immunity in caenorhabditis elegans

Immunity in Caenorhabditis elegansAnne CM Millet and Jonathan J Ewbank1

Until very recently it was not known whether the invertebrate

Caenorhabditis elegans was capable of mounting a specific

immune response to protect itself from pathogens. It has only

just become clear that this simple nematode in fact possesses

a complex innate immune system, involving multiple signalling

pathways and an armoury of antimicrobial proteins and peptides.

Genetic and microarray approaches are now revealing the

molecular cross-talk that exists between the different

signalling cascades.

AddressesCentre d’Immunologie de Marseille Luminy, Institut National de la

Sante et de la Recherche Medicale/Centre National pour la Recherche

Scientifique /Universite de la Mediterranee, Case 906, 13288 Marseille

Cedex 9, France1e-mail: [email protected]

Current Opinion in Immunology 2004, 16:4–9

This review comes from a themed issue on

Innate immunity

Edited by Bruce Beutler and Jules Hoffmann

0952-7915/$ – see front matter� 2003 Elsevier Ltd. All rights reserved.

DOI 10.1016/j.coi.2003.11.005

AbbreviationsABF antibacterial factor

DAF abnormal Dauer formation

IGF insulin-like growth factor

LPS lipopolysaccharide

LYS lysozyme

MAP mitogen-activated protein

MAPK MAP kinase

MEF-2 myocyte-specific enhancer factor-2

RNAi RNA interference

TGF-b transforming growth factor-b

IntroductionThe nematode Caenorhabditis elegans has been widely

used as a model organism in biology for some thirty years.

In the last four or five years, it has emerged as a very

powerful model for the study of host–pathogen interac-

tions. A wide variety of pathogens have been described

that infect C. elegans (for example, see [1–4]; reviewed in

[5,6]) and this nematode can be used to identify universal

bacterial virulence factors that are important for patho-

genicity in a broad range of hosts [7,8�,9�]. This review,

however, will concentrate on studies that have elucidated

the defence mechanisms of C. elegans, particularly those

that are important for the survival of worms following

bacterial infection. As well as having a fundamental

interest, this research is being undertaken in the hope

that it will shed light on conserved aspects of mammalian

innate immunity, as has been the case for similar work

using the fruit fly Drosophila melanogaster [10�].

The immune system of Caenorhabditiselegans: an inducible defence systemAlthough in Drosophila, as in vertebrates, both cellular

and humoral mechanisms contribute to antimicrobial

defences [11,12�], C. elegans appears to lack the cellular

arm of immunity [6,10�]. One central feature of the

humoral response in most animals is the production of

peptides that act directly against pathogens. Worms pro-

duce several cysteine-stabilised ab (CSab)-type antimi-

crobial peptides (called ABFs, for antibacterial factors),

which are more closely related to molluscan myticin than

to insect defensins [13]. Among these peptides, ABF-2

has been shown to possess potent antibacterial activity

in vitro [14]. ABFs are rapidly induced upon injection of

heat-killed bacteria into the parasitic nematode Ascarissuum [15], but whether their expression is induced follow-

ing infection in C. elegans remains an open question. The

expression, however, of a class of glycine-rich putative

antimicrobial peptides, including R09B5.3 and NLP-29

(neuropeptide-like protein 29), is upregulated following

infection of C. elegans by the Gram-negative bacterium

Serratia marcescens [16��].

In flies, the Toll pathway plays an important role in

defence against fungal and bacterial infection [17–19],

a role that is conserved in mammals, as it controls the

expression of antimicrobial peptides. Although homol-

ogues of certain components of the Toll pathway are

present in C. elegans, they do not appear to be directly

involved in resistance against fungal or bacterial infection,

at least not against the limited number of pathogens that

have been tested [20�,21]. Results suggest, however, that

the worm Toll homologue could be part of a mechanism

that allows worms to discriminate between bacteria, and

thereby avoid potential pathogens [21].

The TGF-b pathwayAs intimated above, C. elegans does possess an inducible

defence system, which was revealed by microarray anal-

ysis of gene expression levels following infection by S.marcescens [16��]. In addition to antimicrobial peptides,

several lectins and lysozymes (LYS-1, LYS-7 and LYS-8)

show markedly increased expression following infection.

As lysozymes are bactericidal proteins, they presumably

contribute directly to worms defences against infection.

Indeed, overexpression of LYS-1 leads to increased resis-

tance to S. marcescens. Another of the lysozymes, LYS-8,

had previously been shown to be under the control of

Current Opinion in Immunology 2004, 16:4–9 www.sciencedirect.com

dbl-1, a gene that encodes a homologue of transforming

growth factor (TGF)-b [22], and dbl-1 mutants were found

to be hypersusceptible to bacterial infection. Taken to-

gether, these results firmly established the existence of

inducible defences in the worm and showed that they are,

in part, controlled by a TGF-b signalling cascade [16��].

Innate immunity and the stress responseOne interesting observation that came out of the dbl-1mutant study was that the mutants were short-lived on

the standard worm diet, the Escherichia coli strain OP50,

but lived just as long as wild-type worms when grown on

dead bacteria. This is consistent with a previous sugges-

tion that OP50 can act as an opportunistic pathogen,

either when worm defences are compromised through

mutation (as in this case) or more generally as worms get

older [23]. Indeed, the proliferation of OP50 within the

intestine appears to be a frequent cause of death for

C. elegans [24�].

The DAF pathway

Recent work has provided a molecular basis for these

observations. One of the better-characterised mechan-

isms that regulates ageing in C. elegans is the DAF-2 (for

abnormal Dauer formation)/insulin-like growth factor

(IGF) pathway. DAF-2 activity shortens adult life span,

acting through the inhibition of DAF-16, a forkhead

transcription factor. Using microarrays, Murphy et al.[25��] have shown that several DAF-16 targets are anti-

microbial genes, including lys-7 and lys-8, and genes

encoding saposins (related to NK lysins) and thaumatins

(known to have antifungal activity in plants). Currently, it

is not known whether IGF signalling also directly influ-

ences resistance to infection in vertebrates. Other DAF-

16 targets are involved in detoxification (e.g. metallothio-

nein) and resistance to oxidative stress (e.g. glutathione-

S-transferase, catalase and superoxide dismutase), or

more general anti-stress mechanisms (small heat shock

proteins, and the previously identified sperm-coating

glycoprotein [SCP]-like extracellular protein [SCL-1]

[26]). In daf-2 mutants the expression of these genes is

upregulated, especially later in life, and in addition to

being long-lived, daf-2 worms are resistant to infection,

particularly by Gram-positive bacteria [27��], as well

exhibiting an increased resistance to heat, UV, hypoxia

[28] and heavy metals [29]. This suggests that there is

some overlap between the mechanisms of innate immu-

nity and more general stress responses.

The MAPK pathway

Such an idea is reinforced by the results of an elegant

genetic screen carried out in the Ausubel laboratory [30��]that identified worm mutants hypersusceptible to infec-

tion by Pseudomonas aeruginosa. The two least resistant

mutants correspond to loss-of-function alleles of nsy-1 and

sek-1, which encode a mitogen-activated protein (MAP)

kinase kinase kinase (or MAP3K) and a MAP kinase

kinase (or MAP2K), respectively. Kim et al. [30��] were

able to show, using RNA interference (RNAi) of the two

C. elegans p38 homologues pmk-1 and pmk-2, that sek-1 and

nsy-1 act in a pmk-1-dependent manner to mediate resis-

tance to P. aeruginosa infection. The nsy-1-sek-1-pmk-1pathway also regulates the nematodes’ stress response to

arsenic (K Matsumoto, personal communication), sug-

gesting that C. elegans possesses an integrated MAP kinase

(MAPK)-based stress-signalling network, analogous to

that observed in plants and insects (reviewed in [10�]).In the context of the response to arsenic, one target of this

pathway is the transcription factor SKN-1 (K Matsumoto,

personal communication). Originally described as being

necessary for the specification of the mesendoderm,

SKN-1 is structurally related to a conserved family of

proteins that regulate the major oxidative stress response

in organisms as diverse as yeast and mammals. It has now

been shown that SKN-1 accumulates in the nuclei of

intestinal cells in response to oxidative stress (or heat

shock) where it probably directly controls the expression

of a g-glutamyl-cysteine synthetase heavy chain gene that

encodes the enzyme required for the rate-limiting step in

the synthesis of glutathione, a major antioxidant [31�].

For the moment it has not been established whether

SKN-1 also functions in pathogen resistance but, inter-

estingly, other presumed SKN-1 targets include catalase

and superoxide dismutase genes [31�], which are known

DAF-16 targets. Additionally, knocking down pmk-1function by RNAi also renders C. elegans more susceptible

to infection with Salmonella typhimurium, conceivably via

an effect on SKN-1 activity. Salmonella infection is known

to trigger apoptosis in C. elegans, and this is associated with

an increased protection against infection via a poorly

characterised mechanism [32]. The observed augmenta-

tion in resistance against Salmonella infection has now

been shown to to be dependent upon the nsy-1–sek-1–

pmk-1 pathway [20�], but it is not yet known what the

downstream effectors of this response are, nor whether

there is a causal link between apoptosis and resistance.

Salmonella mutants that are defective in lipopolysacchar-

ide (LPS) synthesis do not trigger the nsy-1-sek-1-pmk-1pathway, nor do they induce apoptosis. This suggests that

LPS recognition could play a part in triggering an innate

immune response in C. elegans. It should be pointed out,

however, that no worm receptors for specific pathogens, or

pathogen-associated molecular patterns (PAMPs) have

been identified to date. The induction of the expression

of several lectins by S. marcescens [16��] suggests that this

class of proteins might play such a role.

The true complexity of the systemThus far we have presented the different pathways

involved in worm defences against infection as separate

entities. In reality, there is likely to be considerable cross-

talk between them ([10�]; Figure 1). In vertebrates, for

example, TGF-b and MAPK signalling pathways

Immunity in Caenorhabditis elegans Millet and Ewbank 5

www.sciencedirect.com Current Opinion in Immunology 2004, 16:4–9

intersect at the level of MEF-2 (for myocyte-specific

enhancer factor-2), with phosphorylation of MEF-2 by

p38 MAPK promoting its interaction with Smad proteins

[33]. C. elegans mutants in the worm MEF-2 homologue

(mef-2) are hypersusceptible to infection, and sma-2 func-

tions epistatically to mef-2 (MW Tan, personal commu-

nication). For the moment, however, a direct interaction

between pmk-1 and mef-2 has not been demonstrated,

although the nsy-1-sek-1-pmk-1 and daf-2-daf-16 pathways

do appear to be connected (see above). Finally, some

transcriptional targets, including lys-8, are common to the

dbl-1/TGF-b and daf-2-daf-16 pathways [16��,25��].

Figure 1

UNC-43

SEK-1

PMK-1

SEK-1

INS-18

PiP2 PiP3

PDK-1

MEF-2SMA-3SMA-2SMA-4

MAB-21LON-1

Body size

SMA-6

DBL-1

PMK-1

SEK-1

SKN-1

DAF-2 pathway(b)

(c)

(a)

DAF-2

AGE-1

AKT-1/2

DAF-16

TGF β pathway

DAF-4

Stress response gene Antimicrobial response gene

P

PP

Male tail

Defensemechanisms

?

?

p38 MAP kinase pathway

NSY-1 NSY-1

Pathogenresistance

NSY-1

Cell–fate decision

Arsenicresistance

SKN-1DAF-16

Current Opinion in Immunology

Three signalling pathways important for C. elegans innate immune defences against bacterial infection. (a) The TGF-b homologue DBL-1 binds to

the heterodimeric receptor SMA-6/DAF-4 and signals through the Smad proteins SMA-2, SMA-3 and SMA-4. In addition to its role in defence,

this pathway is known to regulate body size via the protein LON-1 and male tail development via MAB-21. At the moment, it is not known whether

the transcription factor MEF-2 (myocyte-specific enhancer factor 2) functions in all three branches of the pathway. (b) The DAF-2 pathway is an

insulin/insulin-like growth factor 1 signalling cascade that regulates development and life span. The receptor DAF-2, when bound by its ligand

INS-18, activates the phosphatidylinositol-3-OH kinase AGE-1, which catalyses the conversion of phosphatidylinositol bisphosphate (PiP2) into

phosphatidylinositol trisphosphate (PiP3). On one hand, PiP3 binds to the complex AKT-1/AKT-2 (AKT-1/2 in the figure), which leads to the exposure of

two phosphorylation sites. On the other hand, the kinase PDK-1 binds to PiP3 and is recruited to the membrane where it can phosphorylate and

activate AKT-1. The kinase AKT, in turn, phosphorylates the transcription factor DAF-16 and thereby ensures its cytoplasmic retention. In daf-2

mutants, as the pathway is not active, DAF-16 is not phosphorylated and can be translocated to the nucleus where it regulates the expression of a

set of stress response and antimicrobial genes. Note that the expression of the lysozyme gene lys-8 is under the control of the DBL-1/TGF-b and

DAF-2 pathways. (c) Another pathway regulating resistance to infection and to stress in C. elegans is the p38 MAPK pathway. PMK-1 is homologous

to the mammalian p38 MAPK and acts downstream of NSY-1/MAPK kinase kinase and SEK-1/MAPK kinase. These two kinases had previouslybeen shown to act downstream of the Ca2þ/calmodulin-dependent protein kinase II UNC-43 to control the asymmetric expression of an olfactory

receptor gene in one of a pair of sensory neurons. The nsy-1-sek-1-pmk-1 pathway mediates pathogen resistance independently of unc-43. The

nsy-1-sek-1-pmk-1 cassette also functions via SKN-1 to control resistance to arsenic. It is not known whether in the context of pathogen resistance

pmk-1 function requires skn-1. These three pathways (a–c) might be interconnected at the molecular level. In mammals, the association of MEF-2 with

the Smads is dependant upon phosphorylation by p38 MAPK; it has not yet been established whether PMK-1 phosphorylates MEF-2 in C. elegans.

It is also possible that the kinase AKT phosphorylates and negatively regulates NSY-1 (the homologue of the mammalian ASK1), as is the case in

mammals. ASK, apoptosis signal-regulating kinase; NSY, neuronal symmetry; PDK, phosphoinositide-dependent kinase; PMK, p38 MAP kinase;

SEK, SAPK/ERK kinase (SAPK, stress-activated protein kinase; ERK, extracellular-signal-regulated protein kinase); SKN, skinhead.

6 Innate immunity


Although these two pathways may only converge at the

level of their respective target genes, the evidence cited

above suggests that they might be linked via the nsy-1-sek-1-pmk-1 pathway or, again, there may be a direct mole-

cular connection between the two cascades.

ConclusionsRecent work from several laboratories has revealed that a

complex interplay of intracellular signalling cascades

contributes to the antibacterial defences of C. elegans.There is also an emerging picture that intercellular

communication between different cell types plays a role

in worm innate immunity. It was known from studies on

ageing that there are multiple inputs to the daf-2-daf-16pathway, including those derived from the germline and

from sensory neurons that respond to environmental

cues. These neurons produce DAF-2 that then acts in

a cell non-autonomous manner to control intestinal

metabolism (reviewed in [34]). The TGF-b-like ligand

DBL-1 appears to act in a similar manner [35]. Consis-

tent with this, the common daf-2-daf-16 and dbl-1 target

gene lys-8 is known to be expressed in the intestine, and

is presumed to be secreted into the intestinal lumen

where it can act directly against pathogenic bacteria

(Figure 2).

Although overall our understanding of C. elegans defences

is advancing rapidly, future work will need to address the

question of how infection is perceived by the nematode,

and how distinct responses can be triggered by different

pathogens, or indeed by stress, despite the fact that they

involve linked signalling cascades. The tractability and

relative simplicity of C. elegans promises to allow a

detailed dissection of the complexity of conserved innate

immune defences, and to clarify the role of cellular stress

in an organism’s response to infection.

Figure 2

Hypodermis

Pseudocoelom

Cuticle

Intestine

HypodermisReceptor

Stress resistance

Pathogen resistance

Intestinal cell

Intestinal lumen

?

Receptor

Pathogen receptor ?

Stress resistancePathogen resistance

PseudocoelomSoluble signal

Pathogens

(a)

(b)

Nervoussystem

Grinder

Environmentalsignals

Sensoryneuron

Interneuron

DAF-2 pathwayTGF-β pathwayMAPK pathway

DAF-2 pathwayTGF-β pathwayMAPK pathway LYS-8

Current Opinion in Immunology

Pharynx

Antimicrobial defences in C. elegans. (a) Basic anatomy of C. elegans. Of particular note are the physical barriers, the grinder that mechanically

disrupts the bacteria that form a worm’s normal diet, and the cuticle that envelopes the animal, both of which protect the worm from microbialaggression, and the pseudocoelom, a fluid-filled cavity that separates the intestinal cells from the hypodermis. (b) A model for the cellular basis

of innate immunity in C. elegans. The presence of pathogens in the environment is perceived via the sensory neurons, which generate a signal that is

transmitted to target tissues via the pseudocoelom. Supporting such an idea is the fact that, in contrast to their ligands, which are secreted

factors expressed in the nervous system, the different proteins involved in the DAF-2 and DBL-1 signalling cascades (see Figure 1) are expressed

in the intestine and hypodermis, as are putative antimicrobial proteins, such as LYS-8 and R09B5.3. It is possible that the establishment of an

infection in the intestinal lumen also plays a role in triggering a defence reaction, via an as yet uncharacterised mechanism. It is hypothesised

that antimicrobial proteins and peptides are secreted into the intestine, via specialised vesicular traffic, as illustrated for LYS-8.



AcknowledgementsWe thank numerous colleagues for discussion, especially those whoallowed us to cite unpublished results, and Hinrich Schulenburg forcritical reading of the text. Work in the authors’ laboratory is supportedby grants from the French Ministry of Research, the Centre Nationalpour la Recherche Scientifique (CNRS), the Institut National de la Santeet de la Recherche Medicale (INSERM) and the Universite de laMediterranee.

References and recommended readingPapers of particular interest, published within the annual period ofreview, have been highlighted as:

� of special interest��of outstanding interest

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8.�

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C. elegans is susceptible to a broad range of bacterial pathogens, and thevirulence mechanisms implicated in the killing of the nematode overlap, inpart, those involved in mammalian infections. Thus, as demonstrated inthese studies (see also [8�] and the pioneering work of the Ausubel group[7]), the use of C. elegans as a model host to screen banks of bacterialmutants can lead to the identification of universal virulence factors.

10.�

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13. Zhang H, Kato Y: Common structural properties specificallyfound in the CSab-type antimicrobial peptides in nematodesand mollusks: evidence for the same evolutionary origin?Dev Comp Immunol 2003, 27:499-503.

14. Kato Y, Aizawa T, Hoshino H, Kawano K, Nitta K, Zhang H: abf-1and abf-2, ASABF-type antimicrobial peptide genes inCaenorhabditis elegans. Biochem J 2002, 361:221-230.

15. Pillai A, Ueno S, Zhang H, Kato Y: Induction of ASABF (Ascarissuum antibacterial factor)-type antimicrobial peptides bybacterial injection: novel members of ASABF in the nematodeAscaris suum. Biochem J 2003, 371:663-668.

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Using high-density cDNA microarray analysis to evaluate the gene ex-pression levels upon Serratia marcescens infection, the authors show thatC. elegans possesses inducible defence mechanisms.

17. Rutschmann S, Kilinc A, Ferrandon D: The Toll pathway isrequired for resistance to Gram-positive bacterial infections inDrosophila. J Immunol 2002, 168:1542-1546.

18. Lemaitre B, Nicolas E, Michaut L, Reichhart JM, Hoffmann JA: Thedorsoventral regulatory gene cassette spatzle/Toll/cactuscontrols the potent antifungal response in Drosophila adults.Cell 1996, 86:973-983.

19. Lau GW, Goumnerov BC, Walendziewicz CL, Hewitson J, Xiao W,Mahajan-Miklos S, Tompkins RG, Perkins LA, Rahme LG: TheDrosophila melanogaster Toll pathway participates inresistance to infection by the Gram-negative human pathogenPseudomonas aeruginosa. Infect Immun 2003, 71:4059-4066.

20.�

Aballay A, Drenkard E, Hilbun LR, Ausubel FM: Caenorhabditiselegans innate immune response triggered by Salmonellaenterica requires intact LPS and is mediated by a MAPKsignaling pathway. Curr Biol 2003, 13:47-52.

Salmonella enterica infection triggers gonadal programmed cell death(PCD or apoptosis) in C. elegans, associated with an increased resistanceto infection [32]. In this paper, the authors show that PCD occurs down-stream of the p38 MAPK signalling cascade and that intact SalmonellaLPS is required to elicit PCD. The transduction of the LPS-dependentsignal is independent of the C. elegans Toll homologue and, thus, thefactors upstream of the p38 MAPK signalling cascade remain to beidentified.

21. Pujol N, Link EM, Liu LX, Kurz LC, Alloing G, Tan MW, Ray KP,Solari R, Johnson CD, Ewbank JJ: A reverse genetic analysis ofcomponents of the Toll signalling pathway in Caenorhabditiselegans. Curr Biol 2001, 11:809-821.

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24.�

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In this paper, the authors demonstrate that mutations in the insulin/IGF-1pathway, which render worms long-lived, slow ageing at the tissue level.They show that a C. elegans heat shock factor that regulates the responseto heat and oxidative stress controls, in part, the rate of ageing. Finally,they present evidence that a cause of death for old worms is theproliferation of bacteria in the intestinal lumen, confirming previous data[23] and suggesting that, when worms age, they lose the capacity toprevent such proliferation and become susceptible to normally innocuousbacteria and hypersusceptible to pathogens.

25.��

Murphy CT, McCarroll SA, Bargmann CI, Fraser A, Kamath RS,Ahringer J, Li H, Kenyon C: Genes that act downstream of DAF-16 to influence the lifespan of Caenorhabditis elegans.Nature 2003, 424:277-283.

Through an extensive microarray analysis, DAF-16 target genes wereidentified, and the role of many of these genes in ageing was demon-strated using RNAi. Among the genes found were those involved either instress or antimicrobial responses.

8 Innate immunity


26. Ookuma S, Fukuda M, Nishida E: Identification of a DAF-16transcriptional target gene, scl-1, that regulates longevity andstress resistance in Caenorhabditis elegans. Curr Biol 2003,13:427-431.

27.��

Garsin DA, Villanueva JM, Begun J, Kim DH, Sifri CD,Calderwood SB, Ruvkun G, Ausubel FM: Long-lived C. elegansdaf-2 mutants are resistant to bacterial pathogens.Science 2003, 300:1921.

In comparison to wild-type worms, the long-lived daf-2 and age-1mutants are resistant to infection by Gram-positive bacteria. Mutationsin the daf-16 gene suppress the pathogen-resistant phenotype of thesetwo mutants. Thus, the mechanisms that govern ageing and the immuneresponse appear to be interrelated in C. elegans.

28. Scott BA, Avidan MS, Crowder CM: Regulation of hypoxic deathin C. elegans by the insulin/IGF receptor homolog DAF-2.Science 2002, 296:2388-2391.

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30.��

Kim DH, Feinbaum R, Alloing G, Emerson FE, Garsin DA, Inoue H,Tanaka-Hino M, Hisamoto N, Matsumoto K, Tan MW et al.: Aconserved p38 MAP kinase pathway in Caenorhabditis elegansinnate immunity. Science 2002, 297:623-626.

Genetic screens to isolate mutant worms hypersusceptible to infectioncaused by Pseudomonas aeruginosa led to the identification of a con-

served p38 MAPK pathway composed of the three genes nsy–1, sek–1and pmk–1.

31.�

An JH, Blackwell TK: SKN-1 links C. elegans mesendodermalspecification to a conserved oxidative stress response.Genes Dev 2003, 17:1882-1893.

In addition to its developmental role, SKN–1 functions postembryonicallyin the ASI neurons and intestine to regulate the expression of phase IIdetoxification genes. Under conditions of oxidative stress, SKN–1 accu-mulates in intestinal nuclei and the skn–1 mutant phenotype indicates thatthis transcription factor plays a key role by regulating the expression ofantioxidant factors, such as glutathione-S-transferase.

32. Aballay A, Ausubel FM: Programmed cell death mediated byced-3 and ced-4 protects Caenorhabditis elegans fromSalmonella typhimurium-mediated killing. Proc Natl Acad SciUSA 2001, 98:2735-2739.

33. Quinn ZA, Yang CC, Wrana JL, McDermott JC: Smad proteinsfunction as co-modulators for MEF2 transcriptional regulatoryproteins. Nucleic Acids Res 2001, 29:732-742.

34. Guarente L, Kenyon C: Genetic pathways that regulate ageing inmodel organisms. Nature 2000, 408:255-262.

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immunity in caenorhabditis elegans

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