Insights into the molecular determinants involved in Mycobacterium tuberculosis persistence and their therapeutic implications

Lay Summary

The main reason for failures in treating clinical tuberculosis is the persistence of mycobacteria, which is transiently tolerant to drugs used in tuberculosis therapy. It provides a clear indication that conventional therapeutic options, such as the BCG vaccine and a combination of tuberculosis drugs, are insufficient to eradicate tuberculosis infection. In the past decade, the researches on bacterial persistence have made significant progress. However, persistence remains to be a major issue to public health, so detailed investigation about the biology of persisters and their mechanisms is required to achieve better clinical results. Overall, there is an urgent need for the development of therapeutic options aimed at both active and latent M. tb bacteria. Although the development of some therapeutics, such as bedaquiline drug and M72-based vaccine had shown promising results, but the lag at the level of comprehensive understanding about the tuberculosis pathogenesis impedes the development of better therapeutics and diagnostics.

Research studies have found that multiple genes and regulatory pathways of both host and mycobacteria are responsible for persistence and their eventual relapse to actively-replicating wild type populations. The cohesive efforts of persister enrichment through approaches like fluorescence-activated single cell sorting and laser capture microdissection and analysis techniques such as time lapse microscopy, microfluidics technique, omics technologies, and next-generation sequencing, can provide robust information to understand the mechanism of persister formation and their reactivation. Gene network analysis and system biology techniques could assist to unravel the ways through which the molecular determinants of bacterial cells interact in stressful environments giving rise to numerous persister phenotypes, who even differ at their frequency level under different stress conditions.

Intriguingly, the in vitro model system that mimics the different stress conditions imposed by the host immune system on the pathogen provides a screening approach that recognizes the significance of M. tb genes in the adaptive response during infection. Various in vitro and ex-vivo models have been developed to imitate the stress conditions faced by the M. tb inside the host during infection. These models are established to understand the mycobacterial factors responsible for adaptation of bacteria to persistent state. But notable limitation of these stress models is that their information is not significant compared to the in vivo scenario in clinical and animal models. For instance, nutrient availability studies in the context of persistence in vitro differ considerably to those of in vivo conditions. As a matter of fact, different micro niches such as adipose tissues, macrophages, and mesenchymal stem cells of the human body are exploited by the mycobacterial cells to hide away from the host immune response. These hidden bacterial cells then utilize host fatty acids and cholesterol as carbon and energy sources to persist for long-term within the host. Thus, unraveling the relationship between the bacterial persistence and host metabolism can present newer avenues to develop therapeutics and diagnostics. The molecular determinants that are identified to be implicated in mycobacterium persistence are well described in this review, which gives certain insights into the biology of persister formation and its reactivation in mycobacteria. In addition, this information will also facilitate the development of biomarkers that could demarcate between active and latent tuberculosis to promote the molecular diagnosis of tuberculosis.

Another uncharted field of research includes the study of persistence in context of host microbiota, which is currently deemed interesting by many researchers. Although, bacterial persistence is assumed to be adverse as it is the reason for the recalcitrance of chronic infections, but persistence could be favorable for the survival as well as diversity of healthy microbes of host microbiome under conditions like pathogenic or viral infections, change in diet, age, and antibiotic treatment. Although, it is not substantiated that persister cell formation occurs in the host microbiome however, it is important to comprehend the possibilities of utilization of the persistence phenomenon to reestablish the host microbiota.

For M. tb a major obstacle to comprehend the mechanism of persister formation and subsequent relapse is the unavailability of clinical specimens and tissue samples from individuals with latent or persistent tuberculosis. In addition, there is a lack of imaging techniques and diagnostic tools to classify the persister cells in clinical specimens. Thus, due to the lack of thorough information about the persistent tuberculosis infection, creating clinically relevant persistence models is an arduous task. So, it is imperative to build well-designed specimen banks to preserve the clinical samples from individuals with latent or persistent tuberculosis, both prior or upon reactivation. This data is pivotal to develop therapeutic interventions for successful identification and targeting of the persistent or latent tuberculosis bacteria before it relapses in the host.

Abstract

The establishment of persistent infections and the reactivation of persistent bacteria to active bacilli are the two hurdles in effective tuberculosis treatment. Mycobacterium tuberculosis, an etiologic tuberculosis agent, adapts to numerous antibiotics and resists the host immune system causing a disease of public health concern. Extensive research has been employed to combat this disease due to its sheer ability to persist in the host system, undetected, waiting for the opportunity to declare itself. Persisters are a bacterial subpopulation that possesses transient tolerance to high doses of antibiotics. There are certain inherent mechanisms that facilitate the persister cell formation in Mycobacterium tuberculosis, some of those had been characterized in the past namely, stringent response, transcriptional regulators, energy production pathways, lipid metabolism, cell wall remodeling enzymes, phosphate metabolism, and proteasome protein degradation. This article reviews the recent advancements made in various in vitro persistence models that assist to unravel the mechanisms involved in the persister cell formation and to hunt for the possible preventive or treatment measures. To tackle the persister population the immunodominant proteins that express specifically at the latent phase of infection can be used for diagnosis to distinguish between the active and latent tuberculosis, as well as to select potential drug or vaccine candidates. In addition, we discuss the genes engaged in the persistence to get more insights into resuscitation and persister cell formation. The in-depth understanding of persistent cells of mycobacteria can certainly unravel novel ways to target the pathogen and tackle its persistence.

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