Lazy, Dynamic or Minimally Recrudescent? On the Elusive Nature and Location of the Mycobacterium Responsible for Latent Tuberculosis

In the absence of symptoms characteristic of tuberculosis (TB), a condition termed clinical latency, diagnosis is currently impossible by detection of the microorganism itself and resorts to the demonstration of an immunological memory response to antigens of Mycobacterium tuberculosis (Mtb). Whether latency is synonymous to chronic persistent infection with viable Mtb in all instances has been difficult to establish. The physical and physiological state of Mtb during latency is much disputed: are organisms mostly dormant, in a nonreplicating state of persistence, and characterized by lipid inclusions and metabolic adaptation to hypoxia, or do they continue to replicate and sometimes even escape from the fringes of granulomatous lesions or alveolar epithelial cells into adjacent airways, thereby inducing recurring immune responses? The physical nature of Mtb during latency is important as it determines which antimicrobial agents may be used to kill it, which immunomodulating strategies (including post-exposure vaccines) may be appropriate to contain it, and which diagnostic measures may be most useful to discriminate latent from reactivating infection. Two major viewpoints exist: one argues that Mtb persists mostly in a lazy state within granulomatous lesions, but periodically recrudesces, and that there is considerable heterogeneity for different sites within the lesion and within the infected lung. Throughout latency, there is a dynamic immunological interplay between Mtb and the host, necessitating continuous recruitment of cells into the granuloma, and reactivation occurs when this dynamic cellular exchange becomes dysregulated. Another view holds that dormant Mtb reside within alveolar epithelial cells in the lung apices and in adipocytes, with reactivation being associated with the upregulation of resuscitation promoting factors within Mtb and the escape of newly dividing microorganisms into alveoli and bronchi in the form of lipid pneumonia. These views need not be mutually exclusive. However, if minimal intermittent recrudescence were to take place within the alveolar space, this would contradict the very definition of latency, which implies that no access of Mtb to the airways exists during latency.