Thread by @JavierApfeld

Hey twitterworld! I am super excited to share our new paper!

We show that worms use their brain to decide whether to induce their hydrogen peroxide defenses or use those of E. coli.

Thread. 1/

elifesciences.org/articles/56186

This project was led by my amazing graduate student Jodie Schiffer, with major help from gs Frank Servello and Xuyan Xu, and everyone in the lab, and collaborations with @nstroustrup1 and A. Ghazi’s labs. 2/

For 100 years we’ve known that cells of all kinds are waging chemical warfare against each other.

Hydrogen peroxide is the weapon of choice on the microscopic battlefield! /3

Because the threat of hydrogen peroxide is so serious, cells rely on many highly conserved enzyme systems to degrade hydrogen peroxide and avoid the damage that hydrogen peroxide inflicts on their proteins, nucleic acids, and lipids. 4/

Yet inducing these defenses at the wrong time can be energetically costly, toxic, and interfere with the intracellular signaling functions of hydrogen peroxide.

How do the cells of an animal decide when to express these defenses? 5/

Using our favorite multicellular animal, the awesome nematode C. elegans, we set out to answer a variation of that question:

Does the brain coordinate cellular hydrogen peroxide defenses? 6/

We systematically ablated smell, taste, touch, temperature, and oxygen sensing neurons.

We found 10 classes of sensory neurons that regulate how long C. elegans survives in the presence of peroxides in the environment. 7/

We will be busy for years to come studying how all these neurons act together control the worm’s peroxide defenses.

We focused on answering how removing just two neurons could have such a large effect on survival. 8/

The two ASI neurons regulate peroxide resistance by secreting a hormone, DAF-7/TGF beta.

This effect is large and specific!

DAF-7 does not affect resistance to other lethal chemicals: sodium arsenite, paraquat, and DTT. 9/

By the way, these absolutely beautiful survival curves were acquired using a C. elegans Lifespan Machine scanner cluster. lifespanmachine.crg.eu/lsm 10/

DAF-7 signals indirectly to target tissues, the information is relayed by redundant sets of interneurons.

We think that this circuit logic ensures that peroxide resistance remains low unless all interneurons agree that DAF-7 levels are low. 11/

In response to DAF-7/TGFb from ASI, interneurons signal to target tissues via insulin/IGF1 signaling, leading to the repression of the DAF-16/FOXO and SKN-1/NRF transcription factors. 12/

Using mRNA-seq, we found that reduced DAF-7/TGFb signaling upregulates expression of defense responses involving DAF-16/FOXO and SKN-1/NRF target genes. 13/

Ok, we know how ASI regulates peroxide resistance.

When is this regulatory system important? 14/

We found that this regulatory system enables the worms to increase their peroxide defenses in when they are not eating enough food (E. coli). 15/

Previous work from @betenoire1, Queelim Ch’ng and Young-Jai You labs showed that TAX-4-dependent sensory perception of E. coli stimulates the expression of DAF-7 in ASI. 16/

This was very puzzling, why would worms turn off their peroxide defenses (instructed by expressing DAF-7 in ASI) when they sensed E. coli? 17/

We reasoned that perhaps C. elegans decreases its own peroxide self-defenses via DAF-7 signaling from the ASI neurons when E. coli is abundant because C. elegans expects to be safe from peroxide attack in that setting. 18/

This turned out to be true. But answering this question required that we re-examine the conditions of our peroxide assays and that we re-visit a whole set of experiments that we performed years before and seemingly never worked. 19/

Briefly, for about a year, we were frustrated and puzzled that we could not kill worms with hydrogen peroxide, even at implausibly high concentrations, and yet we could kill them with a comparable amount of tert-butyl hydroperoxide. 20/

We were using tBuOOH because that was the “default” peroxide that people in the field used.

Frustratingly, we could not test if sensory signals that regulate tBuOOH resistance would protect worms from other peroxides, as most other peroxides are highly unstable explosives. 21/

After many insightful conversations with microbiologist colleagues @Northeastern, we realized that the E. coli lawn present in our assays may have been degrading the hydrogen peroxide but not the tBuOOH we were adding to the survival-assay petri plates! 22/

The two E. coli catalases, KatG and KatE, are the predominant scavengers of hydrogen peroxide in the environment, and the peroxiredoxin, AhpCF, plays a minor role. 23/

When we used an E. coli triple mutant lacking catalases and peroxiredoxin, we could kill worms with hydrogen peroxide!!

And daf-7/TGFb mutants survived longer! 24/

Also, worms induced the expression of their own catalase gene when DAF-7-pathway signaling was low.

And this catalase gene induction protected the worms from hydrogen peroxide killing! 25/

In the microbial battlefield, worms use a sensory-neuronal circuit to determine whether to defend themselves from hydrogen peroxide attack or to freeload off protective defenses from another species. 26/

In the complex and variable habitat where worms live, deciding whether to induce hydrogen peroxide defenses is challenging.

C. elegans cells manage this challenge by relinquishing control of their cellular hydrogen peroxide defenses to a neuronal circuit in the brain. 27/

We think that DAF-7/TGFb coordinates the induction of a broad phenotypic response to the perceived threat of hydrogen peroxide.

The phenotypic responses to lower DAF-7 signaling follow the expected desirable outcomes for animals that anticipate exposure to hydrogen peroxide 28/

While a freeloading strategy may provide maximum fitness by inactivating self-defenses in environments where hydrogen peroxide is not a threat, this strategy need not provide maximum health or longevity to the organism. 29/

Indeed @Alcedo_lab and @ctmurphy1 lab showed that ASI and DAF-7 shorten the worm’s lifespan in environments with no hydrogen peroxide. 30/

Our work builds on @prahlad_veena's awesome experiments showing that AFD temperature-sensing neurons control the induction of defenses to a physical threat (heat) in target tissues. 31/

We think that sensory modulation offers a promising approach to induce latent defenses that could increase health and longevity! /fin

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