The Metabolism of Infection
We hope to translate results from work probing the role of organelles and metabolism in the cellular response to an understanding of how human metabolism influences the progression of infectious disease.
Intracellular pathogens depend on their hosts for metabolites essential for growth, and therefore compete with host metabolic processes for a limited set of nutrients. Key players in this competition are the host organelles that store, breakdown, utilize, import, and export specific metabolites.
We have recently defined one example of organelle vs. microbe competition: during infection, the human parasite Toxoplasma gondii exploits host lipophagy to gain access to cellular fatty acids essential for its growth. To counter this, host mitochondria fuse during infection to enhance fatty acid uptake, limiting Toxoplasma access to a key host resource and thereby restricting its growth.
Pulsed fluorescent fatty acids (FAs) remain largely in lipid droplets in uninfected cells but increasingly accumulate in mitochondria (indicated by white arrowheads) at early stages of Toxoplasma infection (parasite vacuoles indicated by dashed lines).
This work shows that mitochondria, which are essentially domesticated parasites, actively and metabolically defend the cell during infection, and opens important questions about the role of host organelles and metabolism in executing the cellular response to infection. Using Toxoplasma gondii as a model intracellular pathogen we will ask:
How do organelles sense and respond to pathogens?
Host mitochondria (red) surrounding Toxoplasma (green)
We have defined a host metabolic mitochondrial response to Toxoplasma, but we know nothing about the signals that enable mitochondria to sense and metabolically respond to Toxoplasma. Furthermore, we suspect that other organelles are capable of sensing and responding to pathogens. For example, lipid droplets, peroxisomes, and endoplasmic reticulum traffic to and surround several intracellular pathogens. We seek to understand the pathways that orchestrate how these organelles respond to microbes, and define what role they play in the cellular response to infection.
How is metabolism weaponized against microbes?
Uninfected (left) and Toxoplasma-infected (right) adipocytes. Parasite vacuoles are pseudocolored red, scale bar 5um. N-nucleus, LD-lipid droplet.
If an intracellular pathogen’s access to nutrients can be limited by host metabolic processes, one logical prediction would be that host metabolism is actively rewired as part of the cellular response to infection. For example, to increase the efflux or limit the import of nutrients important for microbial growth. We will define the set of host metabolic pathways that impact the outcome of infection at the level of the cell, and organism, and dissect how the rewiring of these pathways modulates parasite growth.
What is the secret of Toxoplasma’s long-lived success?
Toxoplasma establishes a chronic, seemingly asymptomatic infection, in an estimated 2 billion + of the world’s population. The fact that this parasite is able to persist without overt inflammation or symptoms suggests that Toxoplasma engages its host in a mutualistic or commensalistic symbiosis. To this end, we are exploring synergies between Toxoplasma and its host and asking how such synergisms evolve in during various stresses.