(a) Graphical representation depicting Rv load at day 1 (n = 4) and day 56 (n = 5) of infection in lungs and spleen of mice. Lung homogenates prepared at indicated time points were plated on 7H11 plates to enumerate CFU per lung or per spleen (b) Lung and spleen lysates were prepared from uninfected and Rv infected mice 56 days p.i. 100 µg lung lysates were subjected to immunoblotting with α-γH2AX, α-pATM(S1981) α-ATM, α-pCHK2(T68), α-CHK2, α-pAkt (S473), α-Akt, α-p53 and α-β-actin antibodies. (c) PΦ were infected with Rv at high MOI (1:10) as described above. 24 h p.i, cells were treated with either 3.6 µM isoniazid (INH) or 10 µM ATM-I alone or INH + ATM-I together. CFUs were enumerated at 24, 48 and 72 hr post treatment. (d) Schematic representation of the mice infection and drug treatment protocol used. (e–f) CFUs were enumerated in lungs of mice at Day 1, and in the lungs (e) and spleen (f) on day 15 and 30 of infection. Number of mice in each batch was 6 (n = 6) except in Rv at Day 1(n = 5). Error bar, SD. *, p≤0.05; **, p≤0.005; ***, p≤0.0005. (g) Model depicting the findings. Rv induces genotoxicity and causes deleterious DSBs in the host genome through SecA2 secretome. Host cell in response to the occurrence of DSBs activate ATM kinase and is recruited at the site of damage by the sensor, MRN complex. Activated ATM autophosphorylates itself and phosphorylates H2AX in the chromatin flanking the sites of DNA damage, which becomes the foundation for the recruitment of mediator protein MDC1, thus amplifying DDR. pATM promote recruitment of 53BP1 at the damage site. pATM as a part of DDR also activates downstream effectors, Chk2 and p53, which are responsible for alterations in the host cell cycle. pATM in a parallel pathway also activates Akt, which is known inhibit apoptosis and promote cell survival. Activation of ATM and Akt and subsequent inhibition of apoptosis provides survival advantage to Rv. Inhibition of ATM or Akt activation through inhibitors, ATM-I or Akt-I, respectively, promote host cell apoptosis, which impedes the bacilli growth. Phosphorylation status of proteins is depicted with a P in a circle.