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The Toll pathway inhibits tissue growth and regulates cell fitness in an infection-dependent manner

Federico Germani, Daniel Hain, Denise Sternlicht, Eduardo Moreno, Konrad Basler

Preprint posted on 23 November 2018 https://www.biorxiv.org/content/early/2018/11/14/470419

To win or to lose: infection affects epithelial tissue growth and cell survival in a Toll dependent manner

Selected by Rohan Khadilkar

Background: Cell competition is a process where cells compete with each other for survival. It is a homeostatic process where proliferating cells produce signals that induce apoptosis in the neighboring slower dividing but otherwise viable healthy cells. Cell competition can be driven by competition for growth factors or due to differences in expression of genes like myc that are involved in cellular proliferation or ribosomal genes which influence translation rates. This particular study by Germani et al., explores the inter-relationship between infection, Toll pathway induced innate immune response and cell competition during organismal development. The authors show that Toll signalling acts as an important pro-apoptotic regulator. This study explores how systemic responses like innate immune response regulate localized changes at the cellular level which is relatively less studied.

Learn more about innate immunity in Drosophila:

https://www.youtube.com/watch?v=t_yV7oLUrEw

Key findings:

  1. The authors show that in a cell competition model in Drosophila, inhibition of Toll signalling by over-expressing Cactus, the inhibitor for Toll pathway rescues the elimination of loser cells (the slower dividing cells) and also provides a growth advantage to wild type cells.
  2. Activation of the Toll pathway in a clonal cell competition scenario induces apoptosis and causes cellular delamination. Since Toll pathway plays an important role in mounting an innate immune response, cellular competition and the role of Toll signalling was assessed in three conditions: Normal (basal infection levels), upon infection and under axenic conditions (germ/pathogen-free conditions). The authors show that involvement of Toll signalling in cell competition depends on the presence of pathogens in the environment. Toll pathway inhibition in loser cells did not rescue cell competition driven elimination of these loser cells under axenic conditions.
  3. The authors also go on to show that pathway activation induced cell lethality can be ameliorated under conditions of extra-infection.

These key findings show that there is a trade-off between innate immune response mediated by Toll pathway and its role in growth control during development.

Figure 4: Infection-dependent role of the Toll pathway in cell growth: Under axenic conditions, no pathogens are present in the environment and independently of the amount of IκB inhibitor in the cytoplasm, the NFκB transcription factors are unable to translocate to the nucleus. The outcome is a similar amount of growth between wild-type and Cactus over-expressing cells (A). When cells are exposed to infectious agents, Toll pathway gets activated In wild-type cells causing NFκB translocation. On the contrary, Cactus over-expressing cells remain unresponsive. This generates a strong growth advantage over the surrounding wild-type cells (B).

 

What’s exciting/why I think this is important: There have been independent efforts to understand cellular/tissue level growth control and cellular response to infection but very few studies integrate the two aspects to investigate and focus on a more holistic scenario. This study particularly elucidates and seamlessly integrates the role of Toll signalling during infection and cell competition during growth control.  I believe this study holds special importance as it paves way for understanding how systemic responses govern localized changes at the cellular level in an organism.

Open questions:

  1. Since the authors show that the phenomenon of cell competition depends on Toll signalling and basal level of infection by performing experiments in axenic conditions; does the gut microflora play any role in regulating cell competition in this context? This would be an interesting avenue to pursue further.
  2. Does Toll signalling act in a parallel manner or in concert with any other signalling pathway that is known to be involved in cell competition? Were there any that were tested?
  3. How does systemic response to infection dictate local responses in tissues where cell competition occurs? What sort of systemic signals regulate the production of cytokines or signalling ligands that are involved in cell competition?

 

Related references:

  • Katsukawa, M., Ohsawa, S., Zhang, L., Yan, Y., & Igaki, T. (2018). Serpin Facilitates Tumor-Suppressive Cell Competition by Blocking Toll-Mediated Yki Activation in Drosophila. Current Biology.
  • Alpar, L., Bergantiños, C., & Johnston, L. A. (2018). Spatially restricted regulation of Spätzle/Toll signaling during cell competition. Developmental cell46(6), 706-719.
  • Baker, N. E. (2017). Mechanisms of cell competition emerging from Drosophila studies. Current opinion in cell biology48, 40-46.

 

 

Tags: bacteria, cell biology, fruit flies, genetics, immunity, infection, pathogens, signalling

Posted on: 24 November 2018 , updated on: 26 November 2018

doi: https://doi.org/10.1242/prelights.5840

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