Building a robust immune response [electronic resource]

How does your immune system prepare for all of the potential pathogens it might face over the course of a lifetime? Trade-offs occur when you invest in responses that are beneficial when fighting one pathogen but are actively detrimental for fighting another. Due to the diversity of pathogens, immunity is potentially rife with this type of antagonism; to appreciate the full scope of potential trade-offs we must think about all of the possible immune responses a host can bring to bear on a pathogen. I propose that an "immune response" is any response to infection that influences the outcome of that infection. This includes processes that affect either resistance, the ability to clear pathogen, or tolerance, the ability to cope with pathology induced by infection. This broad definition of immunology will bring research of classically "non-immune" physiologies - metabolism, circadian rhythm and mating -- into the immune arena. Throughout this thesis I will explore, using Drosophila melanogaster as a model, a number of different trade-offs in immunity from the antagonism inherent in a resistance response to the benefits and consequences of energy expenditure during infection. First, I demonstrate that there is an inherent trade-off due to investment in phagocytosis when flies encounter two different infections: Listeria monocytogenes and Streptococcus pneumoniae. L. monocytogenes is a facultative intracellular pathogen that harnesses the additional phagocytosis, increasing entry into a desirable niche; S. pneumoniae is an extracellular pathogen that is better cleared by increased phagocytosis. I discovered the trade-off by comparing and contrasting the phenotypes caused by mutants in two Drosophila immunity genes: ets21c, a putative transcription factor, and wntD, a negative regulator of immunity. Further exploration of the immune phenotypes of the ets21c mutant revealed that these mutants have a range of phenotypes during infection, suggesting a complex picture. Ets21c affects both tolerance and resistance to infection, and the class of phenotype observed in ets21c mutants cannot be predicted solely by the intracellular versus extracellular nature of the infecting pathogen. Ets21c mutants also have a strikingly altered basal metabolic state, resembling sick wild-type flies, and have a muted change in transcript levels in response to infection. This thesis also deepens our understanding of developmental-immune pleitropy in the wntD pathway. Pleitropy itself causes trade-offs; for while pleitropy promotes efficiency in the genome, it also restricts the ability to evolve. WntD, a negative regulator of the toll pathway, impacts both immunity and dorsal-ventral development. Recently, work with the developmental phenotypes led to the discovery of components in the wntD signaling pathway. I show that these developmental mediators are also involved in immunity and impact survival during L. monocytogenes infection. L. monocytogenes infection causes infection induced anorexia in Drosophila and this thesis shows that infection with L. monocytogenes affects a number of metabolic pathways at both the transcript and metabolite level. This metabolic and transcriptome data generated a number of more specific and mechanistic hypotheses concerning additional potential trade-offs. First, energy stores, metabolic intermediates and transcripts for beta-oxidation and glycolysis decrease during infection. This reduction of available energy can both negatively impact the host when it runs out of energy for essential processes and positively impact the host by restricting the nutrients available to the pathogen. By infecting mutants with either initially low energy stores or an inability to access stores, we show that access to energy stores is important to the host during infection, although the flip-side of this trade-off remains untested. A second potential trade-off seen through our metabolomics are changes in the level of an anti-oxidant, uric acid. The flies enzymatically reduce levels of uric acid during L. monocytogenes infection. A reduction in an anti-oxidant should cause the reactive oxygen species to have additional potency. This would be helpful in combating the bacterial load, but potentially detrimental due to an increase of damage to the host itself. However, mutants in uricase, which fail to lower uric acid levels during infection, do not have such easily explainable phenotypes potentially due to compensation through other anti-oxidants. While not conclusive, these data suggest that the flies regulate their anti-oxidant levels during infection and that this complexly affects immunity. To address the dilemma of how to build a robust immune response, I contend that one must consider many different variables: diversity of pathogens, genetic efficiency, and the energetic cost. Years of evolution have honed the immune responses with many potential solutions. I found that Drosophila immune systems are likely constrained by a variety of tradeoffs -- antagonistic abilities of resistance responses, metabolic links with immunity, and developmental-immune pleitropy. We still need to better understand how these tradeoffs are regulated and their downstream implications. Understanding these antagonistic relationships will help us manipulate them to develop more effective treatment, as we can tailor medicine to the individual pathogen and the individual person's physiology.

Keywords: Microbiology and Immunology
Advisor: Schneider David (David Samuel)
Monack Denise M. advisor. Thesis advisor
Mudgett Mary Beth
Relman David A. advisor. Thesis advisor