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

Kutzer, Megan A. M.; Gupta, Vanika; Neophytou, Kyriaki; Doublet, Vincent; Monteith, Katy M.; Vale, Pedro F.

doi:10.1101/2022.06.09.495537

Cited by 3 publications

(3 citation statements)

References 81 publications

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“…Statistical analyses were performed in R v.4.0.4 and R Studio 1.4.1106. All data and code is available at https://doi.org/ 10.5281/zenodo.6651851 [59]. Models 1a and 1b were analysed with a Cox mixed effects survival model using the coxme function in the coxme package [60].…”

Section: Methodsmentioning

confidence: 99%

“…First, we examined the effects of DCV dose and sex on survival across 10 genotypes to determine if hosts varied in their susceptibility to viral infection. Because pst is known to affect fly mortality following DCV infection, we selected five S lines (138, 373, 380, 765, 818) and five R lines(59,75, 379, 502, 738), based on previously described infected lifespans[30]. As expected, R lines tended to live longer than S lines (figure1a, table 1, Model 1a, pst allele: p < 0.0001), though this was also the case in the absence of infection (i.e.…”

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confidence: 99%

“…Data accessibility. All data and code for analysis can be accessed at: https://zenodo.org/record/6651851 [59].…”

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confidence: 99%

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Intraspecific genetic variation in host vigour, viral load and disease tolerance during Drosophila C virus infection

et al. 2023

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Genetic variation for resistance and disease tolerance has been described in a range of species. In Drosophila melanogaster , genetic variation in mortality following systemic Drosophila C virus (DCV) infection is driven by large-effect polymorphisms in the restriction factor pastrel (pst) . However, it is unclear if pst contributes to disease tolerance. We investigated systemic DCV challenges spanning nine orders of magnitude, in males and females of 10 Drosophila Genetic Reference Panel lines carrying either a susceptible (S) or resistant (R) pst allele. We find among-line variation in fly survival, viral load and disease tolerance measured both as the ability to maintain survival (mortality tolerance) and reproduction (fecundity tolerance). We further uncover novel effects of pst on host vigour, as flies carrying the R allele exhibited higher survival and fecundity even in the absence of infection. Finally, we found significant genetic variation in the expression of the JAK-STAT ligand upd3 and the epigenetic regulator of JAK-STAT G9a. However, 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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Intraspecific genetic variation in host vigour, viral load and disease tolerance during Drosophila C virus infection

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Negative immune regulation contributes to disease tolerance in Drosophila

Prakash

Monteith

Vale

2021

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Disease tolerance is an infection phenotype where hosts show relatively high health despite harbouring elevated pathogen loads. Compared to the mechanisms of immune clearance our knowledge of the mechanisms underlying increased tolerance remains incomplete. Variation in the ability to reduce immunopathology may explain why some hosts can tolerate higher pathogen burdens with reduced pathology. Negative immune regulation would therefore appear to be a clear candidate for a mechanism underlying disease tolerance but this has not been tested directly for bacterial infections. Here, we examined how the negative regulation of the immune deficiency (IMD) pathway affects disease tolerance in Drosophila melanogaster when infected with the gram-negative bacterial pathogen Pseudomonas entomophila. We find that UASRNAi-mediated reduced expression of the negative regulators of IMD (pirk & caudal) severely reduced the ability to tolerate infection in both males and females across a wide range of infectious doses. While flies unable to regulate the IMD response exhibited higher expression of antimicrobial peptides and lower bacterial loads as expected, this was not accompanied by a proportional reduction in mortality. Instead, tolerance (measured as fly survival relative to its microbe load) was drastically reduced, likely due to the combination of increased immunopathology and cytotoxicity of elevated AMP expression. Our results therefore highlight that in addition to regulating an efficient pathogen clearance response, negative regulators of IMD also contribute to disease tolerance.

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Genetic variation in trophic avoidance shows fruit flies are generally attracted to bacterial pathogens

Monteith,

Thornhill,

Vale

2024

Preprint

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Pathogen avoidance behaviours are often assumed to be an adaptive host defence from infection. However, there is limited experimental data on the prerequisite for this assumption: heritable, intra-population phenotypic variation for avoidance. We investigated trophic pathogen avoidance in 122 inbred Drosophila melanogaster lines, and in a derived outbred population. Using the FlyPAD system, we tracked the feeding choice that flies made between substrates that were either clean or contained a bacterial pathogen. We uncovered significant, but weakly heritable variation in the preference index among fly lines. However, instead of avoidance, most lines demonstrated a preference for several bacterial pathogens, showing avoidance only for extremely high bacterial concentrations. Bacterial preference was not associated with susceptibility to infection and was retained in flies with disrupted immune signalling. Phenotype-genotype association analysis indicated several novel genes (CG2321, CG2006, ptp99A) associated with increased preference for the bacterial substrate, while the amino-acid transporter sobremesa was associated with greater aversion. Together with previous work showing fitness benefits of consuming high-protein diets, our results suggest that bacterial attraction may instead reflect a dietary preference for protein over carbohydrate. More work quantifying intra-population variation in avoidance behaviours is needed to fully assess its importance in host-pathogen evolutionary ecology.

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

Cited by 3 publications

References 81 publications

Intraspecific genetic variation in host vigour, viral load and disease tolerance during Drosophila C virus infection

Intraspecific genetic variation in host vigour, viral load and disease tolerance during Drosophila C virus infection

Negative immune regulation contributes to disease tolerance in Drosophila

Genetic variation in trophic avoidance shows fruit flies are generally attracted to bacterial pathogens

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