Striking a balance: modulation of host cell death pathways by legionella pneumophila

Abstract

Programmed cell death is considered the ultimate solution for the host to eliminate infected cells, leading to the abolishment of the niche for microbial replication and the ablation of infection. Thus, it is not surprising that successful pathogens have evolved diverse strategies to reprogram the cell death pathways for their proliferation. Using effector proteins translocated by the Dot/Icm type IV secretion system, the facultative intracellular pathogen Legionella pneumophila manipulates multiple host cellular processes to create a niche within host cells to support its replication. Investigation in the past decade has established that in mammalian cells this bacterium actively modulates two host cell death pathways, namely the canonical apoptotic pathway controlled by the mitochondrion and the pyroptotic pathway controlled by the Nod-like receptor Naip5 and the Ipaf inflammasome. In this review, I will discuss the recent progress in understanding the mechanisms the bacterium employs to interfere with these host cell death pathways and how such modulation contribute to the intracellular life cycle of the pathogen.

Keywords: Bcl-2 protein; apoptosis; caspase; effector; infection; type IV secretion.

Figure 1

Host cell death pathways targeted by L. Pneumophila. Internalized L. pneumophila translocates a large number of effectors into host cytosol via the Dot/Icm type IV secretion system. A yet unidentified set of effectors trigger an imbalance between the pro-death and pro-survival members of the Bcl-2 protein family, leading to the insertion of Bax/Bak into the mitochondrial out membrane, thus the release of cytochrome c and subsequent activation of the caspases 3 and 7. Another set of effectors, including LegK1 and LnaB, activate NF- B, most likely by initiating the kinase cascade that ultimately causes phosphorylation and subsequent degradation of I B, the inhibitor of NF- B, leading to nucleus translocation of NF- B and the induction of anti-apoptotic genes such as Xiap and Pai-2, whose product inhibits cell death by targeting caspases 3 and 7. Activation of the MAP kinase pathway by another set of unknown effectors can lead to similar effects. A third set of proteins such as SidF and SdhA, which inhibit host cell death by targeting pro-apoptotic proteins BNIP3 and Bcl-rambo or by unknown mechanisms. In non-permissive mouse macrophages, flagellin reached the cytosol probably via the Dot/Icm transporter is sensed by the NLR receptor Naip5, which together with Ipaf and the inflammasome activates caspase-1, leading to pyroptotic cell death. CREB, cAMP response element-binding protein; LCV, Legionella containing vacuole; MAPK, mitogen-activated protein kinases; Mito, mitochondrion; N, nucleus; Naip5, NLR family, apoptosis inhibitory protein 5; PAI-2, plasminogen activator inhibitor-2; XIAP, X-linked inhibitor of apoptosis protein.