Network Dissection of Host-Pathogen Interactions in Mycobacterium tuberculosis Infection

摘要 感染是宿主和病原体之间的动态相互作用，通过每个生物体的信号和 基因调控网络。世界上最致命的病原体结核分枝杆菌(Mtb)可以利用它的 与宿主分子相互作用的网络，以引发使其持续感染的稳定状态 在长达数十年的时间里没有症状。MTB或主机的网络活动中的扰动，打破了 这种分子动态平衡将改变感染结果：要么从病原学上转向有症状的结核病 (结核病)结核杆菌生长猖獗和病理性炎症，可能导致死亡或保护性疾病 向感染清除迈进。我将剖析宿主信号和结核分枝杆菌调控网络活动，以确定感染的命运- 确定影响结核分枝杆菌活性和宿主感染期间宿主炎症的临界点基因 单核细胞来源的巨噬细胞(MDM)，体内主要受感染的宿主细胞。我会分析寄主和病原体 对这些感染改变扰动的转录反应以确定潜在的分子机制 宿主-病原体的相互作用，我将利用这些信息来确定协同联合干预， 同时作为目标寄主和病原体。鉴定寄主-病原体界面上的这些临界点基因 应该提供新的治疗干预策略，共同针对宿主和病原体，以诱导宿主保护， 同时也揭示了对发病机制的基本见解。

ABSTRACT Infection is a dynamic interplay between host and pathogen, coordinated through each organism's signaling and gene regulatory networks. The world's deadliest pathogen, Mycobacterium tuberculosis (Mtb), can exploit its network of molecular interactions with the host to elicit an infection steady state that enables it to persist asymptomatically for up to decades. Perturbations in Mtb's or the host's network activities that tip the balance of this molecular homeostasis will alter infection outcomes: either pathogenically toward a symptomatic tuberculosis (TB) disease with rampant Mtb growth and pathological inflammation that could lead to death, or protectively toward infection clearance. I will dissect host signaling and Mtb regulatory network activities for infection fate- deciding tipping-point genes that impact Mtb viability and host inflammation during infection in primary human monocyte-derived macrophages (MDMs), a major infected host cell in vivo. I will profile the host and pathogen transcriptional responses to these infection-altering perturbations to define molecular mechanisms underlying the host-pathogen interplay, and I will use this information to identify synergistic joint interventions that concurrently target host and pathogen. Identifying these tipping-point genes at the host-pathogen interface should inform new therapeutic intervention strategies that jointly target host and pathogen to elicit host protection, while also revealing fundamental insights into pathogenesis.