Opening Pandora's Box: Mechanisms of Mycobacterium tuberculosis Resuscitation

Abstract

Mycobacterium tuberculosis (Mtb) characteristically causes an asymptomatic infection. While this latent tuberculosis infection (LTBI) is not contagious, reactivation to active tuberculosis disease (TB) causes the patient to become infectious. A vaccine has existed for TB for a century, while drug treatments have been available for over 70 years; despite this, TB remains a major global health crisis. Understanding the factors which allow the bacillus to control responses to host stress and mechanisms leading to latency are critical for persistence. Similarly, molecular switches which respond to reactivation are important. Recently, research in the field has sought to focus on reactivation, employing system-wide approaches and animal models. Here, we describe the current work that has been done to elucidate the mechanisms of reactivation and stop reactivation in its tracks.

Figure 1

Definition of clinical and bacterial terms. Latency and reactivation refer to clinical states of disease during TB. Latency is a period during which there are no symptoms of the disease and the patient is not infectious. Reactivation is the return of symptoms and the patient is infectious. During latency, the bacilli are hypothesized to be dormant. Dormancy is defined as low levels of replication, minimal metabolism, and a thick cell wall. In favorable conditions, the bacilli is thought to resuscitate and begin replication and metabolism again and this is believed to lead to reactivation of disease.

Figure 2

Expression of probable key regulons during the transition from dormancy to resuscitation. In vitro expression of dosR (devR), sigH, sigE, and clgR regulons after 6 hours of re-aeration. clgR, sigH, and sigE regulons are both generally expressed while the dosR regulon is being down-regulated including those genes shared with the other regulons. These regulons may be interacting through the shared members. Red indicates induction of that gene while blue indicates repression of that gene. Genes with a gray background do not have expression data. The members of the regulons were identified using the cutting-edge technology, ChIPseq [96]. The expression data was generated by our lab and previously published [19] and the program Cytoscape [97] show interconnected regulons.

Figure 3

Bacterial changes from dormancy to resuscitation. Dormancy is characterized by low metabolism and growth and increased lipids and DosR regulon expression. Accumulation of Rpf proteins may be part of the groundwork for future resuscitation. Resuscitation is characterized by decreased DosR and increased ClgR regulon expression and increased metabolism using lipids as an energy source which are different pathways than aerobic respiration metabolism. The bacilli will increase in number and escape the granuloma.