Impact of the elderly lung mucosa on <i>Mycobacterium tuberculosis</i> metabolic adaptation during infection of alveolar epithelial cells

ABSTRACT 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 increased M.tb replication in human macrophages and alveolar epithelial cells (ATs) is mediated by age-associated changes in human ALF. Here we determine the transcriptional profile of M.tb when 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 upregulates M.tb genes 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 key M.tb genes 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 of M.tb , enabling greater adaptation to the host and potentially explaining Mtb’ s increased survival within host cells. Importantly, we present the first transcriptomic analysis on the impact of the elderly lung mucosa on M.tb pathogenesis during intracellular replication in ATs.