Adaptation to the intracellular environment of primary human macrophages influences drug susceptibility of Mycobacterium tuberculosis

TY - JOUR

T1 - Adaptation to the intracellular environment of primary human macrophages influences drug susceptibility of Mycobacterium tuberculosis

AU - Lanni, Faye

AU - Wijnant, Gert Jan

AU - Xie, Min

AU - Osiecki, Paulina

AU - Dartois, Véronique

AU - Sarathy, Jansy P.

N1 - Publisher Copyright: © 2023

PY - 2023/3

Y1 - 2023/3

N2 - As a facultative intracellular pathogen, M. tuberculosis (Mtb) is highly adapted to evading antibacterial mechanisms in phagocytic cells. Both the macrophage and pathogen experience transcriptional and metabolic changes from the onset of phagocytosis. To account for this interaction in the assessment of intracellular drug susceptibility, we allowed a 3-day preadaptation phase post-macrophage infection prior to drug treatment. We found that intracellular Mtb in human monocyte-derived macrophages (MDM) presents dramatic alterations in susceptibility to isoniazid, sutezolid, rifampicin and rifapentine when compared to axenic culture. Infected MDM gradually accumulate lipid bodies, adopting a characteristic appearance reminiscent of foamy macrophages in granulomas. Furthermore, TB granulomas in vivo develop hypoxic cores with decreasing oxygen tension gradients across their radii. Accordingly, we evaluated the effects of hypoxia on preadapted intracellular Mtb in our MDM model. We observed that hypoxia induced greater lipid body formation and no additional shifts in drug tolerance, suggesting that the adaptation of intracellular Mtb to baseline host cell conditions under normoxia dominates changes to intracellular drug susceptibility. Using unbound plasma concentrations in patients as surrogates for free drug concentrations in lung interstitial fluid, we estimate that intramacrophage Mtb in granulomas are exposed to bacteriostatic concentrations of most study drugs.

AB - As a facultative intracellular pathogen, M. tuberculosis (Mtb) is highly adapted to evading antibacterial mechanisms in phagocytic cells. Both the macrophage and pathogen experience transcriptional and metabolic changes from the onset of phagocytosis. To account for this interaction in the assessment of intracellular drug susceptibility, we allowed a 3-day preadaptation phase post-macrophage infection prior to drug treatment. We found that intracellular Mtb in human monocyte-derived macrophages (MDM) presents dramatic alterations in susceptibility to isoniazid, sutezolid, rifampicin and rifapentine when compared to axenic culture. Infected MDM gradually accumulate lipid bodies, adopting a characteristic appearance reminiscent of foamy macrophages in granulomas. Furthermore, TB granulomas in vivo develop hypoxic cores with decreasing oxygen tension gradients across their radii. Accordingly, we evaluated the effects of hypoxia on preadapted intracellular Mtb in our MDM model. We observed that hypoxia induced greater lipid body formation and no additional shifts in drug tolerance, suggesting that the adaptation of intracellular Mtb to baseline host cell conditions under normoxia dominates changes to intracellular drug susceptibility. Using unbound plasma concentrations in patients as surrogates for free drug concentrations in lung interstitial fluid, we estimate that intramacrophage Mtb in granulomas are exposed to bacteriostatic concentrations of most study drugs.

KW - Drug tolerance

KW - Intracellular

KW - Lipid bodies

KW - Macrophage

KW - Tuberculosis

UR - http://www.scopus.com/inward/record.url?scp=85149765768&partnerID=8YFLogxK

U2 - 10.1016/j.tube.2023.102318

DO - 10.1016/j.tube.2023.102318

M3 - Article

C2 - 36889104

SN - 1472-9792

VL - 139

JO - Tuberculosis

JF - Tuberculosis

M1 - 102318

ER -