Mycobacterium tuberculosis Adaptation to Gradually Oxygen Depletion Condition Is a Key Factor for Latency of Tuberculosis

Abstract

Background: There is ample evidence that the basis for latent tuberculosis infection in humans is persistence of tubercle bacilli for long periods of time even though lifetime. This status is currently defined as non-replicating persistence (NRP). Documented evidence from both macrophage physiology & the nature of TB granuloumas in human lungs suggests that gradually depletion of oxygen, hypoxia and micro aerobic condition is a major factor in inducing NRP state of tubercle bacilli. Methods: 100 clinically isolated tubercle bacilli were examined by the slowly stirred head space ratio method (0.5 HSR), which involve a slow depletion of oxygen within a sealed, slow stirred culture tube. The in-vitro induced hypoxically different stages of NRP was setting up, and the expression of the alpha-crystalline chaperone protein that are expressed when MTB undergoes to NRP srate was detected. Indeed the activity of rifampin, isoniazide, pyrazynamide, ciprofloxacin and meteronidazole were evaluated against two NRP stages of MTB. Results: During oxygen shift-down bacterial physiology changes from active growth to a NRP state. Two characteristic stages of NRP are seen; NRP-1 occurs when the oxygen concentration gradually dropped to microaerophilic condition. The 16 KD α- crystalline protein was expressed at just beginning of NRP-1 stage. The NRP-2 stages occur when the oxygen concentration dropped to anaerobic condition. When the NRP-2 state transferred to an oxygen – reach fresh medium the bacteria consume oxygen and resume growth in a synchronized replication manner from NRP-2 state. Conclusion: slow depletion of O2 appears to permit the occurrence of adaptations that favor long-term non replicating persistence of tubercle bacilli under microaerophilic conditions and also enhance the ability of the bacilli to survive in anaerobic conditions. This versatility could account for long-term latency of tuberculosis in the human host. The model presented here should be useful for identifying the molecular events include; mRNA expression and native products such as α-crystalline protein and others that are responsible for the versatility of MTB in surviving under that range of conditions, as well as those associated with reactivation of these bacilli.