TY - JOUR
T1 - Human monocyte-derived macrophage responses to M. tuberculosis differ by the host's tuberculosis, diabetes or obesity status, and are enhanced by rapamycin
AU - Restrepo, Blanca I.
AU - Khan, Arshad
AU - Singh, Vipul K.
AU - Erica de-Leon, de-Leon
AU - Aguillón-Durán, Génesis P.
AU - Ledezma-Campos, Eder
AU - Canaday, David H.
AU - Jagannath, Chinnaswamy
N1 - Funding Information:
This work was supported by the National Institutes of Health , National Institute of Allergy and Infectious Diseases (NIAID) , grant 1R21AI144541 to BIR and CJ, and AI13578 to CJ (and Dr. Deepak Kaushal).
Publisher Copyright:
© 2020 Elsevier Ltd
PY - 2021/1
Y1 - 2021/1
N2 - Human macrophages play a major role in controlling tuberculosis (TB), but their anti-mycobacterial mechanisms remain unclear among individuals with metabolic alterations like obesity (TB protective) or diabetes (TB risk). To help discern this, we aimed to: i) Evaluate the impact of the host's TB status or their comorbidities on the anti-mycobacterial responses of their monocyte-derived macrophages (MDMs), and ii) determine if the autophagy inducer rapamycin, can enhance these responses. We used MDMs from newly diagnosed TB patients, their close contacts and unexposed controls. The MDMs from TB patients had a reduced capacity to activate T cells (surrogate for antigen presentation) or kill M. tuberculosis (Mtb) when compared to non-TB controls. The MDMs from obese participants had a higher antigen presenting capacity, whereas those from chronic diabetes patients displayed lower Mtb killing. The activation of MDMs with rapamycin led to an enhanced anti-mycobacterial activity irrespective of TB status but was not as effective in patients with diabetes. Further studies are warranted using MDMs from TB patients with or without metabolic comorbidities to: i) elucidate the mechanisms through which host factors affect Mtb responses, and ii) evaluate host directed therapy using autophagy-inducing drugs like rapamycin to enhance macrophage function.
AB - Human macrophages play a major role in controlling tuberculosis (TB), but their anti-mycobacterial mechanisms remain unclear among individuals with metabolic alterations like obesity (TB protective) or diabetes (TB risk). To help discern this, we aimed to: i) Evaluate the impact of the host's TB status or their comorbidities on the anti-mycobacterial responses of their monocyte-derived macrophages (MDMs), and ii) determine if the autophagy inducer rapamycin, can enhance these responses. We used MDMs from newly diagnosed TB patients, their close contacts and unexposed controls. The MDMs from TB patients had a reduced capacity to activate T cells (surrogate for antigen presentation) or kill M. tuberculosis (Mtb) when compared to non-TB controls. The MDMs from obese participants had a higher antigen presenting capacity, whereas those from chronic diabetes patients displayed lower Mtb killing. The activation of MDMs with rapamycin led to an enhanced anti-mycobacterial activity irrespective of TB status but was not as effective in patients with diabetes. Further studies are warranted using MDMs from TB patients with or without metabolic comorbidities to: i) elucidate the mechanisms through which host factors affect Mtb responses, and ii) evaluate host directed therapy using autophagy-inducing drugs like rapamycin to enhance macrophage function.
KW - Autophagy
KW - Diabetes
KW - Host-directed therapy
KW - Macrophages
KW - Monocytes
KW - Tuberculosis
KW - Macrophages/microbiology
KW - Cross-Sectional Studies
KW - Humans
KW - Middle Aged
KW - Male
KW - Mycobacterium tuberculosis/drug effects
KW - Diabetes Mellitus
KW - Anti-Bacterial Agents/pharmacology
KW - Sirolimus/pharmacology
KW - Young Adult
KW - Tuberculosis/complications
KW - Adolescent
KW - Obesity/complications
KW - Adult
KW - Female
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U2 - 10.1016/j.tube.2020.102047
DO - 10.1016/j.tube.2020.102047
M3 - Article
C2 - 33418150
AN - SCOPUS:85099253784
SN - 1472-9792
VL - 126
SP - 102047
JO - Tuberculosis
JF - Tuberculosis
M1 - 102047
ER -