Heat-shock transcription factor (HSF)-1 pathway required for Caenorhabditis elegans immunity

Abstract

Innate immunity comprises physical barriers, pattern-recognition receptors, antimicrobial substances, phagocytosis, and fever. Here we report that increased temperature results in the activation of a conserved pathway involving the heat-shock (HS) transcription factor (HSF)-1 that enhances immunity in the invertebrate Caenorhabditis elegans. The HSF-1 defense response is independent of the p38 MAPK͞PMK-1 pathway and requires a system of chaperones including small and 90-kDa inducible HS proteins. In addition, HSF-1 is needed for the effects of the DAF-2 insulin-like pathway in defense to pathogens, indicating that interacting pathways control stress response, aging, and immunity. The results also show that HSF-1 is required for C. elegans immunity against Pseudomonas aeruginosa, Salmonella enterica, Yersinia pestis, and Enterococcus faecalis, indicating that HSF-1 is part of a multipathogen defense pathway. Considering that several coinducers of HSF-1 are currently in clinical trials, this work opens the possibility that activation of HSF-1 could be used to boost immunity to treat infectious diseases and immunodeficiencies.heat-shock protein ͉ innate immunity ͉ MAPK ͉ infection ͉ pathogen I ncreased temperature promotes expression of heat-shock (HS) proteins (HSPs) that are found in high levels in almost all inflammatory diseases (1). However, the precise mechanism by which increased temperature mediates innate immunity is not clear. The nematode Caenorhabditis elegans, which has evolved an immune system to recognize pathogens and respond accordingly (2-4), provides an excellent compromise between complexity and genetic tractability to dissect innate immunity pathways activated by heat stress.A hallmark of C. elegans immunity is activation of defense responses through a conserved p38 MAPK pathway. As in mammalian innate immunity, the p38 MAPK signaling pathway is required for proper C. elegans defense against the human opportunistic pathogen Pseudomonas aeruginosa, which is the major cause of death in cystic fibrosis patients and immunocompromised individuals (5, 6). The pathway also is required to elicit an apoptotic response to Salmonella enterica in the C. elegans germline (7) and for defense to Bacillus thuringiensis toxin Cry5B (8). Based on the fact that C. elegans does not have NF-B-like transcription factors and that the p38 MAPK pathway seems to be more ancient than NF-B (9, 10), it has been postulated that the p38 MAPK pathway is the ancestral immune pathway of a common ancestor of insects, nematodes, and vertebrates (11,12).Although MAPKs have been involved in mammalian defense response and activation of HSPs (13-15), it was unknown whether HSPs and HS transcription factor (HSF)-1 function downstream of the MAPK-mediated immune responses. Here we report that activation of a conserved pathway involving HSF-1 triggers C. elegans immunity to bacterial pathogens. We demonstrate that both small and 90-kDa HSPs activated in an HSF-1-dependent manner are effectors responsible for the immune response. Our res...

Exposure of gnotobiotic Artemia franciscana larvae to abiotic stress promotes heat shock protein 70 synthesis and enhances resistance to pathogenic Vibrio campbellii

“…Asterisk indicates significant difference (p<0.05) between stress treatment and control How Hsp70 and other Hsps protect against pathogenic V. campbellii is unclear, but extracellular Hsps are known to regulate the innate immune response (Pockley 2003;Chen et al 1999). For instance, the heat-induced synthesis of small heat shock proteins and Hsp90 triggers C. elegans immunity to pathogenic Pseudomonas aeruginosa (Singh and Aballay 2006a). The mechanism may involve heat shock transcription factor-1 and the associated DAF2/DAF-16 pathway which regulates aging and immunity in nematodes (Singh and Aballay 2006b).…”

Disease tolerance and immunity in host protection against infection

“…Proteotoxic damage responses are aimed at repairing or eventually degrading unfolded nascent or mature proteins as a means to preserve essential cellular functions 53,54 . Proteotoxic damage responses can act as bona fide tissue damage control mechanisms, promoting the establishment of disease tolerance to bacterial infection 53,[55][56][57][58] ( Figure 2). Of note, proteotoxic damage responses are also involved in the regulation of immune-driven resistance mechanisms against intracellular bacteria and viruses, some of which evolved to modulate these responses as a strategy to repress host resistance to infection 53 59 .…”

Autophagy genes protect against Salmonella typhimurium infection and mediate insulin signaling-regulated pathogen resistance

“…The Salmonella infection survival assay was performed at 25°C to reproduce published experimental conditions in which pathogen resistance was observed (23). Salmonella-infected TJ356 animals lived significantly longer than control N2 wild-type worms (Fig.…”

“…Next, we examined whether autophagy induction is required for the pathogen resistance of TJ356 animals (23). The Salmonella infection survival assay was performed at 25°C to reproduce published experimental conditions in which pathogen resistance was observed (23).…”