Metabolic physiology and pathophysiology.
Immune responses alter metabolic function in all animals. The metabolic changes driven by infection can be productive, promoting immune activity or enhancing the host’s ability to tolerate infection. However, in infections with pathogens, they are often counterproductive, promoting pathology or death. It is often unclear which induced metabolic changes are important in fighting infection, and which are counterproductive consequences of inappropriate immune activation. One of our primary goals is to understand these effects. How do immune-induced metabolic changes help fuel immune responses? Why are these changes non-productive or counterproductive in infections with pathogens? How does immune detection impinge on metabolic regulation?
Visualisation of metabolic changes 3 hours after infection with E. coli, based on LCMS metabolomics data of whole flies. Pathways containing metabolites are highlighted in red (upregulated) or blue (downregulated). Made using iPath 3: Darzi Y et al. (2018) Nucleic Acids Res doi: 10.1093/nar/gky299
The host as environment.
The interaction between host and microbe is often described in metaphorical terms as a battle, but this metaphor is misleading. In fact, the host is the environment in which pathogenic microbes live; the immune response is one of several challenges that must be overcome or endured for microbes to survive. Different hosts represent different kinds of challenges, but some microbes maintain the ability to survive within many different hosts, while others evolve highly specific interactions with specific host species. We want to understand the nature of this interaction between microbe and environment. What are the specific challenges posed by survival in Drosophila? How do bacteria meet these challenges? What are the consequences for their interaction with other hosts?
Intravital image of macrophages in a w[1118]; HmlΔ-Gal4, UAS-2xeGFP male fly injected with M. abscessus (Td-Tomato) smooth morphotype at 48 hours post infection. Green fluorescence shows two individual haemocytes containing areas of red M. abscessus fluorescence. Scale bar represents 10 µm.
Immune defense, treatment, and metabolism.
During infection, availability of nutrients and action of the host immune response are critical factors that influence bacterial physiology. Changes in nutrient availability can alter bacterial virulence, and host immune responses can have the same targets as antibiotics. Thus, the direct and indirect actions of host immunity have significant effects on bacterial pathogenicity and antibiotic effectiveness. We want to understand how this complex set of interactions dictates infection biology and outcomes. How does the host environment affect antimicrobial action? How do treatment and immunity affect microbial pathogenicity? How do immune effectors and exogenous antimicrobials interact?
Four images generated by Stable Diffusion 2.1 with the prompt “infected Drosophila taking antibiotics”. The computers are not yet ready to replace us.