Latent tuberculosis: what the host "sees"?

Abstract

Mycobacterium tuberculosis (MTB), the causative agent of tuberculosis (TB), is the most successful pathogen of mankind and remains a major threat to global health as the leading cause of death due to a bacterial pathogen. Yet 90-95% of those who are infected with MTB remain otherwise healthy. These people are classified as "latently infected," but remain a reservoir from which active TB cases will continue to develop ("reactivation tuberculosis"). Latent infection is defined by the absence of clinical symptoms of TB in addition to a delayed hypersensitivity reaction to the purified protein derivative of MTB used in tuberculin skin test or a T-cell response to MTB-specific antigens. In the absence of reliable control measures for tuberculosis, understanding latent MTB infection and subsequent reactivation is a research priority. This review aims to summarize the recent findings in human and non-human primate models of tuberculosis that have led to new concepts of latent tuberculosis.

Fig. 1

The outcome of MTB infection can be viewed as spectrum “heat map” with corresponding stages of infection from bacterial clearance (cold-lower end [blue]) to disseminated disease (hot-upper end [dark red]). The classical, bimodal classification based on the presence or absence of clinical symptoms: active (marked in dashes [red]) and latent (marked in dashes-dots [blue]) TB are marked, to indicate the variability within those categories. In addition, recent studies support the existence of subclinical infection (marked in dots [green]), which overlaps with both active and latent TB. Bacterial replication is expected to increase up the spectrum of infection. The inflammatory factors [Pro- (P) and Anti- (A) inflammatory] are at balance at the lower end of the spectrum controlling bacterial replication, while as the infection advances up the spectrum, this balance is lost resulting in increase in bacterial burden and/or increased pathology. Similarly, the position in the spectrum depicts the risk of reactivation, higher on the spectrum are at higher risk. Treatment with either combined antiretroviral therapy (cART), isoniazide preventive therapy (IPT) or anti tubercular therapy (ATT), shifts one down the spectrum, and therefore, less susceptible to reactivation. Detectable response to PPD or in IGRA may vary from negative to positive within the latent spectrum, although this is speculative. The type of T cells response in in vitro assays range from less central memory (CM) response at the lower end of the spectrum to effector memory (EM) and terminally differentiated (Tdiff) phenotype with increase in functionality of the T cells as they go higher the spectrum; again this has not been proven. Adapted from [–25] (Color figure online)