Latest post on group Journal Club by David Stirling:

The immune mechanisms responsible for control of Mycobacterium tuberculosis (Mtb) infection and microbial countermeasures to evade this response are a subject of particular interest to our group. Our latest journal club reviewed this paper from Ulrich Schaible’s group, looking at how the mode of cell death in infected neutrophils impacts the ability of macrophages to subsequently control Mtb phagocytosed from the debris.

Unlike attenuated strains such as BCG, Mtb is capable of inducing necrosis in infected neutrophils. The researchers explored the molecular mechanisms behind this effect and found it to be an ESX-1 and reactive oxygen species (ROS)-dependent phenotype. In line with previous reports, mutant bacteria lacking RD1 did not induce substantial necrosis in infected neutrophils, with cells undergoing apoptosis instead. The ability to induce necrosis instead of apoptosis was hypothesised to be important for evasion of host immunity.

Electron microscopy revealed that bacteria from necrotic cells are loosely associated with cellular remnants, whereas those from apoptotic cells remain contained in vesicles. Immunofluorescence on macrophages which had just taken up neutrophil debris was used to investigate the fate of the bacteria upon entry into macrophages. Strikingly, endosomes containing RD1- or ESAT-6-deleted bacteria (from within apoptotic vesicles) rapidly associated with maturation markers such as LAMP1 and Rab7, whereas wild-type bacteria phagocytosed from necrotic cells did not associate with these markers and evaded degradation.

Interestingly, it was also found that inhibitors of ROS pathways could be used to block necrotic cell death in neutrophils and push the cells towards apoptosis. This allowed subsequent control of bacterial growth when the debris from these apoptotic cells was phagocytosed by macrophages.

Overall these findings highlight a fascinating new area for potential host-directed therapies in TB infection. It is possible that regulating the fate of ‘first-responder’ cells in Mtb infection, neutrophils, may in turn tune the ability of macrophages to control the infection downstream. How other components of the tissue immune response to Mtb fit into this model needs to be ascertained, but this paper certainly seems to have opened up a new avenue of investigation.

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