Vale, Pedro

Wilson, Amy B Pedersen

Regan, Jenny

Prakash, Arun

2022-05-26T16:05:47Z

2022-05-26T16:05:47Z

2022-05-26

To regain health following infection, hosts must not only identify and eliminate the source of infection, but also be able to reduce the resulting tissue damage in order to tolerate immunopathology. Compared to the mechanisms of pathogen clearance, we currently know less about how the mechanisms of damage prevention and repair contribute to disease tolerance phenotype. The aim of this thesis is to improve our understanding of mechanisms that enhance disease tolerance during bacterial infections. Here, I employed genetically manipulated fruit flies (Drosophila melanogaster) with disrupted mechanisms of immune regulation, damage prevention and repair to test how these mechanisms contribute to disease tolerance. We find that reduced expression of the negative regulators of IMD (immune deficiency pathway) or absence of regulation of Jak/Stat (Janus kinase/signal transducer and activator of transcription pathway), severely reduced the ability of flies to tolerate systemic infection with Pseudomonas entomophila. Therefore, in addition to regulating an efficient pathogen clearance response, negative immune regulators also contribute to disease tolerance. We also found that loss-of-function mutants lacking damage preventing dcy (drosocrystallin - a major component of the peritrophic matrix), damage signalling upd3 (unpaired protein, a cytokine-like molecule), damage repairing egfr1 (epidermal growth factor receptor) and damage controlling irc (immune-regulated catalase, a negative regulator of reactive oxygen species), affect the ability of flies to tolerate enteric infection, and that these effects are sexually dimorphic. Finally, we also investigated an additional defence mechanism of immune priming in Drosophila. Using UAS-RNAi knockdown, loss-of-function or immune deletion mutants and CRISPR knockout transgenic flies we found that immune priming is a long-lasting response, occurring in several backgrounds and is particularly stronger in male flies. Priming requires the regulation of the IMD-responsive antimicrobial peptide Diptercin in the fat body against the gram-negative bacteria Providencia rettgeri. We further found that priming has the potential to reduce disease spread and transmission by affecting pathogen shedding. The thesis concludes with an outlook on future research in the field of disease tolerance and damage limitation mechanisms to bacterial infections in Drosophila.

https://hdl.handle.net/1842/39028

http://dx.doi.org/10.7488/era/2279

en

The University of Edinburgh

Disease tolerance

negative immune regulation

immune priming

tissue damage repair

pathogen transmission

Immune regulation of disease tolerance and immune priming in Drosophila

Thesis or Dissertation

Doctoral

PhD Doctor of Philosophy