Does hospitalisation of older patients with severe community acquired pneumonia and sepsis lead to long term immunoparesis?

肺炎是一种严重的肺部感染。肺炎是第五大死亡原因，每年每1000名成年人中就有11人在医院外患上肺炎，其中每100人中就有1人死亡。如果病人病情严重到需要住院，死亡率就会高得多，如果出现败血症的并发症，死亡率就会大幅上升。败血症是一种综合症，感染导致人体自然免疫系统发生变化，最终导致肺、大脑和心脏等器官受损。老年人更容易患肺炎，患败血症的风险更高，结果更差（100人中有30人在6个月内死亡）。治疗肺炎的主要方法是抗生素。老年人往往不能完全康复。肺炎发作会导致身体更加虚弱，老年人需要更多的社会支持或住进养老院。肺炎后，老年人更容易发生继发性感染。这包括另一种肺炎，但也包括身体其他部位的感染。继发性感染的后果甚至更糟，但老年人容易感染的原因尚不清楚。目前还没有治疗方法可以帮助免疫系统克服肺炎。鉴于我们的人口正在老龄化，这是一个巨大的未满足需求的领域。中性粒细胞是对抗感染的关键白血球。它们离开血液，准确地移动（迁移）到感染区域，在那里它们摄入细菌，用细胞内的蛋白质库杀死细菌。如果这些蛋白质被释放到细胞外的身体组织中，就会引起损伤和炎症。面对压倒性的感染，中性粒细胞将其细胞内内容物直接释放到组织中（脱颗粒），或者通过在其内部内容物的网（如渔网）上释放有害蛋白质来捕获和杀死细菌。中性粒细胞含有通过决定表达什么蛋白质来控制细胞的基因。这些蛋白质可能是控制中性粒细胞内化学反应的酶，也可能是控制它们如何移动的结构蛋白。其他的白细胞帮助协调我们的免疫系统，通过增加中性粒细胞的反应，使它们清除感染，或更积极地释放它们的有害内容物，或抑制它们的反应，以促进愈合。参与这些控制过程的细胞包括B细胞和T细胞淋巴细胞，它们作为我们过去经历过的感染的记忆。B细胞产生促进细菌摄入的抗体，T细胞协调局部组织反应，在感染开始时增加炎症和中性粒细胞活性，并在感染清除后促进组织愈合。免疫细胞的功能如何随着年龄的增长而退化。随着年龄的增长，我们的免疫系统越来越无法区分“朋友”（安全的东西）和“敌人”（会伤害我们的细菌）。我们的研究表明，中性粒细胞的迁移、细菌的摄入和NET的产生变得不分青红皂白和不准确。免疫记忆逐渐消失，我们对感染做出快速反应的能力也随之减弱。当老年人患上肺炎时，免疫功能会进一步受损。我们的研究表明，中性粒细胞迁移和细菌清除在肺炎后6周内严重受损。我们认为这种免疫系统的瘫痪可能会导致继发性感染。我们希望利用肺炎患者和康复后的免疫细胞以及感染模型来研究肺炎中有害中性粒细胞行为的长期相关性。通过研究B细胞和T细胞以及它们如何与中性粒细胞相互作用，我们将能够确定中性粒细胞行为长期缺陷的原因，包括控制这些细胞的基因。这将为我们的免疫细胞如何在肺炎中发挥作用以及我们如何改善结果提供新的理解。

Pneumonia is a serious lung infection. The 5th leading cause of death, each year 11 in every 1000 adults develop pneumonia outside of hospital, and 1 in 100 of those die. If the person is ill enough to be admitted to hospital, the death rate is much higher, and this rises considerably if a complication called sepsis develops. Sepsis is a syndrome whereby the infection causes changes to the body's natural immune system and ultimately cause damage to organs such as the lungs, brain and heart. Older people are more likely to develop pneumonia, have a higher risk of sepsis, and have worse outcomes (30 in 100 dying within 6 months). The main treatment for pneumonia is antibiotics. Older adults often do not make a full recovery. An episode of pneumonia can lead to increased frailty, with the older person needing more social support or admission to a care home. Following pneumonia, older people are more susceptible to developing a subsequent (secondary) infection. These include another pneumonia, but also infections elsewhere in the body. Secondary infections have even worse outcomes but the reason older people are prone to them is unclear.There are no treatments that help the immune system overcome pneumonia. Given that our population is ageing, this is an area of huge unmet need.Neutrophils are white blood cells crucial for fighting infections. They leave the blood, moving (migrating) accurately to areas of infection, where they ingest bacteria, killing them with an arsenal of proteins contained within the cell. These proteins cause damage and inflammation if they are released outside of the cell into the body's tissues. In the face of overwhelming infection, neutrophils release their intracellular contents either directly into tissues (degranulation) or by releasing injurious proteins on a web of their own internal contents (like a fishing net) to trap and kill bacteria. Neutrophils contain genes that control the cell by dictating what proteins are expressed. These proteins could be enzymes, controlling chemical reactions within the neutrophil, or structural proteins, controlling how they move.Other white blood cells help coordinate our immune system, by increasing neutrophil responses to make them clear infection or release their injurious contents more aggressively or dampening down their responses to promote healing. Cells involved in these controlling processes include B cell and T cell lymphocytes, which act as a memory of infections we have experienced in the past. B cells produce antibodies that promote the ingestion of bacteria and T cells coordinate local tissue responses, increasing inflammation and neutrophil activity at the start of an infection and promoting tissue healing after infection is cleared. How immune cells function deteriorates with age. With ageing, our immune system becomes less able to differentiate "friend" (things that are safe) from "foe" (bacteria that will damage us). Our research shows that neutrophil migration, ingestion of bacteria and NET production become indiscriminate and inaccurate. Immune memory fades and our ability to respond quickly to infection but then heal, is blunted. When older people develop pneumonia, immune function is compromised even further. Our research suggests that neutrophil migration and bacterial clearance is severely impaired for up to 6 weeks after pneumonia. We believe this paralysis of the immune system may lead to secondary infections. We wish to investigate the long-term relevance of injurious neutrophil behaviours in pneumonia, using immune cells from patients with pneumonia and following recovery, and in models of infection. By studying B and T cells and how they interact with neutrophils, we will be able to determine the cause of the prolonged defective neutrophil behaviour, including the genes that control these cells. This will provide a new understanding of how our immune cells function in pneumonia and how we can improve outcome.