Stress and Host Immunity Amplify Mycobacterium tuberculosis Phenotypic Heterogeneity and Induce Nongrowing Metabolically Active Forms

摘要: Nonreplicating and metabolically quiescent bacteria are implicated in latent tuberculosis infections relapses following "sterilizing" chemotherapy. However, evidence linking bacterial dormancy persistence vivo is largely inconclusive. Here we measure the single-cell dynamics of Mycobacterium replication ribosomal activity using quantitative time-lapse microscopy a reporter RNA gene expression. Single-cell exhibit heterogeneity under standard growth conditions, which amplified by stressful conditions such as nutrient limitation, stationary phase, intracellular replication, mouse lungs. Additionally, lungs chronically infected mice harbor subpopulation nongrowing but active bacteria, absent lacking interferon-γ, cytokine essential for antituberculosis immunity. These cryptic forms prominent treated with drug isoniazid, suggesting role postchemotherapeutic relapses. Thus, amplification phenotypic response to host immunity pressure may contribute persistence.