The antidepressant sertraline provides a novel host directed therapy module for augmenting TB therapy
- CSIR- Institute of genomics and Integrative Biology, India
- Academy of Scientific and Innovative Research, India
Figures
Figure 1
Sertraline inhibits Mtb-induced Type I IFN response and restricts intra-macrophage Mtb growth.
(A) IRF-dependent luciferase activity in THP1 Dual macrophages following infection with Mtb at a MOI of 5. Cells were left untreated or treated with increasing concentrations of SRT for 24 hr in …
Figure 2 with 2 supplements
Augmentation property of SRT is due to its ability to inhibit IFN signaling.
(A) Bacterial growth in macrophages treated with HR at C2 and different concentrations of SRT as indicated. Values represented are mean relative CFU at day 5w.r.t day 0 ± SEM of triplicate assays …
Figure 2—figure supplement 1
Bacterial growth in macrophages treated with HR alone or in combination with low doses of SRT as indicated.
The relative CFU w.r.t day 0 is depicted as mean ± SEM of triplicate assays and three independent experiments. (2) In vitro growth of Mtb in 7H9 media containing different concentrations of SRT. Mtb …
Figure 2—figure supplement 2
Effect of sertraline on in vitro Mtb cultures with and without HR.
Figure 3 with 1 supplement
Important role for inflammasome activation in antibiotic potentiation by SRT.
(A) Growth of Mtb in macrophages pre-treated with IFNγ for 16 hr, infected with Mtb for 6 hr and then left untreated or treated with SRT for 3 days. Mean CFU values for triplicate assay wells from …
Figure 3—figure supplement 1
Bacterial growth in naive macrophages or pre-treated with IFNγ.
along with HR. bacterial numbers are plotted as mean CFU ± SEM of triplicate assays and three independent experiments.
Figure 4 with 1 supplement
Adjunct SRT improves host survival in a susceptible mouse model of infection.
(A) Schematic of Mtb infection and drug treatment in C3HeB/FeJ mice. (B) Survival curves of Mtb infected C3HeB/FeJ mice (5) left untreated (red) or treated with SRT alone (blue) or with different …
Figure 4—figure supplement 1
Quantitation of macroscopic lesions in left caudal lobe of lungs of animals infected with Mtb and treated with HR, HRZE or in combination with SRT.
Average number of lesions ± SEM from 10 animals is depicted.
Figure 5
In vivo potentiation of SRT-mediated antimycobacterial activity.
(A) Schematic of infected C3HeB/FeJ mice (10) and treated with HRZE HRC1- 1x: H-100μg/ml, R-40μg/ml, Z-150μg/ml, E-100μg/ml or in combination with SRT (10μg/ml). Animals were euthanized at the end …
Figure 6 with 1 supplement
SRT initiates early bacterial clearance in mice.
(A) Schematic of Mtb infection and drug treatment in C57BL6 mice. Mice were infected with Mtb and treated with HRZE or HRZES (HRC1- 1X: H-100μg/ml, R-40μg/ml, Z-150μg/ml, E-100μg/ml, SRT 10μg/ml) …
Figure 6—figure supplement 1
Balb/c mice were infected with Mtb and the treated with HRZE or HRZES (HRC1- 1 X: H-100μg/ml, R-40μg/ml, Z-150μg/ml, E-100μg/ml, SRT 10 μg/ml).
Lung and spleen CFU at 3 weeks of treatment is depicted as mean CFU ± SEM of five animals.
Figure 7
Addition of SRT helps better control of drug tolerant Mtb in vivo.
(A) Intracellular bacterial growth in THP1 macrophages infected with HR tolerant Mtb strain at a MOI of 5 for 6 hr. Following this, cells were left untreated (NT) or treated with SRT, HR, or HRS for …
Author response image 1
Relative expression of inflammatory cytokines in hMDMs treated with HR or HRS.
Data depict fold expression (transcript abundance) relative to UI alone as mean + SEM from three independent experiments with triplicate wells each at 18h post treatment.
Author response image 2
Relative expression of inflammatory cytokines in mBMDMs treated with HR or HRS.
Data depict fold expression (transcript abundance) relative to UI alone as mean + SEM from two independent experiments with triplicate wells each at 18h post treatment.
Author response image 3
Cytokine levels were determined with a Luminex-based multiplex assay.
Average values + SEM at 18h and 42h post-treatment of three or two independent experiments of triplicate wells (N=2,3).
Author response image 4
IRF dependent luciferase activity in THP1 Dual.
Cells were treated with IFNAR antibody for 2h following infection with mycobactreia and PIC treatment. Data depict luminescence relative to UI and UI + IFNAR Ab as mean + SD experiments with …
Author response image 5
Testing the effect of SRT at lower concentrations: A-IRF dependent luciferase activity in THP1 Dual macrophages following infection with Mtb at a MOI of 5.
Cells were left untreated or treated with increasing concentrations of SRT for 24h in culture and the luminescence in culture supernatants was measured and is represented as mean + SEM from 2 …
Author response image 6
