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Hepcidin’s Antimalarial Arsenal: Safeguarding the Host

*Emmanuel Ifeanyi Obeagu1, Esther U. Alum2,3 and Okechukwu P.C. Ugwu3

1Department of Medical Laboratory Science, Kampala International University, Uganda.

2Department of Biochemistry, Ebonyi State University, Abakaliki, Ebonyi State, Nigeria.

3Department of Publication and Extension, Kampala International University, Uganda.

*Corresponding Author: Emmanuel Ifeanyi Obeagu, Department of Medical Laboratory Science, Kampala International University, Uganda, emmanuelobeagu@yahoo.com, ORCID: 0000-0002-4538-0161

ABSTRACT

Malaria remains a significant global health threat, causing hundreds of thousands of deaths annually. Understanding the host’s protective mechanisms against this parasitic infection is crucial for developing effective prevention and treatment strategies. Hepcidin, a central regulator of iron homeostasis, has emerged as a key player in the host’s defense against malaria. This comprehensive review explores the multifaceted roles of hepcidin in safeguarding the host from malaria infection. We delve into the molecular mechanisms of hepcidin regulation and its impact on the intricate interplay between iron, the immune system, and Plasmodium species. Additionally, we discuss the potential therapeutic implications of targeting hepcidin to enhance antimalarial responses. By shedding light on hepcidin’s antimalarial arsenal, this review aims to contribute to the development of innovative strategies for combating malaria.

Keywords: Hepcidin, antimalaria, malaria and host

INTRODUCTION

Malaria, a devastating parasitic disease caused by Plasmodium species, continues to pose a significant threat to global public health, particularly in regions with limited resources and inadequate healthcare infrastructure [1-4]. With hundreds of thousands of deaths annually, malaria demands innovative approaches to both prevention and treatment. One such approach lies in understanding the host’s innate defense mechanisms against this relentless intruder [5-9]. Hepcidin, a peptide hormone primarily known for its role in regulating systemic iron homeostasis, has recently emerged as a key sentinel in the host’s arsenal against malaria. Its involvement in iron regulation has long been recognized, but its multifaceted roles in the context of malaria defense are a subject of growing interest in the field of infectious diseases [10-16]. Hepcidin’s significance stems from its ability to modulate iron availability, a crucial element in the pathogen-host dynamic [10]. Plasmodium parasites require iron for their survival and replication, making the host’s ability to control iron levels a pivotal factor in the fight against malaria. In this review, we delve into the intricacies of hepcidin’s antimalarial arsenal, unraveling the molecular mechanisms underpinning its protective functions [17-22]. This paper hope to contribute to the growing body of knowledge surrounding the interplay between hepcidin and malaria, ultimately offering new insights and strategies to combat this relentless and deadly disease. Hepcidin’s antimalarial arsenal represents a promising avenue for research and development in the ongoing battle against malaria, and its exploration may hold the key to more effective prevention and treatment strategies [23-28].

Hepcidin’s Regulation and Mechanisms

Hepcidin, a small peptide hormone, is the master regulator of iron homeostasis in the human body. Its pivotal role in maintaining the balance of iron within the bloodstream makes it a crucial player in the host’s defense against various pathogens, including Plasmodium parasites responsible for malaria.

Molecular Pathways Influencing Hepcidin Expression:

Hepcidin Gene Regulation

Hepcidin expression is primarily regulated at the transcriptional level by various factors. Central to this regulation is the bone morphogenetic protein (BMP)-SMAD signaling pathway, which is activated by iron levels in the body. When iron is in excess, BMP6 binds to its receptor on hepatocytes, leading to phosphorylation of SMAD proteins and subsequent hepcidin gene transcription. Conversely, in conditions of iron deficiency, hepcidin production is suppressed, allowing for increased iron absorption and release [29].

Inflammatory Mediators

Inflammation, driven by cytokines such as interleukin-6 (IL-6), can also stimulate hepcidin expression through the JAK-STAT signaling pathway. This mechanism is particularly relevant in the context of infections, including malaria, as the body’s response to the pathogen can lead to an inflammatory state that affects iron regulation [30].

Erythropoiesis

Erythropoietic signals, such as erythropoietin (EPO), can influence hepcidin expression indirectly by modulating the production of red blood cells and, consequently, iron demand in the body [31].

Interactions between Hepcidin, Ferroportin, and Iron Metabolism

Ferroportin Regulation

Hepcidin exerts its antimalarial effects through the regulation of ferroportin, the only known cellular iron exporter. Hepcidin binding to ferroportin leads to its internalization and degradation, effectively reducing the export of iron from macrophages, hepatocytes, and enterocytes into the bloodstream. This action results in decreased serum iron levels, which can inhibit the growth and survival of Plasmodium parasites that depend on host iron stores [32-37].

Systemic and Local Iron Control

Hepcidin’s influence on ferroportin affects iron distribution within the body. In the context of malaria, this control is essential for limiting iron availability to the parasites, depriving them of an essential nutrient. Moreover, local iron control in macrophages is critical for preventing Plasmodium from accessing iron sources within these cells, where they often reside [38].

Hepcidin’s Role in Modulating Systemic and Local Iron Availability:

Systemic Iron Homeostasis

Hepcidin’s responsiveness to iron levels ensures that the body can maintain systemic iron homeostasis. In conditions of iron overload, hepcidin prevents excess iron from entering the bloodstream, while in iron deficiency, hepcidin levels decrease to allow for increased iron absorption [39].

Local Iron Regulation

Hepcidin also plays a vital role in the regulation of iron within tissues. In the context of malaria, local control of iron within macrophages is particularly important, as these cells are often involved in the host’s defense against Plasmodium [40]. Understanding the molecular pathways and mechanisms that govern hepcidin regulation and function is essential for deciphering its antimalarial roles. By modulating systemic and local iron availability, hepcidin plays a key part in the host’s defense against Plasmodium parasites, offering a potential avenue for therapeutic intervention in the fight against malaria. In the subsequent sections of this review, we will delve into hepcidin’s influence on the immune response and its intricate interactions with Plasmodium species.Top of FormBottom of Form

Hepcidin’s Impact on Immune Response

Hepcidin, primarily known for its role in iron homeostasis, also exerts a significant influence on the host’s immune response. In the context of malaria and other infectious diseases, hepcidin’s impact on the immune system plays a crucial role in the body’s defense mechanisms. This section explores the multifaceted relationship between hepcidin and the immune response, shedding light on its role in the defense against malaria [41].

 

Innate Immune Response

Neutrophils and Macrophages

Hepcidin has been shown to influence the function of neutrophils and macrophages, two critical components of the innate immune system. Elevated hepcidin levels can impair the antimicrobial activity of these cells by restricting iron availability, potentially affecting their ability to combat Plasmodium parasites [42].

Inflammation and Cytokines

Inflammatory signals and cytokines that induce hepcidin expression, such as interleukin-6 (IL-6), are central to the innate immune response. However, excessive hepcidin production during inflammation may lead to anemia of inflammation, a condition that negatively impacts the host’s ability to mount an effective immune response against malaria [43].

Adaptive Immune Response

T Lymphocytes

T lymphocytes, including CD4+ and CD8+ T cells, are essential components of the adaptive immune response. Iron restriction mediated by hepcidin can affect T cell proliferation and function. Proper T cell responses are crucial for the development of protective immunity against Plasmodium parasites [44].

Antibody Production

Hepcidin’s regulation of iron levels can influence the production of antibodies, which are central to adaptive immunity. Antibodies play a critical role in the host’s defense against malaria by targeting Plasmodium antigens and preventing parasite invasion of host cells [10].

Inflammatory Responses

Hepcidin and Inflammation

Hepcidin production is often induced by inflammation, which is a common response to infections, including malaria. While hepcidin’s role in limiting iron availability can help restrict pathogen growth, excessive or chronic inflammation may lead to detrimental effects on the host’s immune response and overall health [45].

Iron withholding as a Defense Mechanism

In response to infection, the host can utilize hepcidin as a defense mechanism by reducing serum iron levels. This iron withholding strategy is part of the innate immune response to limit iron availability to invading pathogens, including Plasmodium [46].

Anemia of Inflammation

Anemia and Immune Response

Anemia, often associated with chronic inflammation and high hepcidin levels, can compromise the host’s ability to mount an effective immune response against malaria. The reduced oxygen-carrying capacity of blood due to anemia may impair immune cell function and overall resistance to the disease [47]. Understanding the intricate interplay between hepcidin and the immune response is essential in the context of malaria infection. While hepcidin’s ability to restrict iron availability can be advantageous in limiting pathogen growth, it also poses challenges, particularly in terms of maintaining a robust and effective immune response. The balance between hepcidin’s iron-regulatory functions and its impact on immunity is a critical aspect of the host’s defense against malaria, and it presents opportunities for further research and potential therapeutic interventions. In the subsequent sections of this review, we will explore the complex interactions between hepcidin and Plasmodium species, as well as the potential therapeutic implications of targeting hepcidin in the fight against malaria.

The Interplay between Hepcidin and Plasmodium Species

The intricate relationship between hepcidin, the master regulator of iron homeostasis, and Plasmodium species, the causative agents of malaria, is a crucial aspect of the host-pathogen interaction. Understanding the dynamics of this interplay is essential for unraveling the mechanisms underlying the host’s defense against malaria. This section delves into the multifaceted interactions between hepcidin and Plasmodium, shedding light on how these interactions impact the pathogenesis of malaria and the survival strategies employed by the parasites [48].

Malaria Parasites and Iron Acquisition Strategies

Plasmodium’s Iron Dependence

Plasmodium species rely on host iron stores for various physiological processes, including erythrocyte invasion, growth, and replication. The parasites have evolved sophisticated mechanisms to acquire and utilize host iron, making the host’s regulation of iron levels a critical determinant in the outcome of malaria infection [49].

Heme Detoxification

During the intraerythrocytic phase, Plasmodium parasites digest host hemoglobin to obtain heme, an essential source of iron. However, excess heme can be toxic to the parasites, prompting them to employ detoxification mechanisms. Disrupting these detoxification pathways through iron restriction can impede parasite growth and survival [50].

Host Iron Restriction and its Effects on Plasmodium Survival

Hepcidin-Mediated Iron Sequestration

Hepcidin’s role in restricting iron availability to the parasites can limit their access to the essential nutrient, thereby compromising their ability to thrive within the host. By downregulating ferroportin, hepcidin inhibits iron export from macrophages and other iron-storing cells, creating a hostile environment for Plasmodium.

Effect on Intraerythrocytic Parasites

The availability of iron within the erythrocytes is critical for the survival and growth of intraerythrocytic Plasmodium parasites. Hepcidin-mediated iron sequestration can potentially limit the availability of this crucial nutrient, leading to impaired parasite development and reduced pathogenicity.

The Evolutionary Arms Race between Hepcidin and Plasmodium

Parasite Adaptation Strategies

Plasmodium has evolved various mechanisms to counteract host defenses, including those involving iron restriction. These adaptation strategies enable the parasites to circumvent the host’s attempts to limit iron availability, ensuring their survival and propagation within the host’s bloodstream [51].

Host Defense Mechanisms

Hosts, in turn, have developed defense mechanisms, such as the upregulation of hepcidin in response to infection, to restrict iron availability and limit the growth of Plasmodium. This ongoing evolutionary arms race highlights the critical role of hepcidin in the host’s adaptive responses to malaria infection [52].

Understanding the dynamic interplay between hepcidin and Plasmodium species provides valuable insights into the host’s defense mechanisms and the strategies employed by the parasites to evade these defenses. By deciphering these complex interactions, researchers can identify potential targets for therapeutic interventions aimed at disrupting the parasites’ access to essential nutrients, thus offering new avenues for the development of effective antimalarial strategies. In the subsequent sections of this review, we will explore the therapeutic potential of targeting hepcidin in the context of malaria treatment and discuss the challenges and implications of such interventions.

Hepcidin and Antimalarial Defense Strategies

The multifaceted roles of hepcidin in regulating iron homeostasis and its interactions with Plasmodium species provide a foundation for developing antimalarial defense strategies. By targeting hepcidin and its regulatory mechanisms, researchers aim to enhance the host’s ability to combat malaria [53].

Targeting Hepcidin Expression

Inducing Hepcidin in Response to Infection

One strategy is to develop therapeutics or vaccines that can induce the host to increase hepcidin expression in response to Plasmodium infection. This would lead to a temporary reduction in serum iron levels, limiting iron availability to the parasites and potentially hindering their growth [54].

Therapeutic Use of Hepcidin Mimetics

Hepcidin mimetics, synthetic molecules that mimic the actions of endogenous hepcidin, can be explored as potential antimalarial agents. These mimetics could be administered to directly target ferroportin and limit iron export, effectively starving the parasites of this vital nutrient [55].

Iron Chelation Therapies

Iron Chelators

Iron chelation therapies, which involve the administration of iron-binding molecules, can help sequester iron within the host, making it less accessible to Plasmodium parasites. By limiting the parasites’ access to iron, these therapies can inhibit their growth and replication [56-60].

Combination Therapies

Combining iron chelation therapies with conventional antimalarial drugs may offer a multi-pronged approach to treating malaria. Such combinations could target both the parasites directly and their iron acquisition strategies, potentially improving treatment outcomes [61-63].

Immune Enhancement

Boosting Immune Responses

Strategies aimed at enhancing the host’s immune responses, particularly those affected by hepcidin-mediated iron regulation, can be explored. This includes interventions to improve the function of immune cells, such as T cells and macrophages, by mitigating the impact of hepcidin-induced iron restriction [63-67].

Vaccine Development

Vaccines that target Plasmodium antigens and enhance the host’s immune response can be used in combination with hepcidin-modulating therapies. By bolstering the host’s immunity, these vaccines may lead to improved antimalarial defense [59-63].

Diagnostic Tools

Hepcidin Biomarkers

Developing diagnostic tools to measure hepcidin levels in malaria-infected individuals can aid in identifying those at higher risk of severe disease. This information can guide personalized treatment strategies and help in early intervention to prevent complications [64-67].

Combating Resistance

Monitoring Resistance

As with any therapeutic approach, monitoring the development of resistance to hepcidin-targeted strategies is essential. Continuous research is needed to stay ahead of evolving Plasmodium resistance mechanisms and adapt antimalarial defense strategies accordingly [61]. Developing antimalarial defense strategies based on hepcidin modulation presents a promising avenue for malaria research. By targeting the host’s iron regulation mechanisms and the parasites’ dependence on iron, researchers aim to disrupt Plasmodium’s survival strategies and enhance the host’s natural defenses. These strategies, when developed and implemented effectively, have the potential to contribute to more robust and sustainable antimalarial approaches, ultimately reducing the burden of this devastating disease. However, it’s important to acknowledge the complexity of the host-pathogen interactions and the need for ongoing research to refine these strategies and address potential challenges and limitations.

CONCLUSION

The intricate roles of hepcidin in iron regulation and its multifaceted interactions with Plasmodium species have provided us with a deeper understanding of the host’s defense mechanisms against malaria. Hepcidin, traditionally regarded as the guardian of iron homeostasis, has emerged as a central player in the host’s antimalarial arsenal, safeguarding the host from infection by modulating iron availability and influencing the immune response.The interplay between hepcidin and Plasmodium species has demonstrated the ongoing evolutionary arms race between the host’s defenses and the parasite’s adaptations. Plasmodium has developed strategies to counteract hepcidin-mediated iron restriction, while the host continues to evolve its defense mechanisms to limit parasite access to iron.

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CITE AS: Emmanuel Ifeanyi Obeagu, Esther U. Alum and Okechukwu P.C. Ugwu (2023). Hepcidin’s Antimalarial Arsenal: Safeguarding the Host. NEWPORT INTERNATIONAL JOURNAL OF PUBLIC HEALTH AND PHARMACY 4(2):1-8. https://doi.org/10.59298/NIJPP/2023/10.1.1100

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