Cross-kingdom recognition of bacterial small RNAs induces transgenerational pathogenic avoidance

Rachel Kaletsky, Rebecca S. Moore, Lance L. Parsons, Coleen T. Murphy

Preprint posted on 11 July 2019

Pathogen-derived small RNAs are required for learning and transgenerational inheritance of avoidance behavior in C. elegans.

Selected by Madhuja Samaddar


Transgenerational epigenetic inheritance (TEI) is an intriguing phenomenon implicated in a variety of adaptive physiological responses. Unlike Mendelian inheritance, the mechanisms underlying TEI are less resolved and most studies have been focused on the role of histone and DNA modifications. In recent months, two independent reports have shown that behavior can be epigenetically transmitted across generations (1) and that neuronal small RNAs modulate germline gene expression to control behavior transgenerationally (2). Both studies utilized the nematode C. elegans, an organism in which RNA processing pathways and RNA-mediated gene expression modulation have been studied intensively. This preprint brings forth a new angle to small-RNA dependent TEI, by identifying a pathway that utilizes RNA signals originating in the pathogen itself. In this case, the small RNAs modulate neuronal gene expression indirectly by acting via the germline.


Key findings:

Following up on their recent work (1), the authors now show that:

  • The avoidance of Pseudomonas aeruginosa (PA14) does not require either bacterial exposure or induction of the innate immune response. Instead, purified PA14 small RNAs are sufficient to generate avoidance behavior in parents, which is also inherited by up to four subsequent generations of progeny.
  • Avoidance behavior in progeny of parents trained on either live pathogenic PA14 or on purified PA14 small RNAs, are similar in magnitude. This indicates that the small RNA-mediated pathway is sufficient for transgenerational inheritance.
  • C. elegans employ this small RNA-sensing strategy specifically to detect pathogenic forms of PA14. PA14 grown on plates at 25°C demonstrate a distinct small RNA signature in comparison to PA14 grown under non-pathogenic culture conditions. The non-pathogenic PA14 do not lead to learned pathogenic avoidance or its transgenerational inheritance.
  • Exposure to PA14 small RNAs alone can induce expression of TGF-β ligand DAF-7 specifically in ASI neurons. The induction of DAF-7 in ASI neurons was previously identified by the authors in parental worms exhibiting learned pathogenic avoidance and their progeny who have inherited the response.
  • The small RNA-induced avoidance response requires components of both the canonical RNA interference pathway and the Piwi Argonaute piRNA pathway. Finally, a functional germline is required to induce small RNA-induced avoidance of PA14 even in the parental generation, indicating that DAF-7 expression in ASI neurons relies on signals from the germline.
  • Pathogen avoidance by small RNA-sensing is species specific. Exposure to small RNAs from other species of Pseudomonas bacteria do not induce a learned avoidance behavior in PA14 and vice versa. Further, pathogen avoidance behavior that is not caused by bacterial small-RNAs is not inherited g. Serratia marcescans small RNAs do not induce avoidance or its subsequent inheritance.


What I liked about this preprint:

Transgenerational inheritance of parental experience-derived behavior can provide an organism with a potential survival head start. Multiple studies have previously suggested that neuronal changes in parents can modulate offspring behavior (3, 4).  This study sheds light on an elegant and plastic mechanism which allows worms to modulate behavior in the presence of pathogens, with the ability to reverse this behavior if and when conditions change. This adaptive response is particularly tuned to benefit worms, which feed on bacteria and constantly interact with diverse bacterial species in their natural environment.

These observations also raise the possibility that this small-RNA mediated pathway is a form of an adaptive immune response. Exposure to the pathogen allows parent worms to obtain protection for themselves and their progeny which are likely to experience a similar environment. This is particularly interesting as a canonical adaptive immune response pathway has not been previously identified in C. elegans.


Open questions:

The key question arising from this study is whether this phenomenon is a C. elegans quirk or if it is a general mechanism that is also utilized by other organisms for transmitting beneficial learned behavior. Worms are unique hosts where the same bacteria that serve as food can also infect them as pathogens. It is thus reasonable for worms to evolve an efficient yet plastic mechanism to sense and differentiate the two, resulting in a selective advantage not just for themselves but also for their progeny.



  1. Moore R.S. al., Piwi/PRG-1 Argonaute and TGF-β Mediate Transgenerational Learned Pathogenic Avoidance. (2019) Cell 177, 1827–1841
  2. Posner R. al., Neuronal Small RNAs Control Behavior Transgenerationally (2019) Cell 177, 1814–1826
  3. Remy, J.-J. Stable inheritance of an acquired behavior in Caenorhabditis elegans. (2010) Curr. Biol. 20, R877–R878.
  4. Vassoler, F.M. al., Epigenetic inheritance of a cocaine-resistance phenotype (2013). Nat. Neurosci. 16, 42–47

Tags: behavior, c. elegans, pathogen, small rnas, transgenerational epigenetic inheritance

Posted on: 27 July 2019


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Author's response

Coleen T. Murphy shared

It’s true that we don’t yet know whether this phenomenon is conserved or occurs in other animals, but the molecular components themselves are conserved up through mammals, so it is possible that small RNA mediated TEI occurs in other organisms. It’s also possible that the small RNA pathogen detection part (in the absence of TEI) occurs in other species, which by itself has interesting implications for host-pathogen responses and immunity.

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