SFB 1583: Decisions in Infectious Diseases (DECIDE)

全球出现的多重耐药细菌和流行病，如新型SARS-CoV-2冠状病毒引起的COVID-19大流行，从根本上影响了我们的卫生系统和社会。虽然病原体导向疗法在对抗感染性疾病方面非常成功，但它们引发了对治疗具有抗性的微生物的进化，从而迫使制药行业不断开发新类别的抗菌剂。新的耐药性的发展和新的有效抗菌剂的批准之间的军备竞赛似乎已经决定有利于微生物。此外，宿主免疫应答导致许多传染病的致命结果，例如COVID-19。因此，单独对抗病原体并不具有足够的治疗效果。这些现实要求重新思考目前的治疗方法，重点是病原体引发的宿主反应，而不是病原体本身的战略。虽然这种方法有可能是上级传统的微生物为导向的战略，到目前为止，我们知道的可能的主机目标很少。特别是，尚未以协调一致的方式研究将最初无害的感染转化为严重或慢性疾病的过程。因此，迫切需要确定宿主内控制传染病过程的决策点。一旦被识别，这些可以用于未来的治疗干预。在合作研究中心DECIDE（DECisions in Infectious Diseases）中，我们建议研究决定感染临床结果和严重程度的三个关键决定：（1）初始病原体接触到已建立的感染;（2）过渡到持续感染;（3）开始全身传播。这些决定是由病原体与宿主屏障组织及其肠道微生物群以及局部和全身免疫反应的复杂相互作用定义的。我们预计，这些相互作用的分子事件代表干预的目标。由于最先进的单细胞技术、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。DECIDE的研究人员在病原体库方面的长期专业知识使他们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，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的研究者之间创造最大的协同作用，以完成我们的使命，即确定感染过程中的分子决定点，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.