Mycobacterial Dormancy, Culturability, and Resuscitation: State-of-the-art, Challenges, and Future Prospects

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Background

The genus Mycobacterium carries within it several clinically important pathogens including Mycobacterium tuberculosis, the causative agent of tuberculosis (TB), which claims more than 1.5 million lives per year. During the last decade, notable strides have been made in describing the complexity of TB infection and disease in humans. This has led to an expanded understanding of the spectrum of asymptomatic TB infection together with a greater appreciation of the bacterial heterogeneity associated with active disease. In the face of these developments, renewed focus now needs to be placed on investigating mycobacterial metabolic states that prevail, either at a single-cell level or within a collective bacterial population, during the different stages of TB infection and disease. These efforts will guide the development of novel therapeutics that are able to eliminate all organisms. The importance of this approach is highlighted by the fact that other mycobacterial species cause clinically relevant disease including Mycobacterium leprae, Mycobacterium ulcerans and nontuberculous mycobacteria such as Mycobacterium avium, Mycobacterium kansasii, and Mycobacterium abscessus.

Mycobacterial pathogens have developed a plethora of mechanisms that facilitate successful escape from host immunity ultimately leading to the progression of the disease. Previous descriptions of clinically latent TB disease were hypothesized to be associated with the presence of dormant/nonreplicating bacterial populations. Recent descriptions of subclinical or asymptomatic infection states such as incipient TB, which suggest the presence of metabolically active bacteria, challenge these assumptions. However, there is a notable paucity of research addressing this as sampling tubercle bacteria from asymptomatic individuals is challenging without invasive procedures. As a result, the field has been largely reliant on using laboratory models to recapitulate various aspects of clinical TB. With respect to non-replicating bacteria, various models that use non-optimal growth conditions followed by resuscitation, a process of restoring cell activity and bacterial multiplication, have been used.

These models have all yielded useful data but the complete spectrum of mechanisms responsible for adaptation to challenging microenvironments during TB infection and presence/location of truly dormant M. tuberculosis in the human host remain poorly understood. This has hindered efforts to develop novel strategies to combat TB. Furthermore, how the presence of such non-replicating populations affects drug tolerance and clinical management requires urgent investigation. Further understanding of these issues will provide novel strategies to facilitate the development of shorter, more effective treatment regimens that allow for durable cure and reduce the risk of relapse.

In this Research Topic we welcome original research and review articles concerning all aspects of M. tuberculosis and other non-tuberculosis mycobacteria that focus on adaptation to the non-replicating/non-culturable state and subsequent resuscitation. We are particularly interested in research exploring:

• Modelling of mycobacterial dormancy/culturability both in vitro and in vivo
• Analysis of metabolic adaptation of mycobacteria to non-replicating or non-culturable conditions
• Improved diagnosis of non-replicating bacteria from clinical specimens
• Development of new drugs that inhibit potentially drug tolerant non-replicating mycobacteria
• Host-pathogen interactions and immune response to dormant and resuscitating bacilli
• Any other challenges associated with metabolic transition to altered replication states and subsequent resumption of growth

Keywords: Tuberculosis, Mycobacteria, Mycobacterium tuberculosis, Dormancy, Culturability, Resuscitation, Tuberculosis Infection, Non-Replicating Persistence, Drug tolerance, Host-Pathogen Interaction, Immune Responses

Important note: All contributions to this Research Topic must be within the scope of the section and journal to which they are submitted, as defined in their mission statements. Frontiers reserves the right to guide an out-of-scope manuscript to a more suitable section or journal at any stage of peer review.

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