Role of A1 in repressing mitochondrial apoptosis to limit pathogen clearance

Apoptosis is a genetically encoded programmed cell death pathway essential for mammalian development, cellular homeostasis and immunity. We have been studying the mitochondrial (“intrinsic BCL-2-regulated”) and death receptor (“extrinsic”) apoptosis pathways in macrophages that act as sentinels to detect environmental, pathogen or host danger molecules. Pathogens have evolved mechanisms to evade the host immune system by either inducing or blocking apoptosis. Identifying the role of individual BCL-2 pro-survival members during infection should enable us to develop novel treatment strategies, which will be critical as drug resistance is on the rise. Cancer research has driven the development of cost effective small molecule inhibitors that target pro-survival proteins to kill cancer cells. Repurposing these inhibitors to kill infected cells represents an attractive approach but requires a greater understanding of host-pathogen interactions.
Our past work identified pro-survival protein BCL-XL as the Achilles’ heel in bacterial infection and revealed that BCL-XL-targeted inhibitors, known as BH3-mimetics, promote the clearance of life-threatening Legionella infections (Nat. Microb. 2016)(1). Defining the mechanisms by which apoptosis promotes pathogen clearance by macrophages will be vital to advance selective BCL-2 family inhibitors towards the clinic. Accordingly, our recent work revealed that targeting pro-survival BCL-XL and MCL-1 in macrophages exposed to Gram-negative bacteria-derived LPS not only induces apoptosis, but can also trigger inflammation via NOD-like receptor 3 (NLRP3) inflammasome-dependent and -independent activation of Interleukin-1b (IL-1b) (Senior author Cell Rep. 2018)(2). Excitingly, our new data suggests that upon pathogen recognition increased pro-survival A1 levels dictate whether cell death and IL-1b activation ensues. Consequently, we hypothesise that A1 loss is required to trigger mitochondrial apoptosis and our new pathway to IL-1b activation, and may thereby modulate pathogen clearance. Hence drug strategies targeting A1 alone, or combined with BCL-XL selective drugs, may be an effective strategy kill a diverse range of pathogens