Title: The Bacterivore’s Solution: Fight and Flight to Promote Survival
Abstract: Bacterial avoidance and innate immune response are two ways by which C. elegans respond to pathogenic bacteria. In this issue of Developmental Cell, Kumar et al., 2019Kumar S. Egan B.M. Kocsisova Z. Schneider D.L. Murphy J.T. Diwan A. Kornfeld K. Lifespan extension in C. elegans caused by bacterial colonization of the intestine and subsequent activation of an innate immune response.Dev. Cell. 2019; 49 (this issue): 100-114Scopus (42) Google Scholar and Singh and Aballay, 2019Singh J. Aballay A. Microbial colonization activates an immune fight-and-flight response via neuroendocrine signaling.Dev. Cell. 2019; 49 (this issue): 89-99Abstract Full Text Full Text PDF PubMed Scopus (40) Google Scholar demonstrate that bacterial colonization is essential to induce both responses, which may be associated with somatic and reproductive longevity. Bacterial avoidance and innate immune response are two ways by which C. elegans respond to pathogenic bacteria. In this issue of Developmental Cell, Kumar et al., 2019Kumar S. Egan B.M. Kocsisova Z. Schneider D.L. Murphy J.T. Diwan A. Kornfeld K. Lifespan extension in C. elegans caused by bacterial colonization of the intestine and subsequent activation of an innate immune response.Dev. Cell. 2019; 49 (this issue): 100-114Scopus (42) Google Scholar and Singh and Aballay, 2019Singh J. Aballay A. Microbial colonization activates an immune fight-and-flight response via neuroendocrine signaling.Dev. Cell. 2019; 49 (this issue): 89-99Abstract Full Text Full Text PDF PubMed Scopus (40) Google Scholar demonstrate that bacterial colonization is essential to induce both responses, which may be associated with somatic and reproductive longevity. While germophobia may be a psychological issue for humans, avoiding pathogenic bacteria is a matter of life and death for Caenorhabditis elegans. Upon exposure to certain pathogenic bacteria, worms can die within only hours or days, in contrast to their normal lifespan of 3 weeks (Tan et al., 1999Tan M.W. Rahme L.G. Sternberg J.A. Tompkins R.G. Ausubel F.M. Pseudomonas aeruginosa killing of Caenorhabditis elegans used to identify P. aeruginosa virulence factors.Proc. Natl. Acad. Sci. USA. 1999; 96: 2408-2413Crossref PubMed Scopus (463) Google Scholar). To avoid this fate, worms may run away, and this protective avoidance behavior can be elicited within minutes (rapid) or hours (late), dependent upon the type of pathogen. In this issue of Developmental Cell, findings from Kumar et al., 2019Kumar S. Egan B.M. Kocsisova Z. Schneider D.L. Murphy J.T. Diwan A. Kornfeld K. Lifespan extension in C. elegans caused by bacterial colonization of the intestine and subsequent activation of an innate immune response.Dev. Cell. 2019; 49 (this issue): 100-114Scopus (42) Google Scholar and Singh and Aballay, 2019Singh J. Aballay A. Microbial colonization activates an immune fight-and-flight response via neuroendocrine signaling.Dev. Cell. 2019; 49 (this issue): 89-99Abstract Full Text Full Text PDF PubMed Scopus (40) Google Scholar reveal that bacterial colonization and consequent bloating of the intestine are responsible for the late avoidance behavior in C. elegans. Singh and Aballay, 2019Singh J. Aballay A. Microbial colonization activates an immune fight-and-flight response via neuroendocrine signaling.Dev. Cell. 2019; 49 (this issue): 89-99Abstract Full Text Full Text PDF PubMed Scopus (40) Google Scholar study avoidance behaviors upon exposure to pathogenic bacteria. They discover that with pathogenic Pseudomonas aeruginosa, wild-type worms elicit a late avoidance behavior, which is positively correlated with bacterial colonization in the intestine. They further confirm that the inhibition of bacterial colonization abrogates the avoidance response, while the elevation of bacterial colonization caused by defects in either pharyngeal pumping or defecation motor program (DMP) is sufficient to elicit the avoidance response. Interestingly, like the long-lived pharyngeal pumping mutants, the DMP mutants also show increased lifespan when grown on E. coli that are mildly pathogenic. Kumar et al., 2019Kumar S. Egan B.M. Kocsisova Z. Schneider D.L. Murphy J.T. Diwan A. Kornfeld K. Lifespan extension in C. elegans caused by bacterial colonization of the intestine and subsequent activation of an innate immune response.Dev. Cell. 2019; 49 (this issue): 100-114Scopus (42) Google Scholar reach a similar conclusion through characterization of a mutant from a forward genetic screen. In a previous genetic screen, the authors identified a loss-of-function mutation in phm-2, which extended reproductive span in C. elegans (Hughes et al., 2011Hughes S.E. Huang C. Kornfeld K. Identification of mutations that delay somatic or reproductive aging of Caenorhabditis elegans.Genetics. 2011; 189: 341-356Crossref PubMed Scopus (25) Google Scholar). They now show that a mutation in phm-2 causes abnormalities in pharyngeal grinder function and that this mutation extends lifespan. Interestingly, this mutation also leads to increased avoidance behavior and bacterial colonization in the intestine, which are associated with its pro-longevity effects. Together, these two studies suggest that bacterial colonization induces an avoidance behavioral response and consequently increases organismal longevity under normal growth conditions (Figure 1). To characterize the underlying molecular mechanisms, the two groups both investigate neuronal mechanisms that are linked to avoidance responses but diverge to different signals. Kumar et al., 2019Kumar S. Egan B.M. Kocsisova Z. Schneider D.L. Murphy J.T. Diwan A. Kornfeld K. Lifespan extension in C. elegans caused by bacterial colonization of the intestine and subsequent activation of an innate immune response.Dev. Cell. 2019; 49 (this issue): 100-114Scopus (42) Google Scholar confirm that the increased avoidance response caused by the phm-2 mutation requires TPH-1-mediated serotonin biosynthesis but is independent of NPR-1-mediated neuropeptide signals. On the other hand, Singh and Aballay, 2019Singh J. Aballay A. Microbial colonization activates an immune fight-and-flight response via neuroendocrine signaling.Dev. Cell. 2019; 49 (this issue): 89-99Abstract Full Text Full Text PDF PubMed Scopus (40) Google Scholar reveal that the avoidance caused by increased colonization of P. aeruginosa in the DMP mutants requires NPR-1 and the two neuropeptides FLP-18 and FLP-21, but serotonin biosynthesis through TPH-1 plays a negligible role here. It remains unclear what might cause this discrepancy. One possibility is that increased bacterial colonization caused by defective pharyngeal pumping or DMP employs different neuronal mechanisms to elicit avoidance behavior. The other possibility is that intestinal colonization by different types of bacteria may elicit distinct avoidance behaviors. In addition to the avoidance response, worms protect themselves from bacterial infection by activating the innate immune response (Marsh and May, 2012Marsh E.K. May R.C. Caenorhabditis elegans, a model organism for investigating immunity.Appl. Environ. Microbiol. 2012; 78: 2075-2081Crossref PubMed Scopus (112) Google Scholar). Both studies demonstrate that increased intestinal colonization of bacteria transcriptionally induces innate immune response genes. Specifically, Kumar et al., 2019Kumar S. Egan B.M. Kocsisova Z. Schneider D.L. Murphy J.T. Diwan A. Kornfeld K. Lifespan extension in C. elegans caused by bacterial colonization of the intestine and subsequent activation of an innate immune response.Dev. Cell. 2019; 49 (this issue): 100-114Scopus (42) Google Scholar discover that in the phm-2 mutant, innate immune response genes are induced with mildly pathogenic E. coli, which requires the nuclear accumulation of HLH-30, an ortholog of vertebrate transcription factor EB (TFEB) known to regulate innate immune genes in C. elegans (Visvikis et al., 2014Visvikis O. Ihuegbu N. Labed S.A. Luhachack L.G. Alves A.F. Wollenberg A.C. Stuart L.M. Stormo G.D. Irazoqui J.E. Innate host defense requires TFEB-mediated transcription of cytoprotective and antimicrobial genes.Immunity. 2014; 40: 896-909Abstract Full Text Full Text PDF PubMed Scopus (187) Google Scholar). Singh and Aballay, 2019Singh J. Aballay A. Microbial colonization activates an immune fight-and-flight response via neuroendocrine signaling.Dev. Cell. 2019; 49 (this issue): 89-99Abstract Full Text Full Text PDF PubMed Scopus (40) Google Scholar show that innate immune response genes can be upregulated even by heat-killed E. coli that cause bloated intestinal lumen. Thus, bacterial colonization induced bloating of intestinal lumen, but not pathogenicity, may be the danger signal that provokes innate immune responses. Surprisingly, although both avoidance behavioral and innate immune responses are elicited by intestinal accumulation of bacteria, their regulatory mechanisms appear to be independent of each other. Kumar et al., 2019Kumar S. Egan B.M. Kocsisova Z. Schneider D.L. Murphy J.T. Diwan A. Kornfeld K. Lifespan extension in C. elegans caused by bacterial colonization of the intestine and subsequent activation of an innate immune response.Dev. Cell. 2019; 49 (this issue): 100-114Scopus (42) Google Scholar discover that although mutating hlh-30/TFEB fully abrogates the induction of innate immune response genes, it has no effect on the avoidance response in the phm-2 mutant. One possible explanation for this result is that the innate immune response may occur in the intestine cell autonomously, while the avoidance behavioral response is mediated through neurons cell non-autonomously. Importantly, these two studies also make us reevaluate genetic models of caloric restriction in C. elegans. Mutants defective in pharyngeal pumping decrease food intake and have been commonly utilized to study caloric restriction-mediated lifespan extension. Kumar et al., 2019Kumar S. Egan B.M. Kocsisova Z. Schneider D.L. Murphy J.T. Diwan A. Kornfeld K. Lifespan extension in C. elegans caused by bacterial colonization of the intestine and subsequent activation of an innate immune response.Dev. Cell. 2019; 49 (this issue): 100-114Scopus (42) Google Scholar and Singh and Aballay, 2019Singh J. Aballay A. Microbial colonization activates an immune fight-and-flight response via neuroendocrine signaling.Dev. Cell. 2019; 49 (this issue): 89-99Abstract Full Text Full Text PDF PubMed Scopus (40) Google Scholar discover that several of these mutants have increased intestinal colonization of bacteria and avoidance behavior. Kumar et al., 2019Kumar S. Egan B.M. Kocsisova Z. Schneider D.L. Murphy J.T. Diwan A. Kornfeld K. Lifespan extension in C. elegans caused by bacterial colonization of the intestine and subsequent activation of an innate immune response.Dev. Cell. 2019; 49 (this issue): 100-114Scopus (42) Google Scholar further show that the phm-2 mutation does not enhance the lifespan extension in the eat-2 mutant and requires pha-4, the FOXA transcription factor acting downstream of the eat-2 mutant, to prolong lifespan. In addition, they show that the hlh-30 mutation that mediates the induction of innate immune response in the phm-2 mutant also partially suppresses the lifespan extension. Together with the lifespan extension observed in the DMP mutants that induce innate immune response without pathogen infection, these studies support the idea that the longevity benefit in the pharyngeal defective mutants is not simply a result of reduced food intake, but a combination of bacterial colonization, innate immune activation, bacterial avoidance, and caloric restriction. It has been a long-term mystery why different regimes of caloric restriction in C. elegans act through different molecular mechanisms (Greer and Brunet, 2009Greer E.L. Brunet A. Different dietary restriction regimens extend lifespan by both independent and overlapping genetic pathways in C. elegans.Aging Cell. 2009; 8: 113-127Crossref PubMed Scopus (425) Google Scholar). These two studies shed light on this question and nicely integrate intestinal recognition of microbes, neural control of behaviors, and longevity responses to dietary intervention. Microbial Colonization Activates an Immune Fight-and-Flight Response via Neuroendocrine SignalingSingh et al.Developmental CellFebruary 28, 2019In BriefSingh and Aballay describe a mechanism by which a fight-and-flight response against pathogenic microbes is activated. They show that in C. elegans microbial colonization induces bloating of the intestinal lumen, which enhances the expression of innate immune genes and neuroendocrine pathway genes required for the elicitation of a microbial aversion behavior. Full-Text PDF Open ArchiveLifespan Extension in C. elegans Caused by Bacterial Colonization of the Intestine and Subsequent Activation of an Innate Immune ResponseKumar et al.Developmental CellApril 08, 2019In BriefKumar et al. link immunity and aging in C. elegans. The authors characterize phm-2 and eat-2, mutants that allow live bacteria to accumulate in the intestine, causing delayed reproductive and somatic aging. The mechanism combines molecular immune activation and behavioral food avoidance, leading to dietary restriction and extended lifespan. Full-Text PDF Open Archive