Mechanisms of damage prevention, signalling, and repair impact disease tolerance

Prakash, Arun; Monteith, Katy M.; Vale, Pedro F.

doi:10.1101/2021.10.03.462916

Cited by 7 publications

(4 citation statements)

References 79 publications

(187 reference statements)

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“…For oral priming and live infection, we adjusted the final concentration to OD 600 =25 (Prakash et al, 2022; Siva-Jothy et al, 2018). We initially prepared vials for oral priming by pipetting 350-400 µl of standard agar [see (Siva-Jothy et al, 2018)] onto lid of a 7ml tubes (bijou vials) and allowed it to dry.…”

Section: Methodsmentioning

confidence: 99%

IMD-mediated innate immune priming increases Drosophila survival and reduces pathogen transmission

Prakash

Fenner

Shit

et al. 2023

Preprint

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Invertebrates lack the specialized immune-memory cells responsible for vertebrate-like acquired immunity. However, there is increasing evidence that past infection by the same pathogen can "prime" the insect immune response, resulting in improved survival upon reinfection. The mechanisms underlying these phenomenological accounts of priming are diverse, and often not completely clear. Here, we investigated the generality, specificity and mechanistic basis of immune priming in the fruit flyDrosophila melanogasterwhen infected with the gram-negative bacterial pathogenProvidencia rettgeri. We further explore the epidemiological consequences of immune priming and find it has the potential to curtail pathogen transmission by reducing pathogen shedding. We find that priming inDrosophilais a long-lasting, pathogen-specific response, occurring in several fly genetic backgrounds and is particularly stronger in male flies. Mechanistically, we find that the enhanced survival of individuals primed with an initial non-lethal bacterial inoculum coincides with a transient decrease in bacterial loads, and that this is likely driven by the IMD-responsive antimicrobial-peptide Diptericin-B in the fat body. Further, we show that while Diptericins are required as the effector of bacterial clearance, it is not solely sufficient for immune priming, and requires regulation by the peptidoglycan recognition proteins PGRP-LB, PGRP-LC and PGRP-LE. We discuss potential explanations for the observed sex differences in priming, and discuss the epidemiological consequences of innate immune priming in invertebrates.

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Section: Methodsmentioning

confidence: 99%

IMD-mediated innate immune priming increases Drosophila survival and reduces pathogen transmission

Prakash

Fenner

Shit

et al. 2023

Preprint

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“…All the raw data and analysis code can be accessed under a Creative Commons 4.0 License at [ 78 ]. An earlier preprint is available from the biological preprint server bioRxiv at: [ 79 ].…”

Section: Data Accessibilitymentioning

confidence: 99%

“…An earlier preprint is available from the biological preprint server bioRxiv at: https://www.biorxiv.org/content/10. 1101/2021.10.03.462916v1 [79].…”

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confidence: 99%

Mechanisms of damage prevention, signalling and repair impact disease tolerance

2022

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The insect gut is frequently exposed to pathogenic threats and must not only clear these potential infections, but also tolerate relatively high microbe loads. In contrast to the mechanisms that eliminate pathogens, we currently know less about the mechanisms of disease tolerance. We investigated how well-described mechanisms that prevent, signal, control or repair damage during infection contribute to the phenotype of disease tolerance. We established enteric infections with the bacterial pathogen Pseudomonas entomophila in transgenic lines of Drosophila melanogaster fruit flies affecting dcy (a major component of the peritrophic matrix), upd3 (a cytokine-like molecule), irc (a negative regulator of reactive oxygen species) and egfr 1 (epithelial growth factor receptor). Flies lacking dcy experienced the highest mortality, while loss of function of either irc or upd3 reduced tolerance in both sexes. The disruption of egfr 1 resulted in a severe loss in tolerance in male flies but had no substantial effect on the ability of female flies to tolerate P. entomophila infection, despite carrying greater microbe loads than males. Together, our findings provide evidence for the role of damage limitation mechanisms in disease tolerance and highlight how sexual dimorphism in these mechanisms could generate sex differences in infection outcomes.

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“…In addition to characterizing variation in resistance to and tolerance of DCV infection, we also aimed to link this variation with potential mechanisms, particularly for disease tolerance, where knowledge of the underlying mechanisms has lagged behind the description of their phenotypic effects. As disease tolerance relates to a reduction of pathology independently of pathogen clearance, tolerance mechanisms described to date have included those that prevent, limit or repair tissue damage [3,[34][35][36][37][38]. Inflammation is one common cause of such damage during infection.…”

Section: Introductionmentioning

confidence: 99%

The restriction factor pastrel is associated with host vigor, viral titer, and variation in disease tolerance during Drosophila C Virus infection

Kutzer

Gupta

Neophytou

et al. 2022

Preprint

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Genetic variation for both resistance and disease tolerance has been described in a range of species infected with bacterial, viral and fungal pathogens. In Drosophila melanogaster, genetic variation in mortality following systemic Drosophila C Virus (DCV) infection has been shown to be driven by large effect polymorphisms in the viral restriction factor pastrel (pst). However, it is unclear if pst impacts variation in DCV titres (i.e. resistance), or if it also contributes to disease tolerance. We investigated systemic infection across a range of DCV challenge doses spanning nine orders of magnitude, in males and females of ten Drosophila Genetic Reference Panel (DGRP) lines carrying either a susceptible (S) or resistant (R) pst allele. Our results uncover among-line variation in fly survival, viral titers, and disease tolerance measured both as the ability to maintain survival (mortality tolerance) and reproduction (fecundity tolerance). We confirm the role of pst in resistance, as fly lines with the resistant (R) pst allele experienced lower viral titers, and we uncover novel effects of pst on host vigor, as flies carrying the R allele exhibited higher survival and fecundity even in the absence of infection. Finally, we found significant variation in the expression of the JAK-STAT ligand upd3 and the epigenetic regulator of JAK-STAT G9a. While G9a has been previously shown to mediate tolerance of DCV infection, we found no correlation between the expression of either upd3 or G9a on fly tolerance or resistance. Our work highlights the importance of both resistance and tolerance in viral defence.

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Mechanisms of damage prevention, signalling, and repair impact disease tolerance

Cited by 7 publications

References 79 publications

IMD-mediated innate immune priming increases Drosophila survival and reduces pathogen transmission

IMD-mediated innate immune priming increases Drosophila survival and reduces pathogen transmission

Mechanisms of damage prevention, signalling and repair impact disease tolerance

The restriction factor pastrel is associated with host vigor, viral titer, and variation in disease tolerance during Drosophila C Virus infection

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