Keywords

Introduction

Caenorhabditis elegans is a small , generally free-living , non-parasitic nematode whose natural habitats include soil, compost, rotting fruit, and snails. The worm has been a powerful model for the study of many important biological processes, many of which can be very effectively transferred into studies of higher organisms. For example, the core apoptotic signaling pathway was first dissected in the worm (Horvitz and Lecture 2002), and a mutant screen revealed the first longevity-control pathway (Kenyon et al. 1993). Much of the power of C. elegans in basic research comes from its small size and easy handling in the laboratory, as well as a vast array of resources and infrastructure, including mutant and RNA interference libraries, a very active and open community of researchers, facilities for strain collection and distribution, and data curation. Another remarkable feature of the worm that increases its power as a model system is that the adult worms (which develop via the transition between four main larval stages), with the exception of the germline, are entirely post-mitotic. Following the fourth (and final) larval stage, further development consists only of growth, with no additional change in the number of somatic cells. Furthermore, the number and identity of the cells are invariable from worm to worm, and the full lineage for each cell, from fertilized oocyte to terminal differentiation, has been completely dissected. For this reason, some of the complexities of working with a multicellular organism in which cells turn over quickly are eliminated. The worm has been found to be susceptible to several human pathogens, including Pseudomonas aeruginosa, Serratia marcescens, Salmonella enterica, and Enterococcus faecalis, as well as fungi, including Cryptococcus neoformans (Marsh and May 2012). This feature of the worms’ response to pathogens spawned the productive and active field of nematode innate immunity. Furthermore, several nematode-specific pathogens have been identified, which allow the analysis of aspects of the immune response that may be part of the natural existence of the animals. These organisms include the bacteria Microbacterium nematophilum (Hodgkin et al. 2000), the fungus Drechmeria coniospora (Jansson 1994), and a positive-strand RNA virus (Orsay virus ) (Félix et al. 2011).

The C. elegans immune system (see the overview in Fig. 1) evolutionarily predates those of higher organisms and seems to be relatively simple, particularly in that it lacks an adaptive immune system. Furthermore, the worms have no specialized or mobile immune cells. While they possess three pairs of cells involved in detoxification (the coelomocytes), these cells have not been assigned any immune functions. Because the worm relies only on its innate immune response to resist and tolerate pathogens, the complex interactions that exist between innate and adaptive immune responses in higher organisms do not cloud the study of specific features of innate immunity.

Fig. 1
figure 1

Overview of the Caenorhabditis elegans innate immune response . The worm innate immune response consists of both cell-autonomous processes (a) and systemically disseminated responses (b). The transcription-based response can be stimulated via disruption of cellular processes (surveillance mediated immunity) or by direct cellular damage (damage-associated molecular pattern [DAMP]-mediated immunity). Signals from neurons appear to limit the immune response and DNA damage in the germ cells stimulates a robust immune response; however, most of the molecular mechanisms for these pathways remain to be clarified

Full size image

Signaling Pathways in the Caenorhabditis elegans Innate Immune Response

The worm innate immune response generally occurs at the level of transcriptional regulation (Shivers et al. 2008) and is controlled by several signaling cascades, depending on the type and location of the pathogen challenge. To date, at least four pathways have been identified:

  1. 1.

    p38/PMK-1 signaling

  2. 2.

    ERK/MPK-1 signaling

  3. 3.

    Insulin-like signaling (DAF-16 and DAF-2)

  4. 4.

    DBL-1 pathway

The p38/PMK-1 Signaling Pathway

Genetic screens to identify mutants with increased sensitivity to P. aeruginosa uncovered the p38 mitogen-activated protein kinase (MAPK)–related pathway as an important regulator of immunity in the worm (Bolz et al. 2010; Kim et al. 2004; Troemel et al. 2006). The signaling cascade underlying this pathway consists of several players: the neuronal symmetry family member 1 (NSY-1), stress-activated protein kinase (SAPK)/extracellular signal–regulated kinase (ERK) kinase 1 (SEK-1), and PMK-1, the worm p38 homolog. Signal propagation occurs via sequential phosphorylation of SEK-1 by NSY-1 and PMK-1 by SEK-1 in a strictly linear fashion (Fig. 2). The primary downstream effector of the pathway is the transcription factor ATF-7, which, when activated, induces a large repertoire of putative immune factors (Pujol et al. 2001; Shivers et al. 2010). As discussed in more detail in section “Missing Links”, the nematode’s genome encodes only one Toll-like receptor (TLR) protein (TOL-1) , which has been only loosely associated with the immune response (Tenor and Aballay 2007). In mammals, all characterized TLRs seem to rely on adaptor proteins that contain Toll/interleukin-1 receptor (TIR) domains for the signal transduction that ultimately leads to the nuclear factor (NF)-κB-mediated pro-inflammatory response (i.e., TRAM [Trif-related adaptor molecule], TICAM [TIR domain-containing adapter molecule]/Trif [TIR-domain-containing adapter-inducing interferon-β], TIRAP [TIR domain-containing adapter protein]/Mal, and myeloid differentiation primary response gene 88 [MyD88]). A fifth TIR-containing protein, SARM (sterile alpha and TIR motif-containing protein), also exists and, while it is the least understood in mammals, it is also the only one that has a direct ortholog in C. elegans (tir-1) (Liberati et al. 2004). The tir-1 gene does, in fact, have important roles in worm immunity: in particular, it acts together with NSY-1 and SEK-1 in the p38 pathway . TIR-1, NSY-1, and SEK-1 can be co-immunoprecipitated and probably form a protein complex (Chuang and Bargmann 2004), and phosphorylation of p38/PMK-1 depends on tir-1 (Liberati et al. 2004); thus, it seems to be firmly situated in the p38 signaling pathway. Data suggest that TIR-1 is likely upstream in the pathway (Liberati et al. 2004), placing it in closer proximity to the initiating events of the signaling cascade; however, what signals lead to TIR-1 activation remain entirely unknown.

Fig. 2
figure 2

Signaling in the Caenorhabditis elegans innate immune response. The worm immune response consists of three currently known signaling pathways, the p38 axis (C. elegans PMK-1), the DBL-1 axis, and the extracellular signal-regulated kinase (ERK) axis (C. elegans MPK-1). The outcomes of these pathways following pathogen exposure are the transcriptional induction of many genes thought to be involved in pathogen tolerance and resistance, although the functions of these genes remain mostly unknown (see text)

Full size image

The ERK/MPK-1 Signaling Pathway

The p38 MPK signaling cascade seems to be the most important in terms of innate immune function in C. elegans; however, the ERK1/ERK2 MAPK homolog MPK-1 can also be activated by some pathogens, in particular infection by M. nematophilum leads to an MPK-1-dependent immune response (Gravato-Nobre et al. 2005; Hodgkin et al. 2000; Nicholas and Hodgkin 2004). The upstream factors in this signaling cascade are LIN-45 and MEK-2, which have also been assigned various functions in development and fertility (Fig. 2). Thus, it is clear that this signaling cascade is not exclusively dedicated to the immune response pathway, but instead regulates a plethora of processes ranging from stress responses to multiple aspects of the animal’s development. The most upstream element of the pathway and the terminal effector protein remain unknown.

Insulin-Like Signaling (DAF-16 and DAF-2)

The insulin-like signaling (IIS) pathway involving the insulin-like growth factor receptor DAF-2 and the forkhead box O (FOXO) transcription factor DAF-16 were first identified as regulators of the extraordinarily long-lived dauer larval stage (Kenyon et al. 1993), an alternative developmental fate of worms under starvation stress, as well as determinants of adult longevity in C. elegans. Subsequently, they have been shown to be part of a larger network of pathways that confer stress resistance, which is intimately intertwined with the worm’s immune response (Cezairliyan et al. 2013; Mahajan-Miklos et al. 1999). In the presence of its ligand DAF-28, DAF-2 is activated, which goes on to activate the phosphatidylinositol-3 OH kinase AGE-1 (Li et al. 2003; Malone et al. 1996). AGE-1 then catalyzes the conversion of phosphatidylinositol bisphosphate (PIP2) into phosphatidylinositol triphosphate (PIP3) (Tazearslan et al. 2009). PIP3 then binds to the AKT-1/AKT-2 complex to reveal two phosphorylation sites that are phosphorylated by the PDK-1 kinase (which also depends on PIP3 binding for its function). The AKT complex then phosphorylates the transcription factor DAF-16, which is blocked from entering the nucleus (Paradis and Ruvkun 1998). In contrast, in the presence of an antagonistic ligand (e.g., INS-1 [Insulin-like peptide]), the pathway is inactive and DAF-16 is not phosphorylated, leading to its translocation into the nucleus, where it activates stress response and putative antimicrobial genes. Genetic inactivation of daf-2 leads to the same outcome as DAF-16 remains constitutively hypophosphorylated. Not entirely unexpectedly, loss of daf-2 leads to pathogen resistance and this effect seems to be primarily rooted in the intestinal cells (Garsin et al. 2003; Hsin and Kenyon 1999; Libina et al. 2003; Lin et al. 2001). As is the case for ERK signaling, the outcomes of DAF-16 activation extend far beyond immune function, indicating that the pathway is not a dedicated immune pathway.

The DBL-1 Signaling Pathway

The gene dbl-1 encodes one of four transforming growth factor (TGF)-β-like ligands in C. elegans and is (in part) required for resistance to both P. aeruginosa and S. marcescens (Kurz and Tan 2004; Mallo et al. 2002). The DBL-1 protein binds to the DAF-4/SMA-6 heterodimeric receptor and, via the SMA-2/SMA-3/SMA-4 complex, controls gene expression levels (Fig. 2), while it also has diverse functions independent of immunity (e.g., body size regulation and structural patterning). In fact, loss of the sma genes leads to increased sensitivity to P. aeruginosa (Kurz and Tan 2004; Mallo et al. 2002; Roberts et al. 2010). Interestingly, TGF-β signaling in mammals leads to immunosuppression, demonstrating a remarkable divergence of function during evolution.

The C. elegans Viral Defense Strategy

To date, only a single virus that can infect and replicate in C. elegans has been identified (Félix et al. 2011). This virus , called Orsay after the site of its discovery in France, is a member of the Nodaviridae family and is a positive-strand RNA virus. Infection leads to easily observable morphological defects in the worm’s intestine. The first indication of an antiviral response came from the observation that viral load was increased when factors of the RNAi pathway were deactivated, such as RDE-1, RDE-4, MUT-7 (RNaseD), and DRH-1 (Dicer) (Ashe et al. 2013; Félix et al. 2011; Guo et al. 2013). The implication of the RNAi pathway in viral defense (also supported by viral infection experiment using isolated worm cells) provided a sturdy scaffold for considering the evolutionary origins and conservation of the pathway, which is consistent with its function in plants. The current model for antiviral immunity in C. elegans (Fig. 3) proposes that the double-stranded RNA (dsRNA) intermediates produced during viral replication are bound by the dsRNA-binding complex RDE-1/RDE-4 responsible for initial detection and sequestration of exogenous dsRNAs. The canonical RNAi pathway is subsequently recruited: the dsRNA is passed to the DExD box RNA helicase DRH-1, which when interacting with RDE-1/RDE-4 unwinds the molecule to provide accessibility by the dicing complex. The Dicer homolog DCR-1 then produces small RNAs that go on to serve as templates for the RNA-directed RNA polymerase to produce a pool of secondary antisense small RNAs, which mediate the degradation of the full length viral RNA genome.

Fig. 3
figure 3

The Caenorhabditis elegans antiviral response . Protection against viral invasion is mediated by components of the RNA interference (RNAi)-mediated gene-silencing pathway . Following infection by an RNA-based virus, the RNA is bound and processed to yield antisense small interfering RNAs (siRNAs) against the viral genome, ultimately leading to degradation of the viral genetic material to limit the infection

Full size image

Some mammalian viruses have mechanisms to avoid detection by the host immune system; for example, by blocking the major histocompatibility complex (MHC) class I antigen processing and presentation pathway to escape T-killer cells (Horst et al. 2011). In C. elegans, the Flock house virus protein B2 can robustly downregulate the RNAi machinery to increase the sensitivity of worms to Orsay virus (Guo and Lu 2013). Another shared element of mammalian and nematode antiviral pathways is the similarity between DRH-1 and the RIG-I (retinoic acid inducible gene I) RNA helicase, an important sensor of dsRNA in mammals (Ashe et al. 2013; Coffman et al. 2017; Guo et al. 2013). While the RNA-binding domains are highly similar, the proteins do have different functions: DRH-1 presents RNA to Dicer for processing, while RIG-I activates an inflammatory antiviral immune response. Nevertheless, it is plausible that the two antiviral responses are connected over the span of evolutionary time.

Neuronal Regulation of Immunity

The simple body plan and limited number and type of cells has led to functional multitasking in various cell types. As already mentioned, the intestinal cells are a key site of immune function; it turns out that neurons are also key players in worm immunity . C. elegans is an extremely powerful model for studying the nervous system, as the morphology, identity, and synaptic connectivity of all its 302 neurons is entirely understood; furthermore, a detailed catalog of the relevant neurotransmitters for most of the neurons has also been compiled. In addition to the production of antimicrobial factors, worms also seem to respond to pathogen exposure via neuron-driven behavioral programs, most notably pathogen avoidance. A polymorphism in the gene encoding the G-protein-coupled receptor (GPCR) protein NPR-1 caused decreased survival during P. aeruginosa infection by limiting the ability of the worms to avoid the pathogen (Reddy et al. 2009); however, it turned out that this is not the sole function of npr-1 in worm immunity. Worms lacking NPR-1 exhibited altered expression of intestinally expressed, PMK-1-regulated genes during infection (Styer et al. 2008). Remarkably, elimination of the sensory neurons AQR, RQR, and URX rescued this phenotype, suggesting that in the absence of NPR-1 these neurons become hyperactive and disturb immune pathways. Worms lacking these neurons are more pathogen resistant, suggesting that they have a negative regulatory function on the immune response.

The neuron-expressed GPCR OCTR-1 also plays a role in worm innate immunity (Sun et al. 2011). Through action in the ASH and ASI neurons, OCTR-1 suppresses the pathogen-dependent activation of PMK-1 and blocks the induction of a non-canonical UPR in distal tissues, indicating a non-cell-autonomous function. While the increased resistance of npr-1 mutant worms to P. aeruginosa involved alterations in pathogen avoidance behavior, octr-1 mutant worms exhibit increased pathogen resistance without such a behavioral change. How the neurons are stimulated by pathogens and the mechanisms underlying these phenotypes remain open questions in the field. Interestingly, the OCTR-1 protein is related to vertebrate adrenergic receptors that bind to their ligand noradrenalin. The outcome of this binding is a response to acute stress that can be accompanied by immune suppression (Aballay 2013).

The Interface Between Innate Immunity and DNA Damage

Study of the innate immune response of C. elegans has primarily focused on host–pathogen interactions; however, it is also now clear that the system can also respond to damaged self-DNA through a process called germline DNA damage-induced systemic stress resistance, or GDISR (Fig. 4) (Ermolaeva et al. 2013). C. elegans has been an especially valuable tool for dissecting the distinctive features and roles of DNA damage responses (DDRs) in the germline versus somatic tissues. In this discussion, we focus on germline processes, as they have so far been shown to be intricately intertwined with the innate immunity of C. elegans.

Fig. 4
figure 4

Non-cell-autonomous stress resistance following immune induction. DNA damage in germline cells leads to the activation of immune genes, stimulating the ubiquitin proteosome system (UPS). This enhanced activity confers systemic stress and pathogen resistance. The mechanism for the detection of the DNA damage and the intermediate signaling pathway leading to gene induction remains unknown

Full size image

The majority of tissues in the adult worm are post-mitotic, as the cellular lineages are invariable and somatic development is generally completed by the last larval stage. The exception is the germline, which contains mitotic cells in a stem cell niche. Once cells leave the stem cell niche, they proceed through meiosis to generate mature germ cells—in hermaphrodites, the most common sex in worms—the production of sperm and oocytes are temporally separated during growth. In hermaphrodites, diakinesis-arrested oocytes are fertilized by sperm produced earlier during development to generate clonal offspring (Kimble and Crittenden 2005). Following DNA damage in germ cells, conserved cell cycle checkpoints are robustly activated to arrest mitotic proliferation, allowing time for DNA repair pathways to remove destabilizing lesions (Ahmed and Hodgkin 2000; Gartner et al. 2000). In a case where checkpoint activation cannot be resolved in a timely manner, apoptosis mediated by the CEP-1, the C. elegans homolog of the highly conserved p53 tumor suppressor , occurs through CEP-1-dependent transcriptional induction of the BH3-only-domain genes egl-1 and ced-13, the protein products of which then trigger the apoptosome (Derry et al. 2001; Hofmann et al. 2002; Schumacher et al. 2001, 2005).

These processes are themselves cell autonomous ; however, it is now clear that the GDISR pathway leads to non-cell-autonomous effects via factors associated with the innate immune response (Ermolaeva et al. 2013). The systemic aspects of the DDR were initially observed in animals that were defective for global-genome nucleotide excision repair, which fail to remove UV light-induced lesions in germ cells, ultimately leading to accumulation of DNA damage. Quite remarkably, the somatic tissues of UV-exposed animals developed profound resistance to both heat and oxidative stress. Importantly, this effect was not specific to UV-induced damage, as DNA damage induced by ionizing radiation or hydroxyurea, as well as endogenously generated DNA double-strand breaks in pachytene germ cells, was sufficient to elicit the stress resistance phenotypes. This induction of stress resistance through damage of endogenous DNA suggests that damaged DNA can be recognized as a damage-associated molecular pattern (DAMP) by C. elegans. The molecular basis of GDISR was shown to depend on the activation of the ERK homolog MPK-1, which subsequently induced expression of a repertoire of immune genes. This added burden of such a broad induction of gene expression subsequently stimulated the ubiquitin proteasome system (UPS), which conferred systemic stress resistance. Importantly, this pathway is distinct from the p38/PMK-1 pathway discussed earlier and the first tendency may be to attribute the effect to CEP-1 activity; however, this was not the case and, in fact, no components of the canonical DNA damage checkpoint signaling were necessary for GDISR. Therefore, GDISR is a distinct response to DNA damage , independent of checkpoint signaling. A connection between UV irradiation and immunity has been demonstrated in human skin cells where UV irradiation leads to a complex and highly coordinated range of immune-associated processes, ranging from localized inflammation to systemic outcomes mediated by cytokines and other growth factors—highly reminiscent of GDISR. It is likely that further study of GDISR in C. elegans may lead to the discovery of fundamental features of such systemic responses and how damaged DNA is recognized as a DAMP. Immune reactions to DNA damage have also been reported following infection with bacteria such as Escherichia coli and Helicobacter pylori, which can both cause DNA damage in eukaryotic cells (Nougayrede et al. 2006; Toller et al. 2011), suggesting that GDISR—at least conceptually—may be an ancestral version of extant mammalian pathways.

Missing Links

A conspicuously missing component of innate immunity in C. elegans is a repertoire of mechanisms for the detection of pathogen-associated molecular patterns (PAMPs) and DAMPs. In higher organisms, a number of pathways have been characterized for the specific detection of a broad list of foreign elements (e.g., Toll-like signaling, cGAS-STING [cyclic GMP–AMP synthase–stimulator of interferon genes], among others). Despite efforts by a number of groups over many years, similar pathways have not been identified in the nematode.

The sole putative DAMP detection mechanism identified in the worm to date is DCAR-1, a GPCR protein that was previously assigned a function in chemosensory neurons (Zugasti et al. 2014). It was subsequently shown to be expressed in the epidermis, a major site of innate immune responses in the worm. In this tissue, DCAR-1 can detect the tyrosine derivative hydroxyphenyllactic acid (HPLA), which accumulates when worms experience wounding or fungal infection. In these situations, HPLA accumulates triggering a signaling cascade that culminates in the canonical p38 (PMK-1)-mediated innate immune response.

While the C. elegans gene encodes one TLR, TOL-1, it has not been assigned a role in detection; rather, it seems to be involved primarily in developmental processes and tissue maintenance (Pujol et al. 2001; Tenor and Aballay 2007). Furthermore, the genome also encodes a large collection of leucine rich repeat (LRR)-containing proteins. It is reasonable to conjecture that such genes may function in detection based on the well-characterized functions of LRRs in ligand binding in the Toll-like and nucleotide-binding oligomerization domain (NOD)-like receptors; however, while one LRR protein has been assigned a function in pathogen resistance (FSHR [follicle-stimulating hormone receptor]-1) (Miller et al. 2015; Powell et al. 2009), it has not been shown to function as a sensor.

As discussed in the section “The Interface Between Innate Immunity and DNA Damage”, worms induce a potent innate immune response to DNA damage in the germline that then confers systemic somatic stress resistance (GDISR) . Pathways for the detection of damaged DNA, including double-strand breaks, single-strand breaks, and stalled replication forks at sites of damage have been identified and well-characterized in C. elegans. Quite unexpectedly, such pathways were clearly shown not to be involved in the induction of this immune response (Ermolaeva et al. 2013).

Another significant gap in our understanding of worm innate immunity is the function of the specific proteins induced as part of the innate immune response. As discussed earlier, the C. elegans innate immune response is characterized in general by the transcriptional upregulation of a large regulon of genes that encode putative secreted factors, many of which have structures indicating that they may function as antimicrobial agents; however, to date we know very little about how they function to combat pathogenic challenges. The one example in which a specific function is coming into focus is a C-type lectin gene (of which the genome encodes hundreds), which is induced following exposure to the Gram-positive bacterial pathogen Bacillus thuringiensis (Pees et al. 2017). Mutants for several C-lectin genes were shown to have either decreased or, surprisingly, increased resistance to the pathogen . Specifically, loss of one gene in particular resulted in enhanced avoidance behavior, which prompts the worms to leave the lawns of the pathogen. Furthermore, the same mutant animals also had increased periods of feeding cessation; thus, in this case, an immune-regulated gene was shown to actually be a negative regulator of pathogen resistance via behavioral modulation. Even with this bit of insight, the roles not only of the C-lectin proteins but essentially of the other immune-regulated genes remain entirely unknown. The elucidation of their functions is particularly hampered by the dazzling similarities between many of the genes, likely resulting in robust redundancy. Overcoming this experimental challenge remains a stubborn block in furthering research in this area.

Surveillance-Mediated Immunity

As mentioned in the section “Missing Links”, our understanding of the sensors and effectors of the C. elegans innate immune response remains rudimentary, as several fundamental components have yet to be identified, most notably pathways for sensing PAMPs and DAMPs. One theory proposed to resolve this issue is that the nematode relies on an alternative approach for immune activation, independent of direct sensing, called “surveillance immunity” (Pukkila-Worley 2016)—similar in principle to the long-studied effect-triggered immunity in plants. The basis for surveillance immunity is that instead of monitoring for pathogens directly, the animals monitor for disruptions in endogenous processes that could be caused by the presence of a pathogen, for example, translation, cellular homeostasis , or structural integrity.

The first identified and best understood surveillance pathway is involved in monitoring host translation. Many bacteria can produce protein toxins that interfere with efficient translation of mRNAs, including ToxA, produced by P. aeruginosa. This protein blocks polymerization of nascent peptides by blocking host elongation factor 2 function via ribosylation in intestinal cells following P. aeruginosa infection (Dunbar et al. 2012). Following this disruption, the transcription factor ZIP-2 (bZip transcription factor) accumulates and, in concert with the conserved protein CEBP-2, regulates an innate immune response (Estes et al. 2010; McEwan et al. 2012; Reddy et al. 2016). What is clear is that both the pathogen and toxin are functionally invisible to the animals and instead disruption of translational function stimulates the response. Quite remarkably, genetic ablation of host-encoded functions can induce a similar response, even in the absence of a pathogen, reinforcing this validity of this concept.

A conceptually similar pathway has also been reported in the mitochondria. Siderophores, toxins produced by pathogens (including P. aeruginosa), can interfere with mitochondrial homeostasis (Kirienko et al. 2015). The unfolded protein response in the mitochondria (UPRmt) helps to ensure mitochondrial function by inducing the expression of nuclear-encoded, mitochondrially targeted chaperone molecules. A central player in this pathway is the transcription factor ATFS-1. ATFS-1 is normally taken up by functionally intact mitochondria, thus limiting cytosolic levels; however, upon disruption of the mitochondria, this uptake is reduced, leading to cytosolic accumulation. Subsequently, the protein can enter the nucleus, where it induces a repertoire of genes encoding putative antimicrobial factors. ATFS-1 also enters the nucleus during P. aeruginosa infection, leading to the expression of genes that confer resistance to the infection (Nargund et al. 2012), while loss of ATFS-1 leads to reduced resistance (Pellegrino et al. 2014). Further work remains to fully understand the interplay between the UPRmt, ATFS-1, and bacterial infection, but as in the case of translation, this pathway provides a satisfying mechanism by which the animals can indirectly sense the presence of a pathogen.

In a large-scale study of the microbiome of the worm’s natural habitat , nearly 20% of isolates examined (a total of 560) induced mitochondrial stress (Liu et al. 2014). This observation strongly supports the broad usefulness of such a surveillance pathway in responding to bacterial challenges. Much work remains to be done to understand the implications and complexity of surveillance immunity, but the concept is already becoming a useful framework in which to consider the innate immune response of worms, given the gaps in the more conventional mechanistic pathways.

To What End: Immunity or General Stress Resistance?

Expression of genes associated with the C. elegans innate immune response can be controlled by pathways that are generally discussed in the context of distinct biological processes (i.e., MAPK signaling in response to pathogen infection and DNA damage and DAF-16 as part of the IIS pathway). Furthermore, activation of overlapping innate immune genes by DNA damage confers resistance not only to pathogens but also to heat and oxidative stresses (Ermolaeva et al. 2013). While the latter two cases seem to be secondary effects due to activation of the UPS driven by the enhanced expression of putative immune factors, rather than effected directly by the immune peptides, the net outcome of the activation of the innate immune response is enhanced stress resistance.

An important conceptual consideration is whether what is studied in C. elegans and labeled as “innate immunity” is rather a complex set of interconnected stress responses , which happen to confer pathogen resistance. The label applied to these responses certainly does not negate the value and usefulness of this field of research in C. elegans as broadly applicable biological processes have been clarified; however, oversimplification of the conceptualization of these responses could lead to missed opportunities for study and interpretation of results. Importantly, however, stress responses appear to comprise an essential component of not only ancestral but also of mammalian immune responses, such as when natural killer cells need to survive their own rampage against infections, during which they produce reactive oxygen species. The nematode might therefore turn out to be particularly instructive for the understanding of how the stress responses could balance the consequences of immune defenses. Given their intimate involvement in the regulation of longevity, stress response pathways could play a central role in alleviating the consequences of innate immunity driving the chronic inflammation during human aging. Deeper insight into the regulation of stress responses during the activation of innate immunity in C. elegans might therefore yield new conceptual avenues for counteracting the pathological consequences of chronic inflammation.

Future work on the responses of C. elegans to environmental challenges, from pathogens to chemicals, and even to radiation, will surely shed light on these questions and provide new and exciting avenues for further research.