How does the body utilize stored iron in response to viral infections like dengue?

Iron Utilization During Viral Infections

During viral infections, the body activates "nutritional immunity" by sequestering iron away from pathogens to limit their growth and replication, as iron is essential for viral replication and pathogen virulence.

Iron Homeostasis and Infection Response

Iron plays a critical role in both host defense and pathogen survival during infections:

Host Defense Mechanisms

• Hepcidin-Ferroportin Axis: During infections, the body increases hepcidin production, which blocks ferroportin (the iron exporter), leading to iron sequestration within macrophages and reduced circulating iron 1
• Transferrin Saturation: Normal transferrin is less than 50% saturated with iron, preventing free iron availability for microbial growth 1
• Acute Phase Response: Infection triggers ferritin production (an acute phase reactant) to sequester iron away from pathogens 1

Impact on Viral Infections

• Dengue Virus:

  • Lower serum iron levels are associated with increased dengue virus acquisition by mosquitoes 2
  • Iron supplementation in a mouse-mosquito model reduced dengue virus prevalence and viral load 2
  • Conversely, iron deficiency in hosts facilitated higher dengue virus acquisition by mosquitoes 2

• West Nile Virus:

  • Reducing intracellular iron levels in mosquito cells (using iron chelators) reduced viral titers 3
  • Mosquitoes respond to viral infection by inducing ferritin expression to sequester iron 3

Clinical Implications

Risks of Iron Administration During Infection

• Increased Infection Risk: IV iron administration is associated with a 16% increased risk of infection compared to oral iron or no iron (RR, 1.16; 95% CI, 1.03-1.29) 1, 4
• Pathogen Growth: Iron is required for growth by almost all human pathogens, providing a biological basis for increased infection risk with iron administration 4
• Specific Risk in IBD: Patients with inflammatory bowel disease show a particularly strong increased risk of infection with IV iron (RR, 1.73; 95% CI, 1.11-2.71) 4

Clinical Recommendations

• Delay Iron Supplementation: Complete antibiotic treatment and resolve the infection before administering iron supplementation 4
• Avoid IV Iron During Active Infection: Multiple guidelines (NCCN, American College of Hematology, KDIGO) recommend avoiding IV iron during active infections 4
• Consider Oral Iron: If iron supplementation is necessary during infection, oral iron may be preferable to IV iron 4

Iron's Role in Immune Function

Iron has dual roles in immunity:

• Innate Immunity:

  • Essential for antimicrobial oxidative burst inside neutrophils 1
  • Required for binding activity of proinflammatory transcription factors 1
  • Necessary for polarization and differentiation of macrophages during infection 1

• Adaptive Immunity:

  • Iron deficiency is associated with reduced proportion of mature T cells 1
  • Impaired T cell activation and proliferation occurs with iron deficiency 1
  • Lymphocytes express transferrin receptor 1 (TfR1) to import iron for proliferation 1

Balancing Iron Needs

The body must balance iron availability between:

1. Erythropoietic needs (preventing anemia)
2. Iron-withholding strategies to limit pathogen growth
3. Immune cell function requirements

During severe infection, iron withholding typically takes precedence until the infection is resolved, even if this temporarily worsens anemia 1, 4.

Conclusion

The body's iron regulation during viral infections represents a critical host defense mechanism. By sequestering iron through increased hepcidin and ferritin production, the host limits iron availability to pathogens while maintaining essential immune functions. Clinical practice should respect this natural defense by avoiding iron supplementation during active infections.