Immune activation of the host cell induces drug tolerance in Mycobacterium tuberculosis both in vitro and in vivo

Abstract

Russell et al. show that activation of Mycobacterium tuberculosis–infected macrophages in vitro and in vivo enhances drug tolerance and renders the bacilli more refractory to drug-dependent killing.

Interplay of human macrophages and Mycobacterium tuberculosis phenotypes

“…Bacterial replication is restricted by phagolysosomal effectors (Paper 1). Although we did not observe drug tolerance of intracellular Mtb, activation of cells hypothetically induces drug tolerance, as demonstrated by Liu et al for murine macrophages [381]. Encapsulated Mtb with ESAT6 on their surface lead to rapid ESAT6-dependent host cell death, hypothetically via integration of ESAT6 into host membranes and membrane lysis (Paper 3).…”

“…Furthermore, passage of M. marinum through macrophages induced drug tolerance, also here independent of the bacterial replication rate [378]. Recently, bacterial tolerance was demonstrated in activated macrophages, and was mainly attributed to nitrosative stress [381]. Whereas these studies used murine macrophages (or human macrophages cultivated at hypoxic conditions [306]), our results from human macrophages incubated in normoxia did not show intracellular tolerance, a finding that we expanded by prolonging antibiotic treatment times and by lowering drug concentrations to the levels inducing tolerance in macrophages in other studies [306,378] (Paper 2, Figure 4).…”

“…Several studies suggested a role for NO in human TB [140,255,256], but it is conceivable that NO production in human macrophages requires further activation signals. If induction of drug tolerance also in humans largely depends on RNS stress as demonstrated in mice [381], the choice of cells could explain why we did not observe antibiotic tolerance in vitro.…”

“…This phenomenon of host cell-induced tolerance was recently confirmed, as mouse macrophages harbored a higher percentage of tolerant Mtb when cells were IFNγ and LPSactivated, and Mtb burden in immunized mice was similar in untreated and INH-treated animals. iNOS-mediated host defenses contributed most to the induction of tolerance in murine cells [381].…”

“…Contrary to other in vitro models, intracellular slow-growing Mtb were not more drug tolerant compared to their replicating phenotypic counterpart. Recent evidence suggests that NO is the major host effector driving induction of drug tolerance inside macrophages [381], but NO production is also host-protective. This ambivalence regarding the effects of NO is not surprising, as Mtb obviously has learned to cope with host pressures.…”