Sex differences in immune tissue function and infection outcomes in Drosophila melanogaster

Abstract

Sex differences in immunity exist across the animal kingdom. These dimorphisms are either chromosomally driven, gonadal hormone derived, or a combination of both. In humans, men are more susceptible to many infections, while women are more prone to develop autoimmune disorders. Interestingly, sex differences in immune responses and outcome to infection are also seen in insects, which lack sex hormones. Drosophila melanogaster is an excellent model organism for the study of innate immunity, renowned for its well established genetic tractability. The tripartite immune repertoire of D. melanogaster is composed of fat bodies (liver analogue regulating humoral immune responses), hemocytes (macrophages) and epithelial barriers such as the gut and cuticle, all of which employ strongly conserved innate defence mechanisms.

Within this thesis I examined how cellular and humoral immunity are differently regulated between males and females. Firstly, I present a published review of sex differences in Drosophila melanogaster immunity, which outlines the potential factors influencing dimorphisms, and highlights the lack of research in the field.

In Chapter 3, I tested how different immune components respond to two different bacteria, P. rettgeri and S. aureus, and how these responses change with selective pressure on cellular immunity. Using D. melanogaster lines that were selected for survival to wasp parasitism, and had a subsequent change in hemocyte composition, I investigated how selection lines survived adult infection with S. aureus, a pathogen primarily controlled by cellular immunity, and P. rettgeri, a pathogen primarily controlled by humoral immunity. I also asked how this strong selection pressure balanced with sex-specific pressures that drive immune sexual dimorphisms.

I then characterised the cellular response to S. aureus in D. melanogaster (Chapter 4), and how the response differs between males and females. The gram-positive bacterium, Staphylococcus aureus, is primarily controlled through phagocytosis. I showed that females are less susceptible to S. aureus, and link this to dimorphisms in hemocyte physiology and transcriptional responses to infection.

In Chapter 5, I investigated how transcriptional responses change during acute and chronic P. rettgeri infections. Here, I showed that females maintain immune activation for a longer period of time than males. I also show that the JAK-STAT pathway contributes to dimorphic susceptibility to P. rettgeri.

Lastly, In Chapter 6, I presented a resource that I developed to allow for the investigation of genetic and non-genetic variation in over 100 traits observed in D. melanogaster. Using this tool, I investigated the genetic influences on host-pathogen interactions by focusing on genetic heritability of pathogen response traits, correlations between traits, and using a genome wide association study to identify mutations that are frequently affecting pathogen response traits.

Throughout this thesis I identify cellular and humoral immune pathways that are differentially regulated between males and females, and are potentially contributing to dimorphic survival to bacterial pathogens. Overall, I found that females exhibit higher levels of constitutive immunity than males, and immune induction is more prolonged in females than males.