Rv0687 a Putative Short-Chain Dehydrogenase Is Required for In Vitro and In Vivo Survival of Mycobacterium tuberculosis
<p><b>Growth kinetics of</b> RvΔ0687. (<b>A</b>) <b>Growth kinetics RvΔ0687 in 7H9 complete media with OADC</b>. The WT, RvΔ0687 and C-Rv0687 strains were grown in 7H9 complete media, and the growth kinetics were measured at day 0, 4, 8 and 12. Aliquots of bacterial cultures were serially diluted and spotted onto 7H10 complete media and colony forming units (CFUs) were calculated per ml of bacterial culture and graphs were plotted. Experiment was performed in duplicates with biological samples and observed that there was no significance between the <span class="html-italic">Mtb</span> strains tested for survival. (<b>B</b>) <b>Growth kinetics RvΔ0687 in 7H9 media with dextrose</b>. The WT, RvΔ0687 and C-Rv0687 strains were grown in 7H9 dextrose media without OADC until day 12, and the growth was observed by serially diluting the bacterial strains and plating onto 7H10-OADC media. The observed colonies were enumerated to calculate CFUs/mL and graphs were plotted. Experiments were repeated with three biological samples (triplicates), mean ± SD was plotted, and significance was calculated using Two-way ANOVA between the bacterial strains at tested time points.</p> "> Figure 2
<p><b>RvΔ0687 is susceptible to oxidative (ROS) and nitrite stress</b>. (<b>A</b>–<b>E</b>) <b>Susceptibility of RvΔ0687 to oxidative (ROS stress)</b>. (<b>A</b>). <b>Untreated Strains</b>. The WT, RvΔ0687 and C-Rv0687 strains were grown in 7H9 complete media, pelleted, washed with PBST, and added to 7H9 dextrose media and the growth was monitored at 0, 6, 24, 48 and 96 h and the CFUs were enumerated by plating onto 7H10 OADC plates. (<b>B</b>) <b>Effect of 5 mM H<sub>2</sub>O<sub>2</sub> stress</b>. The WT, RvΔ0687 and C-Rv0687 strains were grown in 7H9 dextrose media and exposed to 5 mM H<sub>2</sub>O<sub>2</sub> and the growth of all the strains were monitored at 0, 24, 48 and 96 h post-treatment. The cultures were serially diluted at each time point after post-treatment and spotted onto 7H10 OADC plates and CFUs were calculated for 1 mL of bacterial culture. (<b>C</b>) <b>Effect of 10 mM H<sub>2</sub>O<sub>2</sub> stress</b>. The WT, RvΔ0687 and C-Rv0687 strains were grown in 7H9 dextrose media and exposed to 10 mM H<sub>2</sub>O<sub>2</sub> and the growth of all the bacterial strains was monitored. The experiment was carried out in triplicates and significance was calculated using Two-way ANOVA, the error bars indicate the standard deviation (* <span class="html-italic">p</span> < 0.1, ** <span class="html-italic">p</span> < 0.01, *** <span class="html-italic">p</span> < 0.001). Dotted lines represent the limit of detection. (<b>D</b>) <b>Effect of 2 mM tert-butyl hydroxide (tBOOH)</b>. The WT, RvΔ0687 and C-Rv0687 strains were grown in 7H9 complete media. The pellet was washed twice with PBST and suspended in 7H9 dextrose media, and treated with 2 mM tBOOH and monitored at 0, 24, 48, 72 and 96 h after post-treatment. The sensitivity was analyzed by plating the serially diluted cultures in PBST and spotted onto 7H10. CFUs were enumerated per mL of bacteria and graphs were plotted. The experiment was carried out in triplicates and significance was calculated using Two-way ANOVA and T-test between bacterial strains (* <span class="html-italic">p</span> < 0.1) and “n.d” considered as bacteria not detected. (<b>E</b>) <b>Effect of nitrite stress (2 mM SNAP)</b>. The WT, RvΔ0687 and C-Rv0687 strains were grown in 7H9 dextrose media and treated with 2 mM SNAP, and the bacterial strains were spotted onto 7H10 OADC by serially diluting the cultures. The CFUs were estimated after 3 weeks of incubation and CFUs were calculated per ml of bacterial culture. The experiment was carried out in triplicates and, using Two-way ANOVA, significance was calculated between the bacterial strains (** <span class="html-italic">p</span> < 0.01).</p> "> Figure 3
<p>(<b>A</b>–<b>C</b>) <b>Rv0687 deletion in <span class="html-italic">Mtb</span> does not impact intracellular NADH/NAD<sup>+</sup> concentrations</b>.</p> "> Figure 4
<p><b>RvΔ0687 is sensitive to Delamanid and NMR711 treatment</b>. The WT, RvΔ0687 and C-Rv0687 strains of ~1 × 10<sup>6</sup> CFU of bacteria were incubated with serially diluted (<b>A</b>) <b>Delamanid</b>, (<b>B</b>) <b>NMR711</b>, (<b>C</b>) <b>Rifampicin</b>, (<b>D</b>) <b>Isoniazid</b>, (<b>E</b>) <b>Bedaquiline</b>. Alamar Blue was added and plates were incubated at 37 °C. The absorbance was measured at 590 nm using plate reader from day 1 to day 7 to monitor the bacterial survival and growth. Blank wells containing drugs and Alamar Blue were maintained as controls. Graphs were plotted using OD590 nm values at day 7 and Two-way ANOVA with Tukey’s correction method was used to calculate the significance between WT, RvΔ0687 and C-Rv0687 strains (* <span class="html-italic">p</span> < 0.1 and <span class="html-italic">** p</span> < 0.01). This experiment was performed in duplicates using appropriate controls.</p> "> Figure 5
<p>(<b>A</b>) <b>Rv0687 is required for <span class="html-italic">Mtb</span> growth and suppression of inflammatory immune response in BMDMs</b>. The WT, RvΔ0687 and C-Rv0687 strains were used for BMDMs infection at an MOI 1: 5. The in vitro survival was assessed after days 0, 1, 3, 5 and 7 post-infection and bacterial growth was assessed by serially diluting the infected lysate and plated on 7H10 agar and the plates were incubated for 4–6 weeks to calculate the CFUs. The experiment was performed in triplicates and Two-way ANOVA was used to calculate the significance between the bacterial strains. (<b>B</b>–<b>E</b>) <b>Cytokine expression during BMDMs infection</b>. The WT, RvΔ0687 and C-Rv0687 strains infected with BMDMs were analyzed for the expression of TNF-α, IL-1β, MIP-1α and IP-10 cytokines using lysates at day 0, 1 and 5 post-infection. (<b>B</b>) TNF-α, (<b>C</b>) MIP-1α, (<b>D</b>) IL-1β, (<b>E</b>) IP-10. The experiment was performed in triplicates and Two-way ANOVA with Tukey’s correction method was used to calculate the significance between uninfected control and infected bacterial strains (*** <span class="html-italic">p</span> < 0.001, ** <span class="html-italic">p</span> < 0.01 and * <span class="html-italic">p</span> < 0.1). “ns” stands for not significant.</p> "> Figure 6
<p>(<b>A</b>–<b>F</b>) <b>RvΔ0687 is attenuated for survival in</b> the <b>immunocompromised (Rag<sup>−/−</sup>) and immunocompetent (C57BL/6) mice model</b>. (<b>A</b>) <b>Infection strategy</b>. (<b>B</b>,<b>C</b>) <b>Bacterial load in Rag</b><sup>−/−</sup> <b>lungs and spleen.</b> The WT, RvΔ0687 and C-Rv0687 strains were used to infect the Rag<sup>−/−</sup> mice (n = 4 animals per group) and euthanized at W0, W4 and W8. Lungs and spleen were harvested, homogenized, and used to enumerate bacterial load via CFU assay. The experiment was performed with n = 5/group and significance was calculated using Two-way ANOVA ** <span class="html-italic">p</span> < 0.01. (<b>D</b>) <b>Survival analysis of WT and RvΔ0687 in Rag</b><sup>−/−</sup>. The survival of mice post infection with WT, C-Rv0687 and RvΔ0687 was performed with n = 4 animals per group, and the survival was monitored for 125 days and plotted using the Log rank test. (<b>E</b>,<b>F</b>) <b>Bacterial load in C57BL/6 lungs and spleen</b>. The WT, RvΔ0687 and C-Rv0687 strains were used to infect C57BL/6 mice (n = 4 animals per group) and were euthanized at W0, W4 and W8. Lungs and spleen were processed for bacterial enumeration and CFUs were enumerated per lung and spleen. Dotted line in (<b>C</b>,<b>F</b>) represents the limit of detection. The experiment was performed with appropriate statistical numbers and significance was calculated using Two-way ANOVA (** <span class="html-italic">p</span> < 0.01 and * <span class="html-italic">p</span> < 0.1).</p> ">
Abstract
:1. Introduction
2. Results
2.1. Growth Kinetics of RvΔ0687 in Broth Media
2.2. RvΔ0687 Is Sensitive to ROS and Nitrite Stress Generating Agents
2.3. Deletion of Rv0687 Gene Does Not Impact the Mtb NADH, and NAD+ and NADH/NAD+ Ratio In Vitro
2.4. Deletion of Rv0687 Enhances Susceptibility of Mtb to Antimycobacterial Drugs Delamanid and NMR711
2.5. RvΔ0687 Is Required for Intracellular Replication and Suppression of Early Inflammatory Immune Response in Macrophages
2.6. RvΔ0687 Is Attenuated In Vivo in Immunocompromised and Immunocompetent Mice
3. Discussion
4. Materials and Methods
4.1. Bacterial Strains
4.2. Gene Knockout Construction and Confirmation
4.3. Assessing Mtb Response to ROS and Nitrite Stress Generating Agents
4.4. Quantification of Mtb NADH and NAD+ Levels
4.5. Response of Mtb to Mycobacterial Drugs
4.6. Infection of Bone Marrow Derived Macrophages (BMDMs)
4.7. Measurement of ROS and RNS in BMDMs during Infection
4.8. Mouse Infection Experiments
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Bhargavi, G.; Mallakuntla, M.K.; Kale, D.; Tiwari, S. Rv0687 a Putative Short-Chain Dehydrogenase Is Required for In Vitro and In Vivo Survival of Mycobacterium tuberculosis. Int. J. Mol. Sci. 2024, 25, 7862. https://doi.org/10.3390/ijms25147862
Bhargavi G, Mallakuntla MK, Kale D, Tiwari S. Rv0687 a Putative Short-Chain Dehydrogenase Is Required for In Vitro and In Vivo Survival of Mycobacterium tuberculosis. International Journal of Molecular Sciences. 2024; 25(14):7862. https://doi.org/10.3390/ijms25147862
Chicago/Turabian StyleBhargavi, Gunapati, Mohan Krishna Mallakuntla, Deepa Kale, and Sangeeta Tiwari. 2024. "Rv0687 a Putative Short-Chain Dehydrogenase Is Required for In Vitro and In Vivo Survival of Mycobacterium tuberculosis" International Journal of Molecular Sciences 25, no. 14: 7862. https://doi.org/10.3390/ijms25147862