Video在线视频

大家好 
-Hello.

我是Olivier Neyrolles
My name is Olivier Neyrolles

我在图卢兹的药理学
and I work at the Institute

和结构生物学研究所工作 
of Pharmacology & Structural Biology in Toulouse.

在这堂课中
In this part of the MOOC,

我会讲述治疗结核病的新策略 
I will tell you about novel strategies for the treatment of tuberculosis.

首先
First,

是一些关于结核病的知识 
a few things about tuberculosis.

据世界卫生组织称
As you know,

结核病仍然是全球性的重要疾病
it is still a global emergency with more than 10 million new cases every year,

每年有超过一千万的新病例
nearly 2 million deaths every year,

近两百万人死亡
and half a million of drug-resistant tuberculosis

50万耐药结核病（或许是低估的数字） 
which is probably an underestimation of the reality, according to the WHO.

有什么办法来防治结核病呢
What means do we have to fight tuberculosis?

我们有卡介苗
We have a vaccine, the BCG,

但对预防传染性疾病
but it is not efficacious enough to prevent transmissible forms of the disease,

成人肺结核没有效果
pulmonary tuberculosis in adults,

而且抗生素治疗负担太大 
and we have an antibiotic treatment that is too heavy.

每天至少要服用四种药物 
It is at least four drugs that have to be taken daily.

对于耐药性强的结核病来说治疗时间太长
It is too long, at least 6 months and up to 2 years

最少6个月 最长2年 
in the case of very resistant tuberculosis.

即使在成功的情况下
And this treatment can have some consequences on the patient,

这种治疗也会对患者产生一些后果 
even in case of success.

例如
For instance,

一些药物表现出肝毒性 
some of these drugs show some hepatotoxicity.

而且 这些药物可能会在肺部留下后遗症
And also, these drugs can leave some sequelae in the lungs

会导致患者生活质量下降 
which leads to consequences in terms of quality of life of the patient.

所以我们需要可以与常规治疗
So we need new treatments that could be used

结合使用的新疗法 
in combination with these conventional treatments.

关于病原体结核分枝杆菌生命周期的几句话 
A few words about the lifecycle of the pathogen, Mycobacterium tuberculosis.

它通过气溶胶从受感染的宿主传播
It is transmitted from an infected host

到非感染宿主 
to a non-infected host via aerosol.

在大多数情况下
And in most cases,

90％-95％的病例中
90 to 95% of the cases,

感染被包含在一个非常特殊的结构中
the infection is contained in a very special structure

称为肉芽肿 
that is called the granuloma.

这是一个非常有组织的多细胞结构
It is a very well-organized multicellular structure

具有非常特殊的特征
that has very specific characteristics

并且是含氧量极低 
and is very hypoxic.

这导致细菌进入
This leads to the entry of the bacterium into a metabolic state of

称之为休眠的代谢状态 
what we call dormancy.

在这种状态下
In this state,

细菌不再生长或繁殖 
the bacterium does not grow anymore or multiply.

它可以保持这样的状态几年甚至几十年
It can stay like this for years or even decades

直到再度活化
until it reactivates,

在5％的病例中
in 5% of the cases,

导致逐渐破坏肺组织液化的
leading to an exacerbation of the immune response

免疫应答的恶化
which progressively destroys the lung tissue by liquefaction,

这是结核病的标志 
which is a hallmark of tuberculosis.

除了基于抗生素的常规治疗之外
In addition to conventional treatments that are based on antibiotics,

我们现在想要的
what we want now are additional treatments

是可以与这些治疗组合使用的附加治疗 
that could be used in combination with these treatments.

我们能想到的
What we can think of is,

首先是针对病原体的病毒性 
first, targeting the virulence of the pathogen.

这就是所谓的抗病毒治疗 
This is called antivirulence treatments.

而且我们也可以考虑针对宿主本身 
And we can also think about targeting the host itself.

这就是我们所说的宿主导向疗法 
This is what we call host-directed therapy.

在这种情况下
In this case,

我们可以想象
we can imagine,

例如
for instance,

可以帮助受感染的免疫细胞
compounds that could help the infected immune cells,

如巨噬细胞来控制病原体的化合物 
like macrophages, to control the pathogen.

我们也可以考虑能够减少
We could also think about compounds

肺部组织炎症的化合物
that could reduce the inflammation of the lung tissue

肺部组织炎症是结核病的标志 
which is a hallmark of tuberculosis.

首先 关于细菌 
First, regarding the bacterium.

你需要知道和记住的是
What you need to know and to keep in mind

用于治疗结核病的所有药物
is that all the drugs that are used to treat tuberculosis target very essential processes

都针对细菌生理学中的基本过程
in the physiology of the bacterium,

例如RNA、DNA、蛋白质和ATP的合成 
such as the synthesis of RNA, of DNA, of proteins, of ATP.

这面临非常强的选择压力
This is such a strong selective pressure that,

如果细菌群体中
if you have one mutant in a population of bacteria

有一个突变体对这种化合物有耐药性
that is resistant to this compound,

它将导致所有的耐药细菌迅速地无性增殖 
it will lead to the very rapid clonal expansion of a globally resistant population of bacteria.

相反
Instead,

如果针对细菌生命周期中不那么重要的过程
if you target less essential processes in the lifecycle of the bacterium,

那么将会减少细菌的数量
you will stress the bacteria less,

这将导致结核分枝杆菌耐药性无性扩增
which will lead to no or less expansion of resistant clones

或不扩散 
of M. tuberculosis.

病原体病毒性的哪些关键部分
What key steps in the virulence of the pathogen

是我们可以设想的目标呢
could we imagine to target?

有两个明显的关键部分 
There are two obvious key steps.

一是细菌在巨噬细胞内繁殖的能力 
The first is the ability of the bacterium to multiply inside macrophages.

这是一种感染患者肺部的巨噬细胞 
This is an infected macrophage taken from the lung of an infected patient.

你可以看到细菌在这些细胞中疯狂繁殖 
You can see that the bacteria multiply like crazy in these cells.

如果能阻止这些细菌获得营养物质（例如铁）
If you can block the ability of these bacteria to acquire nutrients, such as iron,

就可以减少细菌在细胞内的适应性 
you could reduce the fitness of the bacteria inside the cell.

二是细菌能够持续存在于
The second step we can imagine to target is the ability of the bacterium

这些低氧的病变肉芽肿中 
to persist in these hypoxic lesions, the granuloma.

在这方面 我想引用2017年出版的
In this context, I wanted to quote a very important publication

一本非常重要的出版物
that was published in 2017,

作者可以确定抑制这种称为DosR的
in which the authors could identify a compound

转录调节因子的化合物
that inhibits this transcriptional regulator called DosR

其控制细菌在缺氧条件下的存活能力 
that controls the ability of the bacteri to survive in hypoxia.

如果能抑制DosR
If you can inhibit DosR,

那么就能抑制细菌在肉芽肿中存活的能力 
then you will inhibit the ability of the bacteria to survive in the granuloma.

现在
Now,

就宿主导向疗法而言
regarding host-directed therapy, this is something that is imagined,

不仅是结核病
not only in the context of tuberculosis,

而且在其他传染病方面都存在想象空间 
but also of other infectious diseases.

您可以想象帮免疫系统清除细菌
You can imagine helping the immune system to clear the bacteria

并减轻组织发炎程度 
and also helping the tissues to not get too inflamed.

我会给几个在这方面非常成功的药物例子 
I will give you a few examples of very successful drugs that were used in this context.

两种分别用于治疗癌症和糖尿病的药物
Two drugs, imatinib and metformin,

伊马替尼（imatinib）和二甲双胍（metformin）
that are used to treat cancer and diabetes respectively,

成功用于刺激巨噬细胞
were successfully used to stimulate macrophages

并帮助它们杀死细胞内的分枝杆菌 
and help them kill intracellular mycobacteria.

包括多西环素（doxycyclin）
Other drugs, including doxycyclin,

磷酸二酯酶E4的抑制剂（CC-11050）
CC-11050, an inhibitor of the phosphodiesterase E4,

和齐留通（zileuton属于5-酮脂氧合酶抑制剂）等
and zileuton, an inhibitor of 5-lipoxygenase,

其他药物已成功用于小鼠
were successfully used in mice to reduce the lung inflammation

以减少与肺结核感染有关的肺部炎症 
associated with tuberculosis infection.

在伊马替尼（imatinib）的案例中
In the case of imatinib,

通过一些数据可以看到
to give you some data,

在这个共聚焦显微镜图片中
you can see on this confocal microscopy pictures macrophages infected

巨噬细胞感染红色细菌表达红色荧光蛋白 
with red bacteria expressing red fluorescent proteins.

如果用伊马替尼（imatinib）刺激这些细胞
If you stimulate these cells with imatinib

并用绿色的LysoSensor染料染色细胞中的
and you stain the acidic compartments in the cells in green,

酸性区域
using this LysoSensor dye,

就能看到细菌被运送到细胞内的酸性区域 
you can see that the bacteria are trafficked to acidic compartments inside the cell.

而这些酸性区域对细菌是非常不利的 
And these acidic compartments are very hostile to the bacteria.

使得转化为细胞内细菌的数量
This translates to a very strong reduction in the number of intracellular bacteria

剧烈减少 
inside the cells.

现在
Now,

如果阻断巨噬细胞酸化其细胞区域的能力
if you block the ability of the macrophages to acidify its intracellular compartments,

使用一种叫做concanamycin A的药物
using a drug called for instance concanamycin A,

那么伊马替尼（imatinib）就会失去
then you lose the ability of imatinib

减少细胞内细菌数量的能力 
to reduce the number of intracellular bacteria.

这些实验证明伊马替尼（imatinib）
These experiments really demonstrate

可以通过将细菌运输至酸性区域
that imatinib can help the macrophages control intracellular Mycobacterium tuberculosis

来帮助巨噬细胞控制细胞内的结核分枝杆菌 
by trafficking the bacteria to acidic compartments.

总之
In conclusion,

我想在这个视频中传达的信息是
the message I wanted to convey in this video is that,

除了传统方法
in addition to conventional strategies like vaccines and antibiotics,

如疫苗和抗生素
and of course we need to identify new vaccines and antibiotics,

我们既需要研发新的疫苗和抗生素
we also need to imagine new, unconventional treatments,

还需要新的 非常规的治疗 抗微生物治疗
antivirulence treatments and host-directed therapies

和可以与常规治疗结合使用的宿主定向疗法 
that could be used in combination with conventional treatments.

非常感谢您的关注 
I thank you very much for your attention.