A conserved mitochondrial surveillance pathway is required for defense against Pseudomonas aeruginosa

Abstract

All living organisms exist in a precarious state of homeostasis that requires constant maintenance. A wide variety of stresses, including hypoxia, heat, and infection by pathogens perpetually threaten to imbalance this state. Organisms use a battery of defenses to mitigate damage and restore normal function. Previously, we described a Caenorhabditis elegans-Pseudomonas aeruginosa assay (Liquid Killing) in which toxicity to the host is dependent upon the secreted bacterial siderophore pyoverdine. Although pyoverdine is also indispensable for virulence in mammals, its cytological effects are unclear. We used genetics, transcriptomics, and a variety of pathogen and chemical exposure assays to study the interactions between P. aeruginosa and C. elegans. Although P. aeruginosa can kill C. elegans through at least 5 different mechanisms, the defense responses activated by Liquid Killing are specific and selective and have little in common with innate defense mechanisms against intestinal colonization. Intriguingly, the defense response utilizes the phylogenetically-conserved ESRE (Ethanol and Stress Response Element) network, which we and others have previously shown to mitigate damage from a variety of abiotic stresses. This is the first report of this networks involvement in innate immunity, and indicates that host innate immune responses overlap with responses to abiotic stresses. The upregulation of the ESRE network in C. elegans is mediated in part by a family of bZIP proteins (including ZIP-2, ZIP-4, CEBP-1, and CEBP-2) that have overlapping and unique functions. Our data convincingly show that, following exposure to P. aeruginosa, the ESRE defense network is activated by mitochondrial damage, and that mitochondrial damage also leads to ESRE activation in mammals. This establishes a role for ESRE in a phylogenetically-conserved mitochondrial surveillance system important for stress response and innate immunity.

Interplay between mitochondria and diet mediates pathogen and stress resistance inC. elegans

“…For example, we observed that methylcobalamin supplementation decreased acdh-1 expression by 10-fold or more while proportional increases were seen in resistance to propionate or P. aeruginosa in Liquid Killing. This result corroborates our recent findings that place mitochondrial homeostasis at the heart of this pathogenesis model (Tjahjono and Kirienko, 2017). Although the effect was smaller, benefits from B12 supplementation were still observed when stresses were more pleiotropic (such as heat shock or oxidative stress, where intracellular contents are more uniformly damaged).…”

Caenorhabditis elegans in high-throughput screens for anti-infective compounds

“…Utilizing iron chelators as chemical probes, they found that iron starvation is an important virulence determinant of P. aeruginosa in C. elegans. P. aeruginosa secretes the iron chelating siderophore pyoverdine, which disrupts mitochondrial homeostasis and induces a protective response in C. elegans that involves mitophagy [51] and the activation of innate immune defenses [52,53]. These data support previous studies [54,55], which demonstrate that C. elegans couple mitochondrial homeostasis to immune activation.…”

PqsA Promotes Pyoverdine Production via Biofilm Formation

“…Compromising biofilm development by either genetic or chemical disruption severely decreased pyoverdine biosynthesis and rescued C. elegans from P. aeruginosa pathogenesis. Due to its roles in iron acquisition, regulation of secreted toxins such as the translational inhibitor ToxA and the protease PrpL, disruption of host mitochondrial function, and observations that compromising pyoverdine production is sufficient to rescue hosts from infection, pyoverdine is an important therapeutic target [ 36 , 37 , 38 , 39 , 40 , 41 ].…”