Hemozoin

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Plasmodium falciparum hemozoin crystals under polarised light. Birefringent P.falciparum Pigment.jpg
Plasmodium falciparum hemozoin crystals under polarised light.
Plasmodium ovale microgametocyte in Giemsa-stained thin blood film, with annotated Schuffner's dots and hemozoin pigment. Microphotograph of Plasmodium ovale microgametocyte in Giemsa-stained thin blood film, with Schuffner's dots and hemozoin pigment.png
Plasmodium ovale microgametocyte in Giemsa-stained thin blood film, with annotated Schüffner's dots and hemozoin pigment.

Haemozoin is a disposal product formed from the digestion of blood by some blood-feeding parasites. These hematophagous organisms such as malaria parasites ( Plasmodium spp.), Rhodnius and Schistosoma digest haemoglobin and release high quantities of free heme, which is the non-protein component of haemoglobin. Heme is a prosthetic group consisting of an iron atom contained in the center of a heterocyclic porphyrin ring. Free heme is toxic to cells, so the parasites convert it into an insoluble crystalline form called hemozoin. In malaria parasites, hemozoin is often called malaria pigment.

Contents

Since the formation of hemozoin is essential to the survival of these parasites, it is an attractive target for developing drugs and is much-studied in Plasmodium as a way to find drugs to treat malaria (malaria's Achilles' heel). Several currently used antimalarial drugs, such as chloroquine and mefloquine, are thought to kill malaria parasites by inhibiting haemozoin biocrystallization.

Discovery

Black-brown pigment was observed by Johann Heinrich Meckel [1] in 1847, in the blood and spleen of a person suffering from insanity. [2] However, it was not until 1849 that the presence of this pigment was connected to infection with malaria. [3] Initially, it was thought that this pigment was produced by the body in response to infection, but Charles Louis Alphonse Laveran realized in 1880 that "malaria pigment" is, instead, produced by the parasites, as they multiplied within the red blood cell. [4] The link between pigment and malaria parasites was used by Ronald Ross to identify the stages in the Plasmodium life cycle that occur within the mosquito, since, although these forms of the parasite are different in appearance to the blood stages, they still contain traces of pigment.[ citation needed ]

Later, in 1891, T. Carbone and W.H. Brown (1911) published papers linking the hemoglobin degradation with pigment production, describing the malaria pigment as a form of hematin and disproving the widely held idea that it is related to melanin. Brown observed that all melanins were bleaching rapidly with potassium permanganate, while with this reagent malarial pigment manifests not the slightest sign of a true bleach reaction. [5] [6] The name "hemozoin" was proposed by Louis Westenra Sambon. [7] In the 1930s several authors identified hemozoin as a pure crystalline form of α-hematin and showed that the substance did not contain proteins within the crystals, [4] but no explanation for the solubility differences between malaria pigment and α-hematin crystals was given.[ citation needed ]

Formation

Human red blood cell infected by the malaria parasite Plasmodium falciparum, showing a residual body with brown hemozoin. P.falciparum schizont.jpg
Human red blood cell infected by the malaria parasite Plasmodium falciparum , showing a residual body with brown hemozoin.

During its intraerythrocytic asexual reproduction cycle Plasmodium falciparum consumes up to 80% of the host cell hemoglobin. [8] [9] The digestion of hemoglobin releases monomeric α-hematin (ferriprotoporphyrin IX). This compound is toxic, since it is a pro-oxidant and catalyzes the production of reactive oxygen species. Oxidative stress is believed to be generated during the conversion of heme (ferroprotoporphyrin) to hematin (ferriprotoporphyrin). Free hematin can also bind to and disrupt cell membranes, damaging cell structures and causing the lysis of the host erythrocyte. [10] The unique reactivity of this molecule has been demonstrated in several in vitro and in vivo experimental conditions. [11]

Transport vesicle delivering a heme detoxification protein (hdp) to a malaria food vacuole (fv) containing crystals of hemozoin (hz). Scale bar is 0.5 um. Hemozoin in food vacuole.jpg
Transport vesicle delivering a heme detoxification protein (hdp) to a malaria food vacuole (fv) containing crystals of hemozoin (hz). Scale bar is 0.5 µm.

The malaria parasite, therefore, detoxifies the hematin, which it does by biocrystallization—converting it into insoluble and chemically inert β-hematin crystals (called hemozoin). [13] [14] [15] In Plasmodium the food vacuole fills with hemozoin crystals, which are about 100–200 nanometres long and each contain about 80,000 heme molecules. [4] Detoxification through biocrystallization is distinct from the detoxification process in mammals, where an enzyme called heme oxygenase instead breaks excess heme into biliverdin, iron, and carbon monoxide. [16]

Several mechanisms have been proposed for the production of hemozoin in Plasmodium, and the area is highly controversial, with membrane lipids, [17] [18] histidine-rich proteins, [19] or even a combination of the two, [20] being proposed to catalyse the formation of hemozoin. Other authors have described a heme detoxification protein, which is claimed to be more potent than either lipids or histidine-rich proteins. [12] It is possible that many processes contribute to the formation of hemozoin. [21] The formation of hemozoin in other blood-feeding organisms is not as well-studied as in Plasmodium. [22] However, studies on Schistosoma mansoni have revealed that this parasitic worm produces large amounts of hemozoin during its growth in the human bloodstream. Although the shapes of the crystals are different from those produced by malaria parasites, [23] chemical analysis of the pigment showed that it is made of hemozoin. [24] [25] In a similar manner, the crystals formed in the gut of the kissing bug Rhodnius prolixus during digestion of the blood meal also have a unique shape, but are composed of hemozoin. [26] Hz formation in R. prolixus midgut occurs at physiologically relevant physico-chemical conditions and lipids play an important role in heme biocrystallization. Autocatalytic heme crystallization to Hz is revealed to be an inefficient process and this conversion is further reduced as the Hz concentration increases. [27]

Isolated P. falciparum hemozoin P.falciparum hemozoin.jpg
Isolated P. falciparum hemozoin

Several other mechanisms have been developed to protect a large variety of hematophagous organisms against the toxic effects of free heme. Mosquitoes digest their blood meals extracellularly and do not produce hemozoin. Heme is retained in the peritrophic matrix, a layer of protein and polysaccharides that covers the midgut and separates gut cells from the blood bolus. [28]

Although β-hematin can be produced in assays spontaneously at low pH, the development of a simple and reliable method to measure the production of hemozoin has been difficult. This is in part due to the continued uncertainty over what molecules are involved in producing hemozoin, and partly from the difficulty in measuring the difference between aggregated or precipitated heme, and genuine hemozoin. [29] Current assays are sensitive and accurate, but require multiple washing steps so are slow and not ideal for high-throughput screening. [29] However, some screens have been performed with these assays. [30]

Structure

Structure of hemozoin, showing hydrogen bonds between hematin units as dotted lines, and coordinate bonds between iron atoms and carboxylate side chains as red lines Hemozoin structure.png
Structure of hemozoin, showing hydrogen bonds between hematin units as dotted lines, and coordinate bonds between iron atoms and carboxylate side chains as red lines
Electron micrograph of crystals of hemozoin isolated from the malaria parasite Plasmodium falciparum. Magnified 68,490 times. Hemozoin is produced by template mediated crystallization ("biocrystallization"). Hemozoin crystals.jpg
Electron micrograph of crystals of hemozoin isolated from the malaria parasite Plasmodium falciparum . Magnified 68,490 times. Hemozoin is produced by template mediated crystallization ("biocrystallization").

β-Hematin crystals are made of dimers of hematin molecules that are, in turn, joined together by hydrogen bonds to form larger structures. In these dimers, an iron-oxygen coordinate bond links the central iron of one hematin to the oxygen of the carboxylate side-chain of the adjacent hematin. These reciprocal iron–oxygen bonds are highly unusual and have not been observed in any other porphyrin dimer. β-Hematin can be either a cyclic dimer or a linear polymer, [31] a polymeric form has never been found in hemozoin, disproving the widely held idea that hemozoin is produced by the enzyme heme-polymerase. [32]

Hemozoin crystals have a distinct triclinic structure and are weakly magnetic. The difference between diamagnetic low-spin oxyhemoglobin and paramagnetic hemozoin can be used for isolation. [33] [34] They also exhibit optical dichroism, meaning they absorb light more strongly along their length than across their width, enabling the automated detection of malaria. [35] Hemozoin is produced in a form that, under the action of an applied magnetic field, gives rise to an induced optical dichroism characteristic of the hemozoin concentration; and precise measurement of this induced dichroism (Magnetic circular dichroism) may be used to determine the level of malarial infection. [36]

Inhibitors

Drug heme interaction Drug-heme interaction.png
Drug heme interaction

Hemozoin formation is an excellent drug target, since it is essential to malaria parasite survival and absent from the human host. The drug target hematin is host-derived and largely outside the genetic control of the parasite, which makes the development of drug resistance more difficult. Many clinically used drugs are thought to act by inhibiting the formation of hemozoin in the food vacuole. [37] This prevents the detoxification of the heme released in this compartment, and kills the parasite. [38]

The best-understood examples of such hematin biocrystallization inhibitors are quinoline drugs such as chloroquine and mefloquine. These drugs bind to both free heme and hemozoin crystals, [39] and therefore block the addition of new heme units onto the growing crystals. The small, most rapidly growing face is the face to which inhibitors are believed to bind. [40] [41]

Role in pathophysiology

Hemozoin is released into the circulation during reinfection and phagocytosed in vivo and in vitro by host phagocytes and alters important functions in those cells. Most functional alterations were long-term postphagocytic effects, [42] [43] including erythropoiesis inhibition shown in vitro. [44] [45] [46] In contrast, a powerful, short-term stimulation of oxidative burst by human monocytes was also shown to occur during phagocytosis of nHZ. [47] Lipid peroxidation non-enzymatically catalysed by hemozoin iron was described in immune cells. [48] [49] Lipoperoxidation products, as hydroxyeicosatetraenoic acids (HETEs) and 4-hydroxynonenal (4-HNE), are functionally involved in immunomodulation. [43] [46] [49] [50] [51]

See also

Related Research Articles

Antimalarial medications or simply antimalarials are a type of antiparasitic chemical agent, often naturally derived, that can be used to treat or to prevent malaria, in the latter case, most often aiming at two susceptible target groups, young children and pregnant women. As of 2018, modern treatments, including for severe malaria, continued to depend on therapies deriving historically from quinine and artesunate, both parenteral (injectable) drugs, expanding from there into the many classes of available modern drugs. Incidence and distribution of the disease is expected to remain high, globally, for many years to come; moreover, known antimalarial drugs have repeatedly been observed to elicit resistance in the malaria parasite—including for combination therapies featuring artemisinin, a drug of last resort, where resistance has now been observed in Southeast Asia. As such, the needs for new antimalarial agents and new strategies of treatment remain important priorities in tropical medicine. As well, despite very positive outcomes from many modern treatments, serious side effects can impact some individuals taking standard doses.

<span class="mw-page-title-main">Charles Louis Alphonse Laveran</span> French physician (1845–1922)

Charles Louis Alphonse Laveran was a French physician who won the Nobel Prize in Physiology or Medicine in 1907 for his discoveries of parasitic protozoans as causative agents of infectious diseases such as malaria and trypanosomiasis. Following his father, Louis Théodore Laveran, he took up military medicine as his profession. He obtained his medical degree from University of Strasbourg in 1867.

<i>Plasmodium</i> Genus of parasitic protists that can cause malaria

Plasmodium is a genus of unicellular eukaryotes that are obligate parasites of vertebrates and insects. The life cycles of Plasmodium species involve development in a blood-feeding insect host which then injects parasites into a vertebrate host during a blood meal. Parasites grow within a vertebrate body tissue before entering the bloodstream to infect red blood cells. The ensuing destruction of host red blood cells can result in malaria. During this infection, some parasites are picked up by a blood-feeding insect, continuing the life cycle.

<i>Plasmodium falciparum</i> Protozoan species of malaria parasite

Plasmodium falciparum is a unicellular protozoan parasite of humans, and the deadliest species of Plasmodium that causes malaria in humans. The parasite is transmitted through the bite of a female Anopheles mosquito and causes the disease's most dangerous form, falciparum malaria. It is responsible for around 50% of all malaria cases. P. falciparum is therefore regarded as the deadliest parasite in humans. It is also associated with the development of blood cancer and is classified as a Group 2A (probable) carcinogen.

<span class="mw-page-title-main">Chloroquine</span> Medication used to treat malaria

Chloroquine is a medication primarily used to prevent and treat malaria in areas where malaria remains sensitive to its effects. Certain types of malaria, resistant strains, and complicated cases typically require different or additional medication. Chloroquine is also occasionally used for amebiasis that is occurring outside the intestines, rheumatoid arthritis, and lupus erythematosus. While it has not been formally studied in pregnancy, it appears safe. It was studied to treat COVID-19 early in the pandemic, but these studies were largely halted in the summer of 2020, and the NIH does not recommend its use for this purpose. It is taken by mouth.

<i>Plasmodium vivax</i> Species of single-celled organism

Plasmodium vivax is a protozoal parasite and a human pathogen. This parasite is the most frequent and widely distributed cause of recurring malaria. Although it is less virulent than Plasmodium falciparum, the deadliest of the five human malaria parasites, P. vivax malaria infections can lead to severe disease and death, often due to splenomegaly. P. vivax is carried by the female Anopheles mosquito; the males do not bite.

<i>Plasmodium malariae</i> Species of single-celled organism

Plasmodium malariae is a parasitic protozoan that causes malaria in humans. It is one of several species of Plasmodium parasites that infect other organisms as pathogens, also including Plasmodium falciparum and Plasmodium vivax, responsible for most malarial infection. Found worldwide, it causes a so-called "benign malaria", not nearly as dangerous as that produced by P. falciparum or P. vivax. The signs include fevers that recur at approximately three-day intervals – a quartan fever or quartan malaria – longer than the two-day (tertian) intervals of the other malarial parasite.

<span class="mw-page-title-main">Merozoite surface protein</span>

Merozoitesurface proteins are both integral and peripheral membrane proteins found on the surface of a merozoite, an early life cycle stage of a protozoan. Merozoite surface proteins, or MSPs, are important in understanding malaria, a disease caused by protozoans of the genus Plasmodium. During the asexual blood stage of its life cycle, the malaria parasite enters red blood cells to replicate itself, causing the classic symptoms of malaria. These surface protein complexes are involved in many interactions of the parasite with red blood cells and are therefore an important topic of study for scientists aiming to combat malaria.

<span class="mw-page-title-main">Plasmepsin</span> Group of Plasmodium enzymes

Plasmepsins are a class of at least 10 enzymes produced by the Plasmodium falciparum parasite. There are ten different isoforms of these proteins and ten genes coding them respectively in Plasmodium. It has been suggested that the plasmepsin family is smaller in other human Plasmodium species. Expression of Plm I, II, IV, V, IX, X and HAP occurs in the erythrocytic cycle, and expression of Plm VI, VII, VIII, occurs in the exoerythrocytic cycle. Through their haemoglobin-degrading activity, they are an important cause of symptoms in malaria sufferers. Consequently, this family of enzymes is a potential target for antimalarial drugs.

<span class="mw-page-title-main">Malaria culture</span> Method for growing malaria parasites outside the body

Malaria culture is a method for growing malaria parasites outside the body, i.e., in an ex vivo environment. Although attempts for propagation of the parasites outside of humans or animal models reach as far back as 1912, the success of the initial attempts was limited to one or just a few cycles. The first successful continuous culture was established in 1976. Initial hopes that the ex vivo culture would lead quickly to the discovery of a vaccine were premature. However, the development of new drugs was greatly facilitated.

<span class="mw-page-title-main">Halofantrine</span> Chemical compound

Halofantrine is a drug used to treat malaria. Halofantrine's structure contains a substituted phenanthrene, and is related to the antimalarial drugs quinine and lumefantrine. Marketed as Halfan, halofantrine is never used to prevent malaria and its mode of action is unknown, although a crystallographic study showed that it binds to hematin in vitro, suggesting a possible mechanism of action. Halofantrine has also been shown to bind to plasmepsin, a haemoglobin degrading enzyme unique to the malarial parasites.

<span class="mw-page-title-main">Dihydroartemisinin</span> Drug used to treat malaria

Dihydroartemisinin is a drug used to treat malaria. Dihydroartemisinin is the active metabolite of all artemisinin compounds and is also available as a drug in itself. It is a semi-synthetic derivative of artemisinin and is widely used as an intermediate in the preparation of other artemisinin-derived antimalarial drugs. It is sold commercially in combination with piperaquine and has been shown to be equivalent to artemether/lumefantrine.

<span class="mw-page-title-main">Malaria antigen detection tests</span>

Malaria antigen detection tests are a group of commercially available rapid diagnostic tests of the rapid antigen test type that allow quick diagnosis of malaria by people who are not otherwise skilled in traditional laboratory techniques for diagnosing malaria or in situations where such equipment is not available. There are currently over 20 such tests commercially available. The first malaria antigen suitable as target for such a test was a soluble glycolytic enzyme Glutamate dehydrogenase. None of the rapid tests are currently as sensitive as a thick blood film, nor as cheap. A major drawback in the use of all current dipstick methods is that the result is essentially qualitative. In many endemic areas of tropical Africa, however, the quantitative assessment of parasitaemia is important, as a large percentage of the population will test positive in any qualitative assay.

<span class="mw-page-title-main">Biocrystallization</span>

Biocrystallization is the formation of crystals from organic macromolecules by living organisms. This may be a stress response, a normal part of metabolism such as processes that dispose of waste compounds, or a pathology. Template mediated crystallization is qualitatively different from in vitro crystallization. Inhibitors of biocrystallization are of interest in drug design efforts against lithiasis and against pathogens that feed on blood, since many of these organisms use this process to safely dispose of heme.

<span class="mw-page-title-main">History of malaria</span> History of malaria infections

The history of malaria extends from its prehistoric origin as a zoonotic disease in the primates of Africa through to the 21st century. A widespread and potentially lethal human infectious disease, at its peak malaria infested every continent except Antarctica. Its prevention and treatment have been targeted in science and medicine for hundreds of years. Since the discovery of the Plasmodium parasites which cause it, research attention has focused on their biology as well as that of the mosquitoes which transmit the parasites.

<span class="mw-page-title-main">Piperaquine</span> Chemical compound

Piperaquine is an antiparasitic drug used in combination with dihydroartemisinin to treat malaria. Piperaquine was developed under the Chinese National Malaria Elimination Programme in the 1960s and was adopted throughout China as a replacement for the structurally similar antimalarial drug chloroquine. Due to widespread parasite resistance to piperaquine, the drug fell out of use as a monotherapy, and is instead used as a partner drug for artemisinin combination therapy. Piperaquine kills parasites by disrupting the detoxification of host heme.

Pregnancy-associated malaria (PAM) or placental malaria is a presentation of the common illness that is particularly life-threatening to both mother and developing fetus. PAM is caused primarily by infection with Plasmodium falciparum, the most dangerous of the four species of malaria-causing parasites that infect humans. During pregnancy, a woman faces a much higher risk of contracting malaria and of associated complications. Prevention and treatment of malaria are essential components of prenatal care in areas where the parasite is endemic – tropical and subtropical geographic areas. Placental malaria has also been demonstrated to occur in animal models, including in rodent and non-human primate models.

The mainstay of malaria diagnosis has been the microscopic examination of blood, utilizing blood films. Although blood is the sample most frequently used to make a diagnosis, both saliva and urine have been investigated as alternative, less invasive specimens. More recently, modern techniques utilizing antigen tests or polymerase chain reaction have been discovered, though these are not widely implemented in malaria endemic regions. Areas that cannot afford laboratory diagnostic tests often use only a history of subjective fever as the indication to treat for malaria.

Heme ligase (EC 4.99.1.8, heme detoxification protein, HDP, hemozoin synthase) is an enzyme with systematic name Fe3+:ferriprotoporphyrin IX ligase (β-hematin-forming). This enzyme catalyses the following reaction:

<i>Plasmodium cynomolgi</i> Species of single-celled organism

Plasmodium cynomolgi is an apicomplexan parasite that infects mosquitoes and Asian Old World monkeys. In recent years, a number of natural infections of humans have also been documented. This species has been used as a model for human Plasmodium vivax because Plasmodium cynomolgi shares the same life cycle and some important biological features with P. vivax.

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