A Caspase-Independent Pathway Mediates Macrophage Cell Death in Response toMycobacterium tuberculosisInfection

Abstract

Macrophages can undergo apoptosis after infection with Mycobacterium tuberculosis. This macrophage response deprives the bacillus of its niche cell and supports the host response through better antigen presentation. The intracellular pathways of apoptosis that elaborate this macrophage response are not well understood. To address this issue, we investigated the contribution of various apoptosis pathways to M. tuberculosis-induced macrophage cell death. We found that macrophages die in a caspase-independent manner after infection with M. tuberculosis (at multiplicities of infection ranging from 1 to 20). There was evidence for the involvement of both the mitochondria (cleavage of Bid) and the lysosomes (cathepsin-mediated DNA fragmentation) in this cell death pathway. Dying macrophages displayed several features typical of apoptosis, including DNA fragmentation, nuclear condensation, and exposure of phosphatidylserine on the plasma membrane. However, nuclear fragmentation was not observed, which suggests that M. tuberculosis-induced cell death differs in some respects from classical apoptosis. This novel mechanism of cell death was blocked by serine protease inhibitors. A better understanding of this protective macrophage response may direct new vaccine and treatment options.

Mycobacterial Secretion Systems ESX-1 and ESX-5 Play Distinct Roles in Host Cell Death and Inflammasome Activation

“…Although our observation of cathepsin B dependency in M. tuberculosis-and M. marinum-induced cell death and inflammasome activation is novel, involvement of lysosomal proteases in Mycobacterium-induced cell death is not unprecedented, as Lee and colleagues (40) previously showed that lysosomal cathepsin inhibitors prevented murine macrophage cell death caused by infection with M. tuberculosis H37Rv. By contrast, lysosomal cathepsins have also been reported to be dispensable for macrophage cell death after M. tuberculosis infection (41). A role for cathepsin B in inflammasome activation has also been observed for some Gram-negative pathogens (43)(44)(45).…”

“…Previous infection studies with M. tuberculosis strain H37Rv showed that cathepsin B and L inhibitors reduced DNA fragmentation and macrophage cell death, suggesting the involvement of lysosomal proteases in Mycobacterium-induced cell death (40,41). In this study, we investigated a possible role for lysosomal proteases cathepsin B, D, and L in M. marinum-induced cell death.…”

Cell death in the host response to infection

“…A serine protease inhibitor appears to block this caspase-independent death. 102 Moreover, at high multiplicity of infection (MOI), M. tuberculosis induces a caspaseindependent cell death that is not observed at low MOI. 103 In the case of Shigella, the primary death mode is pyroptosis, induced through the Ipaf-caspase-1 inflammasome.…”

4′-Chloro-3,5-dihydroxystilbene, a resveratrol derivative, induces lung cancer cell death

“…As shown in Figure 6E, 3-MA could partially reverse cell death, which suggested that the 4'-chloro-3,5-dihydroxystilbene-induced cell death was partially mediated by autophagy. Furthermore, we used various protease inhibitors to analyze whether cell death was caused by an acidic lysosomal protease [19,20] . As shown in Figure 6E, two cathepsin inhibitors (CA074-Me and Z-FA-FMK), two serine protease inhibitors (TLCK and AEBSF) and one proteasome inhibitor (MG132) could not prevent cell death; only one serine protease inhibitor, TPCK, slightly reversed cell death.…”