Olmo-Fontánez Angélica M, Allué-Guardia Anna, Garcia-Vilanova Andreu, Glenn Jeremy, Wang Shu-Hua, Merritt Robert E, Schlesinger Larry S, Turner Joanne, Wang Yufeng, Torrelles Jordi B
Population Health and Host-Pathogen Interactions Programs, Texas Biomedical Research Institute, San Antonio, Texas, USA.
Integrated Biomedical Sciences Program, University of Texas Health Science Center at San Antonio, San Antonio, Texas, USA.
Microbiol Spectr. 2024 Nov 8;12(12):e0179024. doi: 10.1128/spectrum.01790-24.
Tuberculosis is one of the leading causes of death due to a single infectious agent. Upon infection, () is deposited in the alveoli and encounters the lung mucosa or alveolar lining fluid (ALF). We previously showed that, as we age, ALF presents a higher degree of oxidation and inflammatory mediators, which favors replication in human macrophages and alveolar epithelial cells (ATs). Here, we define the transcriptional profile of when exposed to healthy ALF from adult (A-ALF) or elderly (E-ALF) humans before and during infection of ATs. Prior to infection, exposure to E-ALF upregulated genes essential for bacterial host adaptation directly involved in pathogenesis. During infection of ATs, E-ALF exposed further upregulated genes involved in its ability to escape into the AT cytosol bypassing critical host defense mechanisms, as well as genes associated with defense against oxidative stress. These findings demonstrate how alterations in human ALF during the aging process can impact the metabolic status of , potentially enabling a greater adaptation and survival within host cells. Importantly, we present the first transcriptomic analysis on the impact of the elderly lung mucosa on pathogenesis during intracellular replication in ATs.IMPORTANCETuberculosis is one of the leading causes of death due to a single infectious agent. Upon infection, () is deposited in the alveoli and comes in contact with the alveolar lining fluid (ALF). We previously showed that elderly ALF favors replication in human macrophages and alveolar epithelial cells (ATs). Here we define the transcriptional profile of when exposed to healthy ALF from adult (A-ALF) or elderly (E-ALF) humans before and during infection of ATs. Prior to infection, exposure to E-ALF upregulates genes essential for bacterial host adaptation and pathogenesis. During infection of ATs, E-ALF further upregulates genes involved in its ability to escape into the AT cytosol, as well as genes for defense against oxidative stress. These findings demonstrate how alterations in human ALF during the aging process can impact the metabolic status of , potentially enabling a greater adaptation and survival within host cells.
结核病是由单一传染源导致死亡的主要原因之一。感染时，（）沉积在肺泡中，并接触肺黏膜或肺泡衬液（ALF）。我们之前表明，随着年龄增长，ALF呈现出更高程度的氧化和炎症介质，这有利于在人类巨噬细胞和肺泡上皮细胞（ATs）中复制。在此，我们定义了在ATs感染之前和期间，当暴露于来自成年人（A-ALF）或老年人（E-ALF）的健康ALF时的转录谱。在感染之前，暴露于E-ALF会上调直接参与发病机制的细菌宿主适应性所必需的基因。在ATs感染期间，暴露于E-ALF的（）进一步上调了与其逃避进入AT细胞质以绕过关键宿主防御机制的能力相关的基因，以及与抗氧化应激相关的基因。这些发现证明了衰老过程中人类ALF的改变如何影响（）的代谢状态，可能使其在宿主细胞内实现更大程度的适应和存活。重要的是，我们首次对老年肺黏膜对ATs细胞内复制期间（）发病机制的影响进行了转录组分析。
重要性
结核病是由单一传染源导致死亡的主要原因之一。感染时，（）沉积在肺泡中并与肺泡衬液（ALF）接触。我们之前表明老年ALF有利于在人类巨噬细胞和肺泡上皮细胞（ATs）中复制。在此我们定义了在ATs感染之前和期间，当暴露于来自成年人（A-ALF）或老年人（E-ALF）的健康ALF时的转录谱。在感染之前，暴露于E-ALF会上调细菌宿主适应性和发病机制所必需的基因。在ATs感染期间，E-ALF进一步上调了与其逃避进入AT细胞质的能力相关的基因，以及抗氧化应激的基因。这些发现证明了衰老过程中人类ALF的改变如何影响（）的代谢状态，可能使其在宿主细胞内实现更大程度的适应和存活。
