Nutritional Immunity: The Host's Defense Strategy
When a pathogen invades the body, the immune response includes a strategy called "nutritional immunity". Recognizing that iron is vital for both host and microbial cells, the immune system strategically alters iron metabolism to create an iron-poor environment, aiming to starve pathogens.
This is primarily managed by the liver hormone hepcidin. During infection, inflammatory signals increase hepcidin production. Hepcidin binds to ferroportin, the protein that exports iron from cells, causing its degradation. This traps iron in cellular storage and blocks gut absorption, resulting in low blood iron levels during infection.
The Role of Hepcidin in Acute and Chronic Inflammation
Iron Regulation During Infection
Hepcidin, a key regulator of iron homeostasis, is significantly affected by inflammation. The table below contrasts the roles of iron-related proteins in normal states versus during infection.
| Feature | Normal Physiology | During Infection (Acute Phase) |
|---|---|---|
| Hepcidin Levels | Low to moderate, regulated by iron status | Dramatically increased due to inflammatory signals |
| Ferroportin Function | Active, exporting iron from cells into plasma | Degraded by hepcidin, trapping iron inside cells |
| Plasma Iron Levels | Stable, bound to transferrin | Decreased (hypoferremia) as iron is sequestered |
| Ferritin | Main storage protein, holding reserve iron | High intracellular levels, hoarding iron away from pathogens |
| Transferrin | Circulates in blood, transporting iron | Lower saturation levels as plasma iron decreases |
Pathogen Iron Acquisition: The Microbial Countermeasure
Pathogens have evolved ways to get iron despite the host's defenses. Bacteria use siderophores, proteins that bind iron tightly.
- Siderophore Production: Bacteria produce siderophores with high iron affinity.
- Iron Scavenging: Siderophores take iron from host proteins like transferrin.
- Receptor-Mediated Uptake: Bacteria use receptors to take in the iron-siderophore complex.
- Heme Utilization: Some pathogens get iron from host heme proteins.
Giving iron supplements during infection can provide pathogens with the iron they need to grow and become more virulent. Studies show iron supplements can increase infection frequency and severity.
Detrimental Effects on the Host Immune Response
Excess iron can also harm the host's immune system, making it harder to fight infection.
- Impaired Neutrophil Function: High iron levels can reduce the effectiveness of neutrophils, immune cells that kill microbes. It can decrease their killing activity and NET formation.
- T-Cell Dysfunction: Iron overload can negatively impact T-lymphocytes, important for adaptive immunity. Proper immune function requires a balanced amount of iron.
- Oxidative Stress: Excess free iron can cause oxidative stress by creating reactive oxygen species (ROS), which damage host cells and contribute to inflammation.
Managing Anemia During Active Infection
Treating anemia during infection is challenging. Anemia of chronic disease (ACD), common with infection, involves low blood iron but normal or high stored iron due to high hepcidin. Giving more iron is usually avoided as it won't be used effectively and may worsen the infection.
Treatment focuses on resolving the infection. As the infection clears, hepcidin drops, allowing iron release from stores for red blood cell production. Severe cases might need blood transfusions or erythropoietin. In less severe cases, or with true iron deficiency, supplementation can be considered after the acute phase.
Conclusion
Avoiding iron supplementation during active infection is based on the body's nutritional immunity defense. Increased hepcidin reduces blood iron, starving pathogens. Supplemental iron bypasses this, potentially boosting microbial growth and weakening the immune system by impairing immune cell function and increasing oxidative stress. Anemia during infection should be addressed by treating the infection first, and iron status re-evaluated post-infection. The NIH offers resources on iron and infection interaction.
