Genetic variation and immune regulation of disease tolerance

Funding: Society in Science Branco Weiss Fellowship; Darwin Trust PhD studentship

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. We employed genetically manipulated fruit flies with disrupted mechanisms of immune regulation, damage prevention and repair to test how these mechanisms contribute to disease tolerance. We found that reduced expression of the negative regulators of IMD (immune deficiency pathway) or disrupted 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. We also found that loss-of-function of 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.

Key publications

• Vale, P.F., Fenton, A. & Brown, S.P. 2014. Limiting damage during infection: lessons from infection tolerance for novel therapeutics. PLoS Biol. 12: e1001769.
• Prakash, A., Monteith, K.M. & Vale, P.F. 2022. Mechanisms of damage prevention, signalling and repair impact disease tolerance. Proceedings of the Royal Society B: Biological Sciences 289: 20220837.
• Kutzer, M.A.M., Gupta, V., Neophytou, K., Doublet, V., Monteith, K.M. & Vale, P.F. 2023. Intraspecific genetic variation in host vigour, viral load and disease tolerance during Drosophila C virus infection. Open Biology 13: 230025. Royal Society.
• Prakash, A., Monteith, K.M., Bonnet, M. & Vale, P.F. 2023. Duox and Jak/Stat signalling influence disease tolerance in Drosophila during Pseudomonas entomophila infection. Developmental & Comparative Immunology 104756.
• Oliveira, J.H., Bahia, A.C. & Vale, P.F. 2020. How are arbovirus vectors able to tolerate infection? Developmental & Comparative Immunology 103: 103514.
• Gupta, V. & Vale, P.F. 2017. Nonlinear disease tolerance curves reveal distinct components of host responses to viral infection. R Soc Open Sci 4: 170342.

Mitochondrial genetic effects on innate immunity in Drosophila

Funding: Leverhulme Trust Research Project Grant

Mitochondria are increasingly recognised as important mediators of innate immune responses. However, it is currently unclear how naturally occurring variation in mitochondrial DNA (mtDNA) contributes to the widespread heterogeneity in infection outcomes. We investigate this using Drosophila melanogaster, an established model of immunity where it is possible to generate cybrid lines with diverse mitochondrial genomes introgressed onto controlled nuclear backgrounds. Using a panel of hybrid flies reflecting global mitochondrial diversity, we employ phenotypic, physiological and genomic approaches to test the effect of specific mitochondrial polymorphisms on cellular and humoral responses to pathogens and parasitoids in Drosophila. We have also investigated how variation in the mitochondrial genome may impact the fitness costs of costly traits like locomotor activity and immune deployment.

Key publications

• Salminen, T.S., Vesala, L., Basikhina, Y., Kutzer, M., Tuomela, T., Lucas, R., et al. 2024. A naturally occurring mitochondrial genome variant confers broad protection from infection in Drosophila. PLOS Genetics.
• Salminen, T.S. & Vale, P.F. 2020. Drosophila as a Model System to Investigate the Effects of Mitochondrial Variation on Innate Immunity. Frontiers in Immunology 11.
• Vesala, L., Basikhina, Y., Tuomela, T., Vale, P.F. & Salminen, T.S. 2024. Mitochondrial perturbation in immune cells enhances cell-mediated innate immunity in Drosophila. BMC Biology 22(1): 60.
• Anderson, L., Camus, M.F., Monteith, K.M., Salminen, T.S. & Vale, P.F. 2022. Variation in mitochondrial DNA affects locomotor activity and sleep in Drosophila melanogaster. Heredity 1–8.
• Kutzer, M.A.M., Cornish, B., Jamieson, M., Zawistowska, O., Monteith, K.M. & Vale, P.F. 2024. Mitochondrial background can explain variable costs of immune deployment. Journal of Evolutionary Biology, doi: 10.1101/2023.10.04.560830.