Impact of the elderly lung mucosa onMycobacterium tuberculosismetabolic adaptation during infection of alveolar epithelial cells

Background: Tuberculosis (TB) is one of the top leading causes of death due to a single infectious agent. Upon infection,Mycobacterium tuberculosis(M.tb) is deposited in the alveoli and encounters the lung mucosa or alveolar lining fluid (ALF). We previously determined that increasedM.tbreplication in human macrophages and alveolar epithelial cells (ATs) is mediated by age-associated changes in human ALF. Here we determine the transcriptional profile ofM.tbwhen exposed to healthy ALF from adult (A-ALF) or elderly (E-ALF) individuals before and during infection of ATs.Results: Prior to infection, exposure to E-ALF upregulatesM.tbgenes associated with the ESX-4 secretion system, immunomodulatory proteins from the ESX-5 system, and genes encoding phospholipases, phosphatases, and proteases. During infection, E-ALF exposure upregulates keyM.tbgenes from the ESX-5 secretion system, genes associated with PDIMs biosynthesis and transport, and genes linked to bacterial oxidative stress defense mechanisms.Conclusions: These findings demonstrate how altered ALF in old age can impact the metabolic status ofM.tb, enabling greater adaptation to the host and potentially explainingM.tbincreased survival within host cells. Importantly, we present the first transcriptomic analysis on the impact of the elderly lung mucosa onM.tbpathogenesis during intracellular replication in ATs.