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The implications of TLR-2 mediated alterations in cytosolic-Ca 2+ ((Ca 2+ ) c ) levels in  M .  smegmatis  infections is not well known. Using headkidney macrophages (HKM) from  Clarias gariepinus , we observed TLR-2 signalling is required in the phagocytosis of  M .  smegmatis .  M .  smegmatis  induced caspase-dependent HKM apoptosis in MOI, time and growth-phase dependent manner. RNAi and inhibitor studies demonstrated critical role of TLR-2 in eliciting (Ca 2+ ) c -surge and c-Src-PI3K-PLC axis playing an intermediary role in the process. The (Ca 2+ ) c -surge triggered downstream ER-stress and superoxide (O 2  − ) generation. The cross-talk between ER-stress and O 2  −  amplified TNF-α production, which led to HKM apoptosis and bacterial clearance. Release of nitric oxide (NO) was also observed and silencing the NOS2-NO axis enhanced intracellular bacterial survival and attenuated caspase activity. Pre-treatment with diphenyleneidonium chloride inhibited NO production implicating O 2  −– NO axis imperative in  M .  smegmatis- induced HKM apoptosis. NO positively impacted CHOP expression and TNF-α production in infected HKM. We conclude that, TLR-2 induced (Ca 2+ ) c -surge and ensuing cross-talk between ER-stress and O 2  −  potentiates HKM pathology by amplifying pro-inflammatory TNF-α production. Moreover, the pro-oxidant environment triggers NO release which prolonged ER-stress and TNF-α production, culminating in HKM apoptosis and bacterial clearance. Together, our study suggests HKM an alternate model to study macrophage-mycobacteria interactions.

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TLR-2 mediated cytosolic-Ca2+ surge activates ER-stress-superoxide-NO signalosome augmenting TNF-α production leading to apoptosis of Mycobacterium smegmatis-infected fish macrophages