TOR functions as a molecular switch connecting an iron cue with host innate defense against bacterial infection

Abstract

As both host and pathogen require iron for survival, iron is an important regulator of host-pathogen interactions. However, the molecular mechanism by which how the availability of iron modulates host innate immunity against bacterial infections remains largely unknown. Using the metazoan Caenorhabditis elegans as a model, we demonstrate that infection with a pathogenic bacterium Salmonella enterica serovar Typhimurium induces autophagy by inactivating the target of rapamycin (TOR). Although the transcripts of ftn-1 and ftn-2 encoding two H-ferritin subunits are upregulated upon S. Typhimurium infection, the ferritin protein is kept at a low level due to its degradation mediated by autophagy. Autophagy, but not ferritin, is required for defense against S. Typhimurium infection under normal circumstances. Increased abundance of iron suppresses autophagy by activating TOR, leading to an increase in the ferritin protein level. Iron sequestration, but not autophagy, becomes pivotal to protect the host from S. Typhimurium infection in the presence of exogenous iron. Our results show that TOR acts as a regulator linking iron availability with host defense against bacterial infection.

The TOR signaling pathway regulates vegetative development, aflatoxin biosynthesis, and pathogenicity inAspergillus flavus

“…Previous findings demonstrated that the Tor kinase could function as a molecular switch connecting an iron cue to defend against pathogen infection in C. elegans [56] .…”

The p38 MAPK/PMK-1 Pathway Is Required for Resistance to Nocardia farcinica Infection in Caenorhabditis elegance

“…The molecular mechanism underlying SKN-1-mediated innate immunity remains unclear. Previously, we and others have demonstrated that autophagy plays an important role in C. elegans defense against a variety of pathogenic bacteria by repairing organismal insults [ 15 , 20 , 48 ]. SKN-1 up-regulates a set of autophagic genes in the germline-deficient glp-1 (e2141ts) mutants [ 49 ].…”

Structural and functional relationship of mammalian and nematode ferritins

“…Recently, the mechanistic target of rapamycin (mTOR) pathway has been described as a regulator of autophagy and ferritin activation (Ma et al, 2021 ). The correlation between these processes was observed in C. elegans following external iron supply and simultaneous infection with pathogens.…”

“…FTN-1 and FTN-2 were demonstrated to be important for defense against pathogen infection, but only when worms were exposed to exogenous iron. In the described conditions, ferritin was responsible for limiting the accessibility of iron used by pathogens for growth (Ma et al, 2021 ).…”

“…Interestingly, it was observed in C. elegans that under stress conditions such as hypoxia, the upregulated FTN-1 level plays an important role in protection against pathogenic bacteria, e.g., Pseudomonas aeruginosa (PA14). Thus, FTN-1 overexpression may be responsible for the increase in worm resistance to pathogens under abnormal environmental conditions (Ma et al, 2021 ; Romero-Afrima et al, 2020 ).…”