Clinically encountered growth phenotypes of tuberculosis-causing bacilli and their in vitro study: A review

The clinical manifestations of tuberculosis (TB) vary widely in severity, site of infection, and outcomes of treatment-leading to simultaneous efforts to individualize therapy safely and to search for shorter regimens that can be successfully used across the clinical spectrum. In these endeavors, clinicians and researchers alike employ mycobacterial culture in rich media. However, even within the same patient, individual bacilli among the population can exhibit substantial variability in their culturability. Bacilli in vitro also demonstrate substantial heterogeneity in replication rate and cultivation requirements, as well as susceptibility to killing by antimicrobials. Understanding parallels in clinical, ex vivo and in vitro growth phenotype diversity may be key to identifying those phenotypes responsible for treatment failure, relapse, and the reactivation of bacilli that progresses TB infection to disease. This review briefly summarizes the current role of mycobacterial culture in the care of patients with TB and the ex vivo evidence of variability in TB culturability. We then discuss current advances in in vitro models that study heterogenous subpopulations within a genetically identical bulk culture, with an emphasis on the effect of oxidative stress on bacillary cultivation requirements. The review highlights the complexity that heterogeneity in mycobacterial growth brings to the interpretation of culture in clinical settings and research. It also underscores the intricacies present in the interplay between growth phenotypes and antimicrobial susceptibility. Better understanding of population dynamics and growth requirements over time and space promises to aid both the attempts to individualize TB treatment and to find uniformly effective therapies.