Sterilization of granulomas is common in active and latent tuberculosis despite within-host variability in bacterial killing

Abstract

Over 30% of the world’s population is infected with Mycobacterium tuberculosis (Mtb), yet only ~5–10% will develop clinical disease1. Despite considerable effort, we understand little about what distinguishes individuals who progress to active tuberculosis (TB) from those who remain latent for decades. The variable course of disease is recapitulated in cynomolgus macaques infected with Mtb2. Active disease in macaques is defined by clinical, microbiologic and immunologic signs and occurs in ~45% of animals, while the remaining are clinically asymptomatic2,3. Here, we use barcoded Mtb isolates and quantitative measures of culturable and cumulative bacterial burden to show that most lesions are likely founded by a single bacterium and reach similar maximum burdens. Despite common origins, the fate of individual lesions varies substantially within the same host. Strikingly, in active disease, the host sterilizes some lesions even while others progress. Our data suggest that lesional heterogeneity arises, in part, through differential killing of bacteria after the onset of adaptive immunity. Thus, individual lesions follow diverse and overlapping trajectories, suggesting critical responses occur at a lesional level to ultimately determine the clinical outcome of infection. Defining the local factors that dictate outcome will be important in developing effective interventions to prevent active TB.

Macrophage arginase-1 controls bacterial growth and pathology in hypoxic tuberculosis granulomas

“…in our model, as compared with aerosol-infected mice (10 6 cfus), could allow the development of more stratified granulomas (37) in which the proportion of neutrophils is lower and necrosis is caused mainly by the death of highly infected macrophages from cytokine-mediated toxicity. These granulomas are more representative of the typical granulomas seen in experimental TB in NHPs, which in turn are considered the models most representative of the human pathology (51). A key difference in our study and NHP studies is the expression of both Arg1 and NOS2 in macrophages in the latter.…”

Immunity and Immunopathology in the Tuberculous Granuloma

“…Although the mechanism of infected macrophage egress remains unclear, it does appear to be the main mode of establishing multiple infection foci early in infection. It is conceivably a mycobacterial bet-hedging strategy because different granulomas within the same individual can expand or contract from the earliest stages of infection as shown by close monitoring of guinea pigs, zebrafish, and monkeys and surmised from detailed histopathological studies of the lungs of infected humans in the prechemotherapy era (Balasubramanian et al 1994;Davis and Ramakrishnan 2009;Adams et al 2011;Lin et al 2014).…”

Rifamycin action on RNA polymerase in antibiotic-tolerant Mycobacterium tuberculosis results in differentially detectable populations

“…In pathologic lesions, these subpopulations can also endure exposure to chemotherapeutics, including within cavities whose bacilli populate infectious respiratory tract secretions and provide most of the material for diagnosis and treatment monitoring. When such stresses are modeled in vitro, they can lead to suppression of Mtb replication and phenotypic tolerance to antimicrobial drugs without impairing the ability of the bacteria to resume growth when the stress is relieved (7)(8)(9)(10).…”