Autophagy May Allow a Cell to Forbear Pyroptosis When Confronted With Cytosol-Invasive Bacteria

Abstract

Inflammatory caspases detect cytosol-invasive Gram-negative bacteria by monitoring for the presence of LPS in the cytosol. This should provide defense against the cytosol-invasive Burkholderia and Shigella species by lysing the infected cell via pyroptosis. However, recent evidence has shown caspase-11 and gasdermin D activation can result in two different outcomes: pyroptosis and autophagy. Burkholderia cepacia complex has the ability invade the cytosol but is unable to inhibit caspase-11 and gasdermin D. Yet instead of activating pyroptosis during infection with these bacteria, the autophagy pathway is stimulated through caspases and gasdermin D. In contrast, Burkholderia thailandensis can invade the cytosol where caspasae-11 and gasdermin D is activated but the result is pyroptosis of the infected cell. In this review we propose a hypothetical model to explain why autophagy would be the solution to kill one type of Burkholderia species, but another Burkholderia species is killed by pyroptosis. For pathogens with high virulence, pyroptosis is the only solution to kill bacteria. This explains why some pathogens, such as Shigella have evolved methods to inhibit caspase-11 and gasdermin D as well as autophagy. We also discuss similar regulatory steps that affect caspase-1 that may permit the cell to forbear undergoing pyroptosis after caspase-1 activates in response to bacteria with partially effective virulence factors.

Gasdermins assemble; recent developments in bacteriology and pharmacology

“…One area of particular interest is the interplay between autophagy and pyroptosis, and how GSDMD is involved to carefully balance host response to pathogenicity of invader, and how invaders inhibit these pathways to shift the balance in their favour ( Figure 1 ). Although covered excellently by Harvest and Miao ( 42 ), who also provide an interesting hypothesis to legitimise the relationship between autophagy and pyroptosis, it is worth briefly covering some of the key findings in the context of this review. As covered above, GSDMD connects direct pathogen sensing to pyroptotic response.…”

“…The cytosolic presence of B. cepacia also activates autophagy in a caspase-11/GSDMD dependent manner, leads to GSDMD-mediated mitochondrial dysfunction and enhances reactive oxygen species (ROS)-induced autophagy, and ultimately restricting the growth of the bacterium without driving pyroptosis ( 51 – 54 ). The balance between pyroptosis and autophagy seems quite contrasting, yet Harvest and Miao present an excellent hypothesis suggesting that autophagy directly deals with intracellular bacteria without sacrificing the host, whereas pyroptosis deals with the infection by recruitment of local phagocytes and immune components ( 42 ). Through an intricate balance of GSDMD-mediated autophagy activation coupled with self-capture of caspase-11 and subsequent limiting of GSDMD-driven pyroptosis, the cell can carefully remove the pathogen without committing explosive suicide, with any remaining pores rescued by the repair machinery ( 55 ).…”

“…At the extreme end of pathogenicity, S. flexneri is able to inhibit caspase-11, GSDMD and autophagy, meaning the cell has limited options and thus explains the lack of innate immunity against S. flexneri . We highly recommend a detailed insight into the processes and proposed mechanisms in the focussed review for a deeper dive into the autophagy-pyroptosis axis in control of bacterial infection ( 42 ).…”