Genetic analysis of host-pathogen interactions has been hampered by the lack of genetically tractable models of such interactions. We showed previously that the human opportunistic pathogen Pseudomonas aeruginosa kills Caenorhabditis elegans, that P. aeruginosa and C. elegans genes can be identified that affect this killing, and that most of these P. aeruginosa genes are also important for mammalian pathogenesis. Here, we show that Salmonella typhimurium as well as other Salmonella enterica serovars including S. enteritidis and S. dublin can also kill C. elegans. When C. elegans is placed on a lawn of S. typhimurium, the bacteria accumulate in the lumen of the worm intestine and the nematodes die over the course of several days. This killing requires contact with live bacterial cells. The worms die with similar kinetics when placed on a lawn of S. typhimurium for a relatively short time (3-5 hours) before transfer to a lawn of E. coli. After the transfer to E. coli, a high titer of S. typhimurium persists in the C. elegans intestinal lumen for the rest of the worms' life. Furthermore, feeding for 5 hours on a 1:1000 mixture of S. typhimurium and E. coli followed by transfer to 100% E. coli, also led to death after several days. This killing correlated with an increase in the titer of S. typhimurium in the C. elegans lumen, which reached 10,000 bacteria per worm. These data indicate that, in contrast to P. aeruginosa, a small inoculum of S. typhimurium can proliferate in the C. elegans intestine and establish a persistent infection. S. typhimurium mutated in the PhoP/PhoQ signal transduction system caused significantly less killing of C. elegans.
A large body of evidence indicates that metazoan innate immunity is regulated by the nervous system, but the mechanisms involved in the process and the biological significance of such control remain unclear. We show that a neural circuit involving npr-1, which encodes a G-protein-coupled receptor related to mammalian neuropeptide Y receptors, functions to suppress innate immune responses. The inhibitory function of NPR-1 requires a cyclic GMP-gated ion channel encoded by tax-2 and tax-4 as well as the soluble guanylate cyclase GCY-35. Furthermore, we show that npr-1-and gcy-35-expressing sensory neurons actively suppress immune responses of non-neuronal tissues. A fullgenome microarray analysis on animals with altered neural function due to mutation in npr-1 shows an enrichment in genes that are markers of innate immune responses, including those regulated by a conserved PMK-1/P38 MAPK signaling pathway. These results present evidence that neurons directly control innate immunity in C. elegans, suggesting that G-protein coupled receptors may participate in neural circuits that receive inputs from either pathogens or infected sites and integrate them to coordinate appropriate immune responses.Innate immune defense comprises a variety of mechanisms used by metazoans to prevent microbial infections. Activation of the innate immune system upon pathogen recognition results in a rapid and definitive microbicidal response to invading microorganisms that is finetuned to prevent deleterious deficiencies or excesses in the response. The nervous system, which can respond in milliseconds to many types of nonspecific environmental stimuli, has several characteristics that make it an ideal partner with the innate immune system to regulate nonspecific host defenses (1-3). However, even though a large body of evidence indicates that metazoan innate immunity is under the control of the nervous system, the mechanisms involved in the process and the biological significance of such control remain unclear. To provide insights into the neural mechanisms that regulate innate immunity, we have taken advantage of the simple and well studied nervous and innate immune systems of Caenorhabditis elegans.The powerful genetic approaches available to C. elegans research have been used to address central questions concerning the functions of the nervous system (4). With its 302 neurons and 56 glial cells, which represent 37% of all somatic cells in a hermaphrodite, the nervous system is perhaps the most complex organ of C. elegans. Ablation of different neurons has demonstrated that sensory neurons regulate a variety of physiological processes, including dauer formation and adult lifespan (5-8). In addition, C. elegans neurons are known to express To study the role of GPCRs in the regulation of innate immune response, we first determined the susceptibility of forty C. elegans strains carrying mutations in GPCRs to the human opportunistic pathogen Pseudomonas aeruginosa strain PA14, a clinical isolate capable of rapidly killing C. elegan...
Huntington's Disease (HD) is a neurodegenerative disease caused by poly-glutamine expansion in the Htt protein, resulting in Htt misfolding and cell death. Expression of the cellular protein folding and pro-survival machinery by heat shock transcription factor 1 (HSF1) ameliorates biochemical and neurobiological defects caused by protein misfolding. We report that HSF1 is degraded in cells and mice expressing mutant Htt, in medium spiny neurons derived from human HD iPSCs and in brain samples from patients with HD. Mutant Htt increases CK2α′ kinase and Fbxw7 E3 ligase levels, phosphorylating HSF1 and promoting its proteasomal degradation. An HD mouse model heterozygous for CK2α′ shows increased HSF1 and chaperone levels, maintenance of striatal excitatory synapses, clearance of Htt aggregates and preserves body mass compared with HD mice homozygous for CK2α′. These results reveal a pathway that could be modulated to prevent neuronal dysfunction and muscle wasting caused by protein misfolding in HD.
The unfolded protein response (UPR), which is activated when unfolded or misfolded proteins accumulate in the endoplasmic reticulum, has been implicated in the normal physiology of immune defense and in several human diseases including diabetes, cancer, neurodegenerative disease, and inflammatory disease. In this study, we found that the nervous system controlled the activity of a non-canonical UPR pathway required for innate immunity in Caenorhabditis elegans. OCTR-1, a putative octopamine G protein-coupled catecholamine receptor (GPCR, G protein–coupled receptor), functioned in sensory neurons designated ASH and ASI to actively suppress innate immune responses by down-regulating the expression of non-canonical UPR genes pqn/abu in non-neuronal tissues. Our findings suggest a novel molecular mechanism by which the nervous system may sense inflammatory responses and respond by controlling stress-response pathways at the organismal level.
Yersinia pestis, the causative agent of plague, must survive in blood in order to cause disease and to be transmitted from host to host by fleas. Members of the Ail/Lom family of outer membrane proteins provide protection from complement-dependent killing for a number of pathogenic bacteria. The Y. pestis KIM genome is predicted to encode four Ail/Lom family proteins. Y. pestis mutants specifically deficient in expression of each of these proteins were constructed using lambda Red-mediated recombination. The Ail outer membrane protein was essential for Y. pestis to resist complement-mediated killing at 26 and 37°C. Ail was expressed at high levels at both 26 and 37°C, but not at 6°C. Expression of Ail in Escherichia coli provided protection from the bactericidal activity of complement. High-level expression of the three other Y. pestis Ail/Lom family proteins (the y1682, y2034, and y2446 proteins) provided no protection against complement-mediated bacterial killing. A Y. pestis ail deletion mutant was rapidly killed by sera obtained from all mammals tested except mouse serum. The role of Ail in infection of mice, Caenorhabditis elegans, and fleas was investigated.
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...
A Caenorhabditis elegans-Salmonella enterica host-pathogen model was used to identify both novel and previously known S. enterica virulence factors (HilA, HilD, InvH, SptP, RhuM, Spi4-F, PipA, VsdA, RepC, Sb25, RfaL, GmhA, LeuO, CstA, and RecC), including several related to the type III secretion system (TTSS) encoded in Salmonella pathogenicity island 1 (SPI-1). Mutants corresponding to presumptive novel virulence-related genes exhibited diminished ability to invade epithelial cells and/or to induce polymorphonuclear leukocyte migration in a tissue culture model of mammalian enteropathogenesis. When expressed in C. elegans intestinal cells, the S. enterica TTSS-exported effector protein SptP inhibited a conserved p38 MAPK signaling pathway and suppressed the diminished pathogenicity phenotype of an S. enterica sptP mutant. These results show that C. elegans is an attractive model to study the interaction between Salmonella effector proteins and components of the innate immune response, in part because there is a remarkable overlap between Salmonella virulence factors required for human and nematode pathogenesis.
Compared to mammals, insects, and plants, relatively little is known about innate immune responses in the nematode Caenorhabditis elegans. Previous work showed that Salmonella enterica serovars cause a persistent infection in the C. elegans intestine that triggers gonadal programmed cell death (PCD) and that C. elegans cell death (ced) mutants are more susceptible to Salmonella-mediated killing. To further dissect the role of PCD in C. elegans innate immunity, we identified both C. elegans and S. enterica factors that affect the elicitation of Salmonella-induced PCD. Salmonella-elicited PCD was shown to require the C. elegans homolog of the mammalian p38 mitogen-activated protein kinase (MAPK) encoded by the pmk-1 gene. Inactivation of pmk-1 by RNAi blocked Salmonella-elicited PCD, and epistasis analysis showed that CED-9 lies downstream of PMK-1. Wild-type Salmonella lipopolysaccharide (LPS) was also shown to be required for the elicitation of PCD, as well as for persistence of Salmonella in the C. elegans intestine. However, a presumptive C. elegans TOLL signaling pathway did not appear to be required for the PCD response to Salmonella. These results establish a PMK-1-dependant PCD pathway as a C. elegans innate immune response to Salmonella.
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