Caenorhabditis elegans innate immune response triggered by Salmonella enterica requires intact LPS and is mediated by a MAPK signaling pathway

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.     

Regulation of aging and innate immunity in C. elegans

The free-living soil nematode Caenorhabditis elegans is a versatile model for the study of the genetic regulation of aging and of host-pathogen interactions. Many genes affecting multiple processes, such as neuroendocrine signalling, nutritional sensing and mitochondrial functions, have been shown to play important roles in determining the lifespan of C. elegans. The DAF-2-mediated insulin signalling pathway is the major pathway that regulates aging in this nematode and this role appears universal; neuroendrocrine signalling also affects aging in Drosophila and mice. Recent studies have shown that the innate immune function in C. elegans is modulated by signalling from the TGF-beta-like, the p38 MAPK and the DAF-2 insulin pathways. The requirement for the DAF-2 pathway in modulating aging and immunity suggests that these processes may be linked at the molecular level. It is well known that as humans age, immunosenescence occurs in which there is a general degradation of immune efficiency. However, the molecular mechanisms involved in this process remain unclear. In this review, we discuss the molecular mechanisms that modulate aging and immune response and attempt to suggest molecular links between these two processes.     

秀丽隐杆线虫先天免疫信号转导途径

秀丽隐杆线虫因其结构简单、易于培养、生命周期短等特点作为一种模式生物已广泛应用于神经系统、衰老机制及细胞程序性死亡的研究。与高等生物不同,秀丽隐杆线虫缺少适应性免疫途径,只有先天免疫途径在抗病原菌、抗氧化应激等方面发挥重要的作用。其体内的胰岛素/胰岛素样生长因子(insulin/ IGF-1)、转化生长因子β(transforming growth factor β,TGF-β)、丝裂原激活的蛋白激酶(mitogen activated protein kinases,MAPK)和细胞程序性死亡(programmed cell death,PCD)4条免疫相关信号转导途径在不同的环境发挥着主要作用。同时,秀丽隐杆线虫的先天免疫系统在进化中有许多保守之处,这为高等生物的免疫机制研究提供了新思路。据此,就有关秀丽隐杆线虫先天免疫信号转导途径的研究进展进行了简述,期望能为人类等高等生物相关联的免疫作用研究提供借鉴和参考。     

The Evolutionarily Conserved Mediator Subunit MDT-15/MED15 Links Protective Innate Immune Responses and Xenobiotic Detoxification

Metazoans protect themselves from environmental toxins and virulent pathogens through detoxification and immune responses. We previously identified a small molecule xenobiotic toxin that extends survival of Caenorhabditis elegans infected with human bacterial pathogens by activating the conserved p38 MAP kinase PMK-1 host defense pathway. Here we investigate the cellular mechanisms that couple activation of a detoxification response to innate immunity. From an RNAi screen of 1,420 genes expressed in the C. elegans intestine, we identified the conserved Mediator subunit MDT-15/MED15 and 28 other gene inactivations that abrogate the induction of PMK-1-dependent immune effectors by this small molecule. We demonstrate that MDT-15/MED15 is required for the xenobiotic-induced expression of p38 MAP kinase PMK-1-dependent immune genes and protection from Pseudomonas aeruginosa infection. We also show that MDT-15 controls the induction of detoxification genes and functions to protect the host from bacteria-derived phenazine toxins. These data define a central role for MDT-15/MED15 in the coordination of xenobiotic detoxification and innate immune responses.     

Caenorhabditis elegans mom-4 is required for the activation of the p38 MAPK signaling pathway in the response to Pseudomonas aeruginosa infection

The p38 mitogen-activated protein kinase (MAPK) plays an evolutionarily conserved role in the cellular response to microbial infection and environmental stress. Activation of p38 is mediated through phosphorylation by upstream MAPKK, which in turn is activated by MAPKKK. In the Caenorhabditis elegans, the p38 MAPK (also called PMK-1) signaling pathway has been shown to be required in its resistance to bacterial infection. However, how different upstream MAP2Ks and MAP3Ks specifically contribute to the activation of PMK-1 in response to bacterial infection still is not clearly understood. By using double-stranded RNA-mediated interference (RNAi) and genetic mutants of C. elegans, we demonstrate that C. elegans MOM-4, a mammalian TAK1 homolog, is required for the resistance of C. elegans to a P. aeruginosa infection. We have also found that the MKK-4 of C. elegans is required for P. aeruginosa resistance, but not through the regulation of DLK-1. In summary, our results indicate that different upstream MAPKKKs or MAPKKs regulate the activation of PMK-1 in response to P. aeruginosa.     

Specificity and complexity of the Caenorhabditis elegans innate immune response

In response to infection, Caenorhabditis elegans produces an array of antimicrobial proteins. To understand the C. elegans immune response, we have investigated the regulation of a large, representative sample of candidate antimicrobial genes. We found that all these putative antimicrobial genes are expressed in tissues exposed to the environment, a position from which they can ward off infection. Using RNA interference to inhibit the function of immune signaling pathways in C. elegans, we found that different immune response pathways regulate expression of distinct but overlapping sets of antimicrobial genes. We also show that different bacterial pathogens regulate distinct but overlapping sets of antimicrobial genes. The patterns of genes induced by pathogens do not coincide with any single immune signaling pathway. Thus, even in this simple model system for innate immunity, striking specificity and complexity exist in the immune response. The unique patterns of antimicrobial gene expression observed when C. elegans is exposed to different pathogens or when different immune signaling pathways are perturbed suggest that a large set of yet to be identified pathogen recognition receptors (PRRs) exist in the nematode. These PRRs must interact in a complicated fashion to induce a unique set of antimicrobial genes. We also propose the existence of an "antimicrobial fingerprint," which will aid in assigning newly identified C. elegans innate immunity genes to known immune signaling pathways.     

Aging impacts isolated lymphoid follicle fevelopment and function

Background  

Immunosenescence is the age-related decline and dysfunction of protective immunity leading to a marked increase in the risk of infections, autoimmune disease, and cancer. The majority of studies have focused on immunosenescence in the systemic immune system; information concerning the effect of aging on intestinal immunity is limited. Isolated lymphoid follicles (ILFs) are newly appreciated dynamic intestinal lymphoid structures that arise from nascent lymphoid tissues, or cryptopatches (CP), in response to local inflammatory stimuli. ILFs promote "homeostatic" responses including the production of antigen-specific IgA, thus playing a key role in mucosal immune protection. ILF dysfunction with aging could contribute to immunosenescence of the mucosal system, and accordingly we examined phenotypic and functional aspects of ILFs from young (2 month old) and aged (2 year old) mice.     

Inducible antibacterial defense system in C. elegans

The term innate immunity refers to a number of evolutionary ancient mechanisms that serve to defend animals and plants against infection. Genetically tractable model organisms, especially Drosophila, have contributed greatly to advances in our understanding of mammalian innate immunity. Essentially, nothing is known about immune responses in the nematode Caenorhabditis elegans. Using high-density cDNA microarrays, we show here that infection of C. elegans by the Gram-negative bacterium Serratia marcescens provokes a marked upregulation of the expression of many genes. Among the most robustly induced are genes encoding lectins and lysozymes, known to be involved in immune responses in other organisms. Certain infection-inducible genes are under the control of the DBL-1/TGFbeta pathway. We found that dbl-1 mutants exhibit increased susceptibility to infection. Conversely, overexpression of the lysozyme gene lys-1 augments the resistance of C. elegans to S. marcescens. These results constitute the first demonstration of inducible antibacterial defenses in C. elegans and open new avenues for the investigation of evolutionary conserved mechanisms of innate immunity.     

Nuclear Hormone Receptor Regulation of MicroRNAs Controls Innate Immune Responses in C. elegans

Nuclear hormone receptors respond to small molecules such as retinoids or steroids and regulate development. Signaling in the conserved p38/PMK-1 MAP kinase pathway regulates innate immunity. In this study, we show that the Caenorhabditis elegans nuclear receptor DAF-12 negatively regulates the defense against pathogens via the downstream let-7 family of microRNAs, which directly target SKN-1, a gene downstream of PMK-1. These findings identify nuclear hormone receptors as components of innate immunity that crosstalk with the p38/PMK-1 MAP kinase pathway.     

The DAF-2 insulin-like signaling pathway independently regulates aging and immunity in C. elegans

The Caenorhabditis elegans DAF-2 insulin-like signaling pathway, which regulates lifespan and stress resistance, has also been implicated in resistance to bacterial pathogens. Loss-of-function daf-2 and age-1 mutants have increased lifespans and are resistant to a variety of bacterial pathogens. This raises the possibility that the increased longevity and the pathogen resistance of insulin-like signaling pathway mutants are reflections of the same underlying mechanism. Here we report that regulation of lifespan and resistance to the bacterial pathogen Pseudomonas aeruginosa is mediated by both shared and genetically distinguishable mechanisms. We find that loss of germline proliferation enhances pathogen resistance and this effect requires daf-16, similar to the regulation of lifespan. In contrast, the regulation of pathogen resistance and lifespan is decoupled within the DAF-2 pathway. Long-lived mutants of genes downstream of daf-2, such as pdk-1 and sgk-1, show wildtype resistance to pathogens. However, mutants of akt-1 and akt-2, which we find to individually have modest effects on lifespan, show enhanced resistance to pathogens. We also demonstrate that pathogen resistance of daf-2, akt-1, and akt-2 mutants is associated with restricted bacterial colonization, and that daf-2 mutants are better able to clear an infection after challenge with P. aeruginosa. Moreover, we find that pathogen resistance among insulin-like signaling mutants is associated with increased expression of immunity genes during infection. Other processes that affect organismal longevity, including Jun kinase signaling and caloric restriction, do not affect resistance to bacterial pathogens, further establishing that aging and innate immunity are regulated by genetically distinct mechanisms.     

The immune system and the impact of zinc during aging

The trace element zinc is essential for the immune system, and zinc deficiency affects multiple aspects of innate and adaptive immunity. There are remarkable parallels in the immunological changes during aging and zinc deficiency, including a reduction in the activity of the thymus and thymic hormones, a shift of the T helper cell balance toward T helper type 2 cells, decreased response to vaccination, and impaired functions of innate immune cells. Many studies confirm a decline of zinc levels with age. Most of these studies do not classify the majority of elderly as zinc deficient, but even marginal zinc deprivation can affect immune function. Consequently, oral zinc supplementation demonstrates the potential to improve immunity and efficiently downregulates chronic inflammatory responses in the elderly. These data indicate that a wide prevalence of marginal zinc deficiency in elderly people may contribute to immunosenescence.     

Neural regulation of immunity: Role of NPR-1 in pathogen avoidance and regulation of innate immunity

The nervous and immune systems consist of complex networks that have been known to be closely interrelated. However, given the complexity of the nervous and immune systems of mammals, including humans, the precise mechanisms by which the two systems influence each other remain understudied. To cut through this complexity, we used the nematode Caenorhabditis elegans as a simple system to study the relationship between the immune and nervous systems using sophisticated genetic manipulations. We found that C. elegans mutants in G-protein coupled receptors (GPCRs) expressed in the nervous system exhibit aberrant responses to pathogen infection. The use of different pathogens, different modes of infection, and genome-wide microarrays highlighted the importance of the GPCR NPR-1 in avoidance to certain pathogens and in the regulation of innate immunity. The regulation of innate immunity was found to take place at least in part through a mitogen-activated protein kinase signaling pathway similar to the mammalian p38 MAPK pathway. Here, the results that support the different roles of the NPR-1 neural circuit in the regulation of C. elegans responses to pathogen infection are discussed.