Molecular mechanisms modulating host epithelial integrity in response to bacterial adhesion

我们最近发现了一个粘连蛋白家族，叫做MAMs，许多不同的细菌在感染期间利用这些粘连蛋白与宿主组织接触。我们还观察到，如果许多mam聚集在宿主细胞表面，这会改变宿主内部的信号传递过程，使其更容易受到感染。我们想了解哪些宿主信号蛋白被MAMs激活，以及MAMs如何启动这些信号过程。回答这些问题有很多好处：首先，我们将能够将MAMs转化为对抗细菌感染的新药，称为粘附抑制剂。这些物质的作用是粘附在宿主细胞上，阻止致病菌附着。如果病原体不能附着自己，它们就会被排出机体而不会引起感染。如果我们能够了解基于mam的分子必须是什么样子才能真正与宿主紧密结合（这样它们就能更好地抵御病原体），但又不会对细胞本身造成伤害，我们将能够制造出可以替代抗生素的新药。优点是它们将在很长一段时间内有效，因为细菌不容易对粘附抑制剂产生抗药性。其次，在更遥远的将来，我们可能能够使用MAMs使其他药物更有效。许多药物不能口服或根本不能使用，因为它们不能穿过肠道和血液之间的屏障。MAMs的一些特性使生物体更容易受到感染，这些特性也可能转化为有用的东西。-它们可以用来使身体的某些组织在短时间内“渗漏”，这样就更容易获得药物。这将增加有效药物的总数，以及可口服而非注射的药物的数量。

We recently found a family of adhesins, called MAMs, and many different bacteria use these sticky proteins to make contact with host tissues during an infection. We have also observed that, if many MAMs are brought together on the host cell surface, this changes signaling processes within the host so that it becomes more prone to infection. We want to understand what host signaling proteins are activated by MAMs and how MAMs can start these signaling processes. There are many benefits to answering these questions: First, we will be able to turn MAMs into new drugs against bacterial infections, called adhesion inhibitors. These materials work by sticking to host cells and stopping pathogenic bacteria from attaching themselves. If pathogens cannot attach themselves, they are flushed out of the organism without causing an infection. If we can understand what MAM-based molecules have to look like to bind to the host really tightly (so they are better at fending off pathogens) but without causing harm to the cells themselves, we will be able to make new drugs which can be used instead of antibiotics. The advantage will be that they will be effective for a long time to come, because bacteria cannot easily become resistant against adhesion inhibitors. Second, in the more distant future, we may be able to use MAMs to make other drugs more effective. Many drugs cannot be taken orally or cannot be used at all because they cannot cross the barrier between the intestine and the blood stream. Some of the properties of MAMs that make an organism more prone to infection may also be turned into something useful. - They can be used to make certain tissues of the body "leaky" for a short period of time so that they are easier accessible for drugs. This will increase the number of useful drugs altogether and the number of drugs that can be taken orally, rather than by injection.