Adhesion to host cell membrane microdomains in cornea as an antimicrobial target to prevent corneal ulceration

在世界各地，抗生素的问题越来越严重：患者、医生甚至农民多年来一直在滥用抗生素，以求从牲畜中获得更高的产量，结果是微生物已经学会了忍受这些曾经有效的药物。这个问题在印度尤其严重，在那里，获得专业医疗保健的机会往往有限，因此患者购买和使用无效的抗生素。对于农业和家庭劳动者来说，眼睛表面的轻微损伤往往会导致细菌和真菌感染；如果治疗不当，可能会导致角膜溃疡，最终导致失明。对于工作年龄的人来说，这可能会给他们和他们的家庭带来灾难性的经济后果。鉴于这些问题，我们现在正在寻找一种替代方法来保护眼睛免受微生物的侵害。我们已经与领先的眼科医院LV Prasad眼科研究所建立了合作伙伴关系。LVPEI开发了一个金字塔结构，以便在海得拉巴的高级研究和手术中心开发的研究可以在其组织内迅速传播。他们的主要动力是开发能让农村患者受益的疗法。我们采取的方法最初来自一项关于我们的细胞如何粘在一起形成皮肤等组织的研究。细胞表面有类似尼龙搭扣的结构，这是一种高度组织化的粘性分子斑块，使细胞能够紧密结合在一起。在某些情况下，它们是持久的和静态的；在另一些情况下，它们是短暂的和动态的，允许移动，例如当我们的白细胞通过组织到达感染部位时。我们发现，某些类型的细菌和酵母菌可以“劫持”动态位置，即使我们的天然防御系统试图用泪水和眨眼把它们赶走，它们也能粘在我们的组织上。这是感染的起点，当一群微生物附着并开始生长时，通常会更深地渗透到组织中，导致严重疾病。即使是表面感染也会引起问题，如果治疗不当，会导致眼表溃烂，最终导致失明。不同类型的微生物使用不同类型的人类分子来附着：以所有这些分子为靶标将非常昂贵。我们的方法不是针对分子钩本身，而是针对它们所在的材料，以形成粘性斑块。在尼龙搭扣上，钩子嵌在编织材料的底层中，但在我们的细胞上，这是由一种称为微域的分子筏形成的。我们已经发现了如何削弱一种类型的微域，以一种类似于拉伸尼龙搭扣的方式，将分子钩拉得更远，并显著降低细胞上贴片的粘性。通过只处理一种类型的微域，我们发现我们不会影响细胞的正常行为，但我们确实使细菌和真菌更容易被清洗掉。与直接针对微生物的抗生素不同，我们的治疗针对的是人类细胞，因此不应导致新形式的抗生素耐药性。如果我们能证明它对在印度引起眼睛感染的微生物类型既安全又有效，我们的目标是为眼睛受伤或患有早期感染的人生产一种廉价而简单的治疗方法。这可以由患者或训练有素的志愿者网络轻松快速地实施。通过帮助预防感染，或给予更多时间寻求专业诊断，我们希望降低印度年轻人常见失明原因的比率。

All over the world, there is a growing problem with antibiotics: there have been years of misuse by patients, doctors and even farmers seeking greater yields from livestock, with the result that microbes have learned to live with these once potent drugs. This problem is particularly acute in India, where access to professional healthcare is often limited and so ineffective antibiotics are bought and used by patients. For agricultural and domestic labourers, minor damage to the surface of the eye frequently results in bacterial and fungal infections; when not properly treated, this can lead to corneal ulceration and, eventually, to blindness. In a working-age person, the economic consequences can be disastrous for them and thier families. Given these issues, we are now looking for an alternative route to protect eyes against microbes. We have formed a partnership with a leading eye hospital, LV Prasad Eye Institute. LVPEI have developed a pyramidal structure so that research developed in the advanced research and surgery centre in Hyderabad can rapidly be disseminated throughout their organisation. They have a major drive to develop therapies that can benefit patients in rural villages.The approach that we have taken came originally from a study of how our cells stick together to form tissues such as skin. There are structures on the surfaces of cells that resemble Velcro, highly organised patches of adhesive molecules that enable cells to cling tightly together. In some cases, these are long-lasting and static; in other cases they are short-lived and dynamic, allowing mobility, for instance when our white blood cells are travelling through tissues to get to the site of an infection. We discovered that some types of bacteria and yeasts can 'hijack' the dynamic sites, to allow them to stick to our tissues even when our natural defences try to dislodge them with tears and blinking. This is the starting point of an infection, when a colony of microorganisms attaches and starts to grow, often then penetrating deeper into tissues to cause serious disease. Even superficial infections can cause problems, leading to ulceration of the surface of the eye and eventually blindness if not properly treated. Different types of microbes use different types of human molecules to cling to: targeting all of them would be very expensive. Our approach is not to target the molecular hooks themselves, but the material in which they are held to form the sticky patches. On Velcro, hooks are embedded in a baselayer of woven material but on our cells this is formed by a sort of molecular raft called a microdomain. We have discovered how to weaken one type of microdomain, in a way that is analagous to stretching Velcro, pulling the molecular hooks further apart and significantly lowering the stickiness of the patches on cells. By addressing only one type of microdomain, we have found that we do not affect the normal behaviour of our cells but we do make bacteria and fungi much easier to wash away.Unlike antibiotics that directly target microbes, our treatment targets human cells and so should not lead to new forms of antibiotic resistance. If we can show that it is both safe and effective on the types of microbes that cause eye infections in India, we aim to produce a cheap and simple treatment for people who have injured their eyes, or who have early stage infections. This could be administered by patients or by a network of trained volunteers, easily and quickly. By helping to prevent infection, or giving more time to seek professional diagnosis, we hope to reduce the rate of a common cause of blindness in young people in India.