The Toll pathway underlies host sexual dimorphism in resistance to both Gram-negative and Gram-positive bacteria in mated Drosophila

Abstract

BackgroundHost sexual dimorphism is being increasingly recognized to generate strong differences in the outcome of infectious disease, but the mechanisms underlying immunological differences between males and females remain poorly characterized. Here, we used Drosophila melanogaster to assess and dissect sexual dimorphism in the innate response to systemic bacterial infection.ResultsWe demonstrated sexual dimorphism in susceptibility to infection by a broad spectrum of Gram-positive and Gram-negative bacteria. We found that both virgin and mated females are more susceptible than mated males to most, but not all, infections. We investigated in more detail the lower resistance of females to infection with Providencia rettgeri, a Gram-negative bacterium that naturally infects D. melanogaster. We found that females have a higher number of phagocytes than males and that ablation of hemocytes does not eliminate the dimorphism in resistance to P. rettgeri, so the observed dimorphism does not stem from differences in the cellular response. The Imd pathway is critical for the production of antimicrobial peptides in response to Gram-negative bacteria, but mutants for Imd signaling continued to exhibit dimorphism even though both sexes showed strongly reduced resistance. Instead, we found that the Toll pathway is responsible for the dimorphism in resistance. The Toll pathway is dimorphic in genome-wide constitutive gene expression and in induced response to infection. Toll signaling is dimorphic in both constitutive signaling and in induced activation in response to P. rettgeri infection. The dimorphism in pathway activation can be specifically attributed to Persephone-mediated immune stimulation, by which the Toll pathway is triggered in response to pathogen-derived virulence factors. We additionally found that, in absence of Toll signaling, males become more susceptible than females to the Gram-positive Enterococcus faecalis. This reversal in susceptibility between male and female Toll pathway mutants compared to wildtype hosts highlights the key role of the Toll pathway in D. melanogaster sexual dimorphism in resistance to infection.ConclusionAltogether, our data demonstrate that Toll pathway activity differs between male and female D. melanogaster in response to bacterial infection, thus identifying innate immune signaling as a determinant of sexual immune dimorphism.Electronic supplementary materialThe online version of this article (doi:10.1186/s12915-017-0466-3) contains supplementary material, which is available to authorized users.

Mitochondrial Dysfunction and Infection Generate Immunity–Fecundity Tradeoffs in Drosophila

“…In our study, infection reduced ( simw 501 ); OreR survival more strongly in females than in males. In general, male Drosophila survive infection better than do females ( Short and Lazzaro 2010 ; Vincent and Sharp 2014 ; Duneau et al. 2017b ), a pattern that we also observed.…”

“…The higher survival of males could result from sex-specific differences in immune expression due to Y-linked regulation ( Fedorka and Kutch 2015 ), differences in antimicrobial peptide production ( Jacobs et al. 2016 ; Duneau et al. 2017b ), or potentially from differential suppression of the immune system by juvenile hormone, which has been shown to underlie differences in immune function between mated and un-mated females ( Schwenke and Lazzaro 2017 ).…”

The Genetic Basis of Natural Variation in Drosophila melanogaster Immune Defense against Enterococcus faecalis

“…As such, it is likely that there is selection for resistance and/or tolerance in D. melanogaster. Indeed, Toll-pathway induced antimicrobial peptides are upregulated in response to E. faecalis infection and play a key role in controlling the infection [19][20][21]. Recently, a new group of immune peptides, the Bomanins, were shown to play an important role in controlling Gram-positive infections such as E. faecalis in D. melanogaster [15,22,23].…”

Transstadial immune activation in a mosquito: Adults that emerge from infected larvae have stronger antibacterial activity in their hemocoel yet increased susceptibility to malaria infection

“…Sex‐specific differences in immunity have been reported in other insects (Duneau et al, ; Jacobs et al, ; Mitaka, Kobayashi, & Matsuura, ). However, the present study is unique in that it examined immune parameters in both female and male mosquitoes, which differs from what has historically been an almost exclusive focus on the immune system of females.…”