SFB 1583: Decisions in Infectious Diseases (DECIDE)

全球出现耐多药细菌和流行病，例如由新型SARS-CoV-2冠状病毒引起的COVID-19大流行，对我们的卫生系统和社会产生了根本性影响。虽然以病原体为导向的治疗方法在对抗传染病方面非常成功，但它们引发了对治疗产生耐药性的微生物的进化，从而迫使制药行业不断开发新型抗菌剂。在开发新的耐药性和批准新的有效抗菌素之间的军备竞赛似乎已经决定有利于微生物。此外，宿主免疫反应会导致许多传染病的致命后果，例如COVID-19。因此，单独对抗病原体并没有足够的治疗效果。这些现实要求我们重新思考当前的治疗方法，转而关注病原体引发的宿主反应，而不是病原体本身。虽然这种方法有可能优于传统的以微生物为导向的策略，但迄今为止，我们对可能的宿主目标知之甚少。特别是将最初无害的感染转变为严重或慢性疾病的过程尚未以协调的方式进行研究。因此，迫切需要确定宿主体内控制传染病过程的决策点。一旦得到承认，这些可以用于未来的治疗干预。在传染病决策合作研究中心，我们建议调查决定临床结果和感染严重程度的三个关键决策：(1)初始病原体接触到确定感染；(2)向持续性感染过渡；(3)引发系统性扩散。这些决定是由病原体与宿主屏障组织及其共生微生物群以及局部和全身免疫反应的复杂相互作用决定的。我们预计这些相互作用背后的分子事件代表了干预的目标。由于尖端单细胞技术、复杂的人体组织和动物模型以及病原体遗传学的最新进展，现在可以以前所未有的分子细节分析感染过程。对病原体的长期专业知识使研究人员能够以独特的多层系统方法探索这些微生物，宿主粘膜组织和免疫系统以及微生物群之间的相互作用。因此，我们的目标是确定总体共同和病原体特异性原则，这将为预防和治疗传染病的新策略提供信息。我们的愿景是在DECIDE的研究人员之间创造最大的协同作用，以完成我们的使命，确定感染过程中的分子决策点，并将其作为抗感染治疗的新基础。

The global emergence of multidrug-resistant bacteria and pandemics, such as the COVID-19 pandemic caused by the novel SARS-CoV-2 coronavirus, fundamentally impact our health systems and societies. While pathogen-directed therapies have been very successful in combating infectious diseases, they provoke the evolution of microbes resistant to treatment and thereby force the pharmaceutical industry to constantly develop new classes of antimicrobial agents. The arms race between the development of new resistances and the approval of new effective antimicrobials seems to be already decided in favour of the microbes. In addition, the host immune response contributes to the fatal outcome of numerous infectious diseases, for example COVID-19. Therefore, fighting the pathogen alone does not have a sufficient therapeutic effect. These realities demand a rethinking of current therapeutic approaches towards strategies that focus on pathogen-triggered host responses and not the pathogen itself. While this approach has the potential to be superior to conventional microbe-oriented strategies, to date we know very little about possible host targets. Especially the processes that convert an initially harmless infection into severe or chronic disease have not been studied in a coordinated manner. Therefore, there is an urgent need to identify decision points within the host that govern infectious disease processes. Once recognised, these can be harnessed for future therapeutic interventions. In the collaborative research centre DECIDE (DECisions in Infectious DisEases) we propose to investigate three key decisions that determine the clinical outcome and severity of infections: (1) the initial pathogen contact to established infection; (2) the transition to a persistent infection; and (3) initiation of systemic spreading. These decisions are defined by a complex interplay of the pathogen with host barrier tissues and their commensal microbiota as well as local and systemic immune responses. We anticipate that the molecular events that underlie these interactions represent targets for intervention. Due to recent advances in cutting-edge single-cell technologies, complex human tissue and animal models and pathogen genetics, the course of infections can now be analysed in unprecedented molecular detail. Long-standing expertise on a repertoire of pathogens allows the investigators of DECIDE to explore interactions between these microbes, the host mucosal tissue and the immune system, as well as the microbiota in a unique multi-layered systems approach. Thereby, we aim to identify overarching common and pathogen-specific principles that will inform novel strategies for preventing and treating infectious diseases. It is our vision to create maximum synergy among the investigators of DECIDE in order to accomplish our mission to identify molecular decision points in infection processes and to exploit these as a new basis for anti-infective therapies.