family had the same mutation as the young patient.

The researchers now had two questions instead of just one: Why did this child get the invasive disease? And why were the rest of her family seemingly immune, even though they shared her immune-compromising mutation?

The answers lie in a second line of immune defense that is not encoded within our DNA at birth. These secondary defenses are dependent on cells that generate antibodies against foreign compounds. "This is not something we are born with, but instead it is resistance that we acquire over the course of our lifetime when we are exposed to new pathogens," Casanova explains.

The researchers found that the patient lacked antibodies against a single molecule, known as LTA, but the levels were normal for all of her family members. LTA is present on the surface of staphylococcal bacteria, and normally it is recognized by immune cells in both lines of defense.

The antibodies against LTA were able to restore the function of the patient's immune cells in culture systems, and the researchers went on to confirm their hypothesis using a mouse model of the disease.

The results explain both why the patient developed life-threatening disease and why her family members didn't. "Her illness likely resulted from failures in both lines of immunity. In her family, the second layer of defense compensated for genetic defects in the first," explains Casanova. "More broadly, it offers insight into how two people with the same infection, and even the same DNA, can have very different illnesses."

Source: Rockefeller University

中原一点红

我们的人体防线竟然这样重要，在不知不觉中做出如此大的贡献

七宝

路过学习了，谢谢老师的分享。

lyluoxiuhua

尽管我们不断地尽量避免与周围的人“共享”细菌，但即使两个人感染了相同的细菌，所造成的疾病也可能会有很大的不同——对于一个人来说只是轻微的感染，而另一个则可能是危及生命的严重感染。

兰兔

二级防御依赖于细胞对抗外来化合物时产生的抗体。