Metabolism is the battleground.
Metabolic capabilities determine which pathogens can infect specific hosts. This isn't random - it's a sophisticated contest where both sides deploy metabolic strategies to survive.
Your body starves invaders of nutrients.
Nutritional immunity - host sequestration of essential nutrients - shapes which pathogens can survive. Iron limitation creates severe acquisition pressure: bacteria need 0.05-2.0 × 10&sup-6; M, but bioavailable concentration is only 1.4 × 10&sup-9; M.
Distinct siderophores evolved by pathogens
Chelated by calprotectin
Creates copper toxicity for pathogens
Pathogen Countermeasures
- Siderophores: Iron-scavenging molecules with specific host compatibility
- Metallophores: Specialized systems like staphylopine for multiple metals
- Metal-independent enzymes: Bypass nutritional immunity entirely
Four distinct metabolic strategies.
Legionella: Engineering the Niche
~300 effectorsActively constructs metabolic niches using the largest known bacterial effector arsenal. Auxotrophic for 7 amino acids, yet this vulnerability becomes a feature - synchronizing with host metabolic rhythms.
Rickettsia: Extreme Parasitism
51 host metabolitesComplete loss of glycolysis, pentose phosphate pathway, and most amino acid synthesis. ATP/ADP translocases enable direct energy parasitism - perhaps the most intimate metabolic coupling known.
Pseudomonas: Metabolic Versatility
190+ carbon sourcesFive terminal oxidases plus complete denitrification. In CF lungs, shifts to anaerobic metabolism with phenazine production that maintains NAD+/NADH balance while generating toxic ROS.
Candida: Morphological Plasticity
Niche-specific adaptationCrabtree-negative - maintains simultaneous glycolysis and respiration even in high glucose. Creates "Goliath cells" under zinc restriction. Glyoxylate cycle essential during macrophage phagocytosis.
Your immune cells are metabolic weapons.
Itaconate
Produced by activated macrophages at millimolar concentrations. Inhibits pathogen succinate dehydrogenase while modulating host inflammation. Delivered to pathogen-containing phagosomes via Rab32.
Warburg Effect
Aerobic glycolysis despite oxygen availability. Rapid ATP supports effector functions while depleting local glucose for pathogens. But many pathogens exploit this shift.
Succinate & Lactate
Succinate acts as danger signal through GPR91, stabilizing HIF-1α. Lactate creates immunosuppressive microenvironments through histone lactylation.
The "Goldilocks Strategy"
Conditions that are "just wrong" for pathogens - too little nutrients to thrive, too many toxic metabolites to survive, but optimal for host tissue preservation.
Metabolic constraints prevent zoonotic spillover.
Amino Acid Auxotrophies
78.4% of bacteria retain complete biosynthetic capability, while auxotrophies concentrate in host-associated strains. Creates species-specific dependencies.
Sialic Acid Recognition
Humans uniquely lack Neu5Gc. Pathogens must recognize specific glycan patterns - influenza requires precise hemagglutinin-sialic acid linkage matching.
Microbiota as Barrier
The microbiota creates additional metabolic barriers through competitive exclusion. However, inflammation can paradoxically benefit certain pathogens - Salmonella exploits inflammation-associated tetrathionate as an alternative electron acceptor.
Targeting the metabolic interface.
Host-Directed Therapies
Metformin enhances immunity against tuberculosis through AMPK activation. Statins inhibit viral infections by disrupting lipid metabolism. Itaconate derivatives show broad-spectrum antimicrobial activity.
Siderophore-Antibiotic Conjugates
"Trojan horses" using bacterial iron uptake machinery to deliver antimicrobials. Effective against multi-drug resistant strains because siderophore systems are essential for virulence.
CRISPR-Identified Targets
Sphingolipid biosynthesis genes essential for EHEC infection. HMGB1 and SWI/SNF complexes support pan-coronavirus replication. Novel vulnerabilities without human equivalents.
Successful pathogens are metabolic engineers.
Rather than simple nutrient competition, we observe complex metabolic dialogues where information is encoded in metabolite concentrations and enzymatic activities signal cellular states. The future of infection control may lie in subtle metabolic interventions that turn dependencies into therapeutic opportunities.