What is the effect of hepcidin on listeria and vibrio infections?

Hepcidin's Effect on Listeria and Vibrio Infections

Hepcidin plays a critical protective role against Vibrio infections by restricting iron availability, while its effect on Listeria may be more complex with evidence suggesting that Listeria can evade hepcidin-mediated iron restriction mechanisms. 1, 2

Mechanism of Hepcidin in Iron Regulation and Host Defense

Hepcidin is a 25-amino acid peptide hormone primarily synthesized by hepatocytes that serves as the master regulator of systemic iron homeostasis. It functions through the following mechanisms:

• Hepcidin binds to ferroportin (the sole iron exporter) on enterocytes, macrophages, and hepatocytes, causing its internalization and degradation, thereby limiting iron release into circulation 1
• During infection and inflammation, hepcidin production increases, leading to decreased intestinal iron absorption and reduced iron release from macrophages 1, 3
• This restriction of iron availability in serum is a critical host defense mechanism that limits iron supply to iron-dependent pathogens 1, 4

Hepcidin's Effect on Vibrio Infections

Vibrio vulnificus is particularly sensitive to hepcidin-mediated iron restriction:

• Vibrio vulnificus is a gram-negative pathogen found in coastal waters that causes severe to life-threatening infections with >50% mortality in patients with fulminant sepsis 1
• Patients with hemochromatosis and other iron overload conditions are especially susceptible to Vibrio vulnificus infections due to high circulating iron levels 1
• In vitro and in vivo studies demonstrate that high iron levels trigger rapid Vibrio vulnificus growth, and plasma iron concentration directly influences bacterial replication and dissemination 1
• The hepcidin-mediated acute hypoferremia (reduction in serum iron) in response to Vibrio vulnificus is a crucial host defense mechanism against this siderophilic pathogen 1, 5
• Hepcidin deficiency, as seen in hemochromatosis, exposes patients to increased risk of severe Vibrio vulnificus infections due to higher levels of circulatory iron 1

Hepcidin's Effect on Listeria Infections

Listeria monocytogenes appears to have a more complex relationship with hepcidin:

• Unlike some other bacterial infections, Listeria monocytogenes infection does not induce hepcidin expression in mouse models 2
• Instead, Listeria infection causes iron redistribution through hepcidin-independent mechanisms, primarily through downregulation of hepatic ferroportin mRNA and protein levels 2
• This suggests that Listeria may have evolved mechanisms to evade or manipulate the hepcidin-mediated iron restriction response 2
• Despite the lack of hepcidin induction, Listeria infection still impacts iron metabolism by decreasing serum iron levels, reducing transferrin saturation, and increasing iron accumulation in the liver 2

Clinical Implications

The differential effects of hepcidin on these pathogens have important clinical implications:

• Patients with hemochromatosis or other conditions with hepcidin deficiency should be advised about their increased susceptibility to Vibrio vulnificus infections 1
• These patients should be particularly cautious about consuming raw or undercooked seafood that may be contaminated with Vibrio vulnificus 1
• For Listeria infections, the hepcidin-independent mechanisms suggest that therapeutic approaches targeting ferroportin directly might be more effective than those targeting hepcidin 2
• In patients with normal serum ferritin and transferrin saturation, the risk of severe Vibrio vulnificus infection is likely reduced due to intact hepcidin response 1

Therapeutic Potential

Emerging research suggests potential therapeutic applications:

• Hepcidin agonists have shown promise in preventing sepsis-associated mortality in mouse models of infection 5
• In mice with genetic iron overload (hepcidin knockout), post-infection treatment with just two doses of a hepcidin agonist completely prevented sepsis-associated mortality by abolishing non-transferrin-bound iron 5
• These findings suggest that hepcidin-based therapies could be effective early interventions in patients with infections and dysregulated iron metabolism 5, 3