Rickettsia conorii is a Gram-negative, cytosolic intracellular bacterium that has classically been investigated in terms of endothelial cell infection. However, R. conorii and other human pathogenic Rickettsia species have evolved mechanisms to grow in various cell types, including macrophages, during mammalian infection. During infection of these phagocytes, R. conorii shifts the host cell's overall metabolism towards an anti-inflammatory M2 response, metabolically defined by an increase in host lipid metabolism and oxidative phosphorylation. Lipid metabolism has more recently been identified as a key regulator of host homeostasis through modulation of immune signalling and metabolism. Intracellular pathogens have adapted mechanisms of hijacking host metabolic pathways including host lipid catabolic pathways for various functions required for growth and survival. In the present study, we hypothesised that alterations of host lipid droplets initiated by lipid catabolic pathways during R. conorii infection is important for bacterial survival in macrophages. Herein, we determined that host lipid droplet modulation is initiated early during R. conorii infection, and these alterations rely on active bacteria and lipid catabolic pathways. We also find that these lipid catabolic pathways are essential for efficient bacterial survival. Unlike the mechanisms used by other intracellular pathogens, the catabolism of lipid droplets induced by R. conorii infection is independent of upstream host peroxisome proliferator-activated receptor-alpha (PPARα) signalling. Inhibition of PPARɣ signalling and lipid droplet accumulation in host cells cause a significant decrease in R. conorii survival suggesting a negative correlation with lipid droplet production and R. conorii survival. Together, these results strongly suggest that the modulation of lipid droplets in macrophage cells infected by R. conorii is an important and underappreciated aspect of the infection process.

中文翻译：

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THP-1 巨噬细胞中的立克次氏体存活涉及宿主脂滴改变和活性立克次体蛋白产生

Rickettsia conorii是一种革兰氏阴性细胞溶质细胞内细菌，已针对内皮细胞感染进行了经典研究。然而，R. conorii和其他人类致病性立克次体物种已经进化出在哺乳动物感染期间在包括巨噬细胞在内的各种细胞类型中生长的机制。在这些吞噬细胞感染期间，R. conorii将宿主细胞的整体代谢转向抗炎 M2 反应，代谢定义为宿主脂质代谢和氧化磷酸化的增加。最近通过调节免疫信号和代谢，脂质代谢被确定为宿主稳态的关键调节因子。细胞内病原体已经适应了劫持宿主代谢途径的机制，包括宿主脂质分解代谢途径，以实现生长和生存所需的各种功能。在本研究中，我们假设在R. conorii感染期间由脂质分解代谢途径引发的宿主脂滴的改变对于巨噬细胞中的细菌存活很重要。在这里，我们确定宿主脂滴调节是在R. conorii早期启动的感染，而这些改变依赖于活性细菌和脂质分解代谢途径。我们还发现这些脂质分解代谢途径对于有效的细菌存活至关重要。与其他细胞内病原体使用的机制不同， R. conorii感染诱导的脂滴分解代谢独立于上游宿主过氧化物酶体增殖物激活受体-α (PPARα) 信号传导。抑制 PPARɣ 信号传导和宿主细胞中的脂滴积累导致R. conorii存活率显着降低，表明与脂滴产生和R. conorii存活呈负相关。总之，这些结果强烈表明，在被R. conorii感染的巨噬细胞中脂滴的调节是感染过程中一个重要且被低估的方面。