We need to be careful with the way we draw lines around biological systems. For example, survival during infection is affected by most physiologies in the body and thus it seems dangerous to gather one group of proteins that are responsible for killing microbes and say “these define immunology.” It matters little if we can explain “the immune system” but don't understand all that helps us survive infections. Drosophila
are a useful innate immunity model, but are also useful for studying microbial pathogenesis to find these “non-immune” factors. Metabolism is an example of such a system that influences immunity and, in Drosophila
, the only explanations we have for how microbes cause disease involve changes in energy stores or gut function 
. Though we don't have a broad understanding of what defines a “sick” metabolic state is during an infection several experiments in Drosophila focus on select groups of metabolites.
Research in Drosophila melanogaster
has repeatedly ascribed metabolism a role in immunity. Mycobacterium marinum
is a model pathogen that causes “consumption” in flies; infected flies lose all of their energy stores and waste to death. Reduction of FoxO, a negative regulatory transcription factor in the insulin signaling pathway, slows the infection induced wasting and increases the mean time to death 
. FoxO is also important in modulating the transcript levels of some immune effectors, anti-microbial peptides (AMPs). In the absence of an infection, starvation causes a FoxO-dependent upregulation of AMPs, effective even in the absence of Toll and Imd, the most notable regulators of AMP transcription 
. Additionally, FoxO binds directly to the promoter of Drosomycin, suggesting that these are direct effects of the protein. Taken together, these data support an intimate connection between insulin and immune signaling.
The relationship between metabolism and immunity is complex and the results depend upon the pathogen tested and measured immune output. Ayres and colleagues found that Listeria monocytogenes
and Salmonella typhimurium
cause infection-induced anorexia. In return, diet restriction alters a fly's tolerance and resistance to infection in a pathogen specific manner, making it worse at resisting L. monocytogenes
but better able to tolerate S. typhimurium
larvae fed Pseudomonas entomophila
have a melanized proventriculus and consume less food, which is potentially one cause of death from infection 
. Pathology also may occur because P. entomophila
causes gut damage using a pore-forming protein, monalysin 
Work in other insects supports the link between diet composition and immunity; in caterpillars of the African spotted leaf worm (Spodoptera littoralis
), Cotter and colleagues showed that the protein and carbohydrate content of food impacted the animals' immune responses in a pathway dependent manner and that there were potential trade-offs and no “perfect” immune diet 
. Adamo and colleagues showed that infected crickets (Gryllus texensis
) were less resistant to infection when fed high fat diets and would self-select lower fat diets when infected and given a choice 
. These studies not only show that a beneficial diet is infection dependent but that animals possess the ability to distinguish and choose more beneficial diets when infected.
Drosophila C Virus infection of the Drosophila
S2 cell line revealed a specific role for a single metabolic pathway: fatty acid biosynthesis 
. RNAi knockdown of components of the synthetic pathway inhibited viral replication. More recently this has been extended into mammalian systems showing that regulation of fatty acid biosynthesis by AMPK is important for a number of viruses 
. This does not appear to be solely a viral pathogenesis phenomenon as branched chain fatty acids promote intracellular growth of Listeria monocytogenes
in a mammalian cell line 
. The ability to obtain energy is important to both host and bacterium and changes in metabolism and nutrition likely impacts both. While each of these papers highlights a narrow aspect of the metabolism-immunity relationship, a more global approach to metabolite changes has the benefit of revealing system-wide changes and unanticipated roles for metabolites.
Here, we take a broad look at the changes in metabolism seen during L. monocytogenes
infection of Drosophila
. We chose L. monocytogenes
as a pathogen because it causes infection-induced anorexia and a previously published microarray analysis from the lab showed infection-induced transcriptional changes in a number of metabolic pathways 
. By combining both a metabolic focused analysis of our microarray to look at metabolism transcripts and broad spectrum chemistry approach to look at the metabolites themselves, a picture emerges of a shifting energy landscape in infected fruit flies.
L. monocytogenes infection reduces metabolite concentrations in the two primary energy generation pathways: beta-oxidation and glycolysis. The messages encoding enzymes in these pathways are also down regulated. As the infection proceeds, triglyceride and glycogen stores fall. In addition, two shifts in metabolites were related to reactive oxygen species (ROS) generation. First, there was enzymatically driven decrease in the anti-oxidant, uric acid, which has a complicated effect on immunity. Second, there was a decrease in tyrosine, an important precursor for L-3,4-dihydroxyphenylalanine (L-DOPA), the substrate for phenol oxidase, which generates microbe killing ROS and helps resolve infections.