Plasmodium vivax and Malaria: Infection, Dormancy, and Relapses
Why Is Plasmodium vivax Important?
Malaria is an infectious disease transmitted by mosquito bites. The disease is caused by parasites in the genus Plasmodium. Plasmodium falciparum is often considered to be the most dangerous species because it causes the most deaths. Plasmodium vivax is frequently considered to be less important because it often causes a milder form of the disease that has a lower fatality rate. An infection may still be deadly, however. In addition, outside of Africa P. vivax is a more common cause of malaria than P. falciparum.
Another problem linked to P. vivax is that the parasite becomes temporarily dormant in the liver and then becomes active again at a later date. The reactivation often causes a relapse, or a return of malaria symptoms. In some people, relapses occur repeatedly. Recent research suggests that the bone marrow acts as a reservoir for one stage of the parasite's life cycle, which may be yet another problem linked to P. vivax.
The name malaria comes from two Italian words: mal, meaning bad, and aria, meaning air. In the medieval period, people thought the disease was caused by inhaling bad air such as that found around swamps. Eventually investigators realized that the mosquitoes that lived by the swamp actually caused the disease instead of the unpleasant air.
What Is Plasmodium?
Four species of Plasmodium are responsible for most cases of malaria: P. falciparum, P. vivax, P. ovale, and P. malariae. P. knowlesi also causes the disease in a limited part of the world.
Plasmodium is microscopic and unicellular. It's often referred to as a protozoan parasite. Protozoa are one-celled organisms that move by extending projections from the cell and flowing into them. They also use this behaviour to surround and trap their prey or food source. The method of locomotion is called amoeboid movement after observations made in an organism known as an amoeba.
All of the species of Plasmodium that cause malaria have a complex life cycle and multiple stages in their development. Not all of the stages are capable of amoeboid movement. The basic life cycle of the different species is the same, but it includes a few features that are specific to the species.
Malaria parasites are spread from one person to another by female members of the Anopheles genus of mosquitoes. The females require mammalian blood in order to produce their eggs. They obtain the liquid by biting a victim and withdrawing blood.
Asexual Reproduction of the Parasite
The life cycle of Plasmodium contains both an asexual stage and a sexual one. The asexual stage is linked to the symptoms of malaria and the sexual stage to the transmission of the disease via mosquitoes. The steps in asexual reproduction are described below. (The numbers represent sequential steps in the process of asexual reproduction. The steps in the life cycle illustration shown above are numbered differently.)
- The mosquito bites a human to obtain a meal of blood. She injects an anticoagulant into the blood to stop it from clotting. In the process, some of her saliva enters the victim's blood. The saliva contains sporozoites.
- The sporozoites travel to the liver via the victim's bloodstream.
- The sporozoites enter the liver cells, or the hepatocytes.
- Inside a liver cell, a sporozoite produces a cell known as a schizont.
- The schizont makes and releases multiple merozoites, which break out of the liver cell and enter the blood.
- A merozoite enters a red blood cell (or an erythrocyte) and produces a ring-like form of the parasite. This is an immature stage that is called the ring-stage trophozoite or simply the ring stage.
- The ring-stage trophozoite matures. The mature trophozoite then becomes a schizont, which produces new merozoites. The red blood cells burst open and release the merozoites.
- The process described in Steps 6 and 7 occurs multiple times. The release of the merozoites from the red blood cells is linked to the unpleasant symptoms of malaria.
An Additional Stage in P. vivax Reproduction
In Plasmodium vivax, an additional step may occur before the schizont forms in Step 4 of the sequence shown above. The sporozoite may form a hypnozoite. This is a dormant form that remains inactive in the liver for weeks, months, or even years. The hypnozoite's name comes from the idea that it acts as though hypnotized. At some point in time, hypnozoites become active. This causes the liver cells to release merozoites, triggering the rest of the parasite's life cycle and the symptoms of malaria.
The photos above show the following stages in the life cycle of Plasmodium vivax: 1 = macrogametocyte, 2 = schizont, 3 = microgametocyte, 4 = trophozoite.
Sexual Reproduction of the Parasite
On some occasions, the ring stage of the parasite produces gametocytes instead of a mature trophozoite. This starts the process of sexual reproduction. Gametocytes are either male or female. The male ones are known as microgametocytes and the female ones as megagametocytes.
The gametocytes enter a mosquito's body as she drinks blood. Fertilization occurs in the mosquito's stomach. A microgametocyte enters a macrogametocyte, producing a zygote. The zygote elongates to form an ookinete, which penetrates the wall of the mosquito's gut. Here the ookinete becomes an oocyst. The mature oocyst releases sporozoites. These travel to the mosquito's salivary glands, enabling the cycle to start again. The video below summarizes the life cycle of Plasmodium.
The possible symptoms of malaria described below are given for general interest only. Anyone with symptoms that worry them should visit a doctor for a diagnosis and treatment recommendations.
Possible Symptoms and Treatment of Malaria
In the case of a P. vivax infection, symptoms of malaria appear about two weeks after transmission of the parasite by a mosquito bite. During the time interval between infection and symptom appearance, the liver produces a large population of merozoites.
Symptoms of uncomplicated malaria may include:
- stomach pain
- muscle pain
- alternating periods of high fever and shaking chills
As in any symptom list, a patient may not experience all of the symptoms and the ones that do appear may indicate the presence of a different health problem. The symptoms listed above are often experienced by malaria patients, however.
A number of drugs are used to treat malaria. A major problem with respect to treatment is the development of drug resistance in the parasite. Some medications are not as effective as they once were. Researchers are continuing the search for new substances that can destroy the parasite while it's in the human body without harming us. Mosquito control and protection from insect bites are valuable strategies for preventing disease but may not be foolproof.
The history of antimalarial medicine has been marked by a constant struggle between evolving drug-resistant parasites and the search for new drug formulations. In many parts of the world, for instance, resistance to chloroquine has rendered the drug ineffective.— Mayo Clinic
Complications of Malaria
Not everyone develops complications from a case of malaria, but the problems may be serious if they do occur. They are most likely to occur after a P. falciparum infection. Some of the problems arise due to the fact that red blood cells containing Plasmodium tend to stick to the walls of blood vessels and block them.
Complications may include:
- anemia due to destruction of red blood cells
- release of bilirubin from the damaged blood cells and the development of jaundice due to bilirubin collection under the skin
- low blood sugar (hypoglycemia)
- kidney failure
- a ruptured spleen
- breathing problems due to fluid in the lungs (pulmonary edema)
- problems in the brain (cerebral malaria) due to blocked blood vessels
- a coma
Blocking Plasmodium vivax Entry into Red Blood Cells
A group of international researchers led by the Walter and Eliza Hall Institute of Medical Research in Australia has made what could be a very significant discovery. They've found that P. vivax attaches to an essential protein on the membrane of young red blood cells. The parasite seems to preferentially attack young erythrocytes. The membrane protein is called the human transferrin receptor protein. It normally transfers iron into the blood cells, which need the chemical in order to make hemoglobin. The parasite "tricks" the receptor and uses it to gain entry into the red blood cells.
In addition to making the discovery described above, the researchers have been able to create antibodies that block the parasite's entry into the red blood cells, at least under experimental conditions. More tests are needed, but the researchers may have found a way to stop P. vivax from causing malaria symptoms. The transferrin receptor is also used by viruses that cause a group of diseases known as New World haemorrhagic fevers. The research might help to treat or prevent these diseases.
P. vivax currently inflicts a huge burden on global health. It is the most common malaria parasite in countries outside of Africa, with more than 16 million clinical cases recorded each year.— Walter and Eliza Hall Institute of Medical Research
Growing and Studying Hypnozoites
The dormant form of P. vivax is hard to destroy. It's resistant to most of the drugs used to treat malaria. In addition, its biology isn't well understood. In what could be a very significant development, researchers at MIT have been able to grow hypnozoites in isolated liver tissue for several weeks. This has allowed them to study critical aspects of a hypnozoite's behaviour, such as how it enters and leaves dormancy. It's also given them hints about how it might be destroyed.
Understanding how to destroy hypnozoites is crucial for Plasmodium vivax treatment. Killing the parasites in the blood isn't very helpful if a fresh crop is released from the liver at a later date. The parasites that enter the blood may not only make the patient ill but may also spread the disease to someone else via a mosquito bite.
A drug called primaquine does kill hypnozoites in the liver. Unfortunately, it can't be given to people with a specific enzyme deficiency because it causes their red blood cells to burst. According to the MIT press release, however, a nonprofit group called Medications for Malaria Venture "has a collection of thousands of drug candidates". Hopefully at least some of these substances will kill hypnozoites without hurting people.
In 1991, Aneityum ... was chosen as a site to test possible measures to eradicate malaria. Researchers sprayed against mosquito larvae and supplied bed nets and malaria medicine across the entire island. These efforts led to the complete eradication of Plasmodium falciparum within a year. In contrast, it took five years to eliminate Plasmodium vivax.— Anne Trafton, Massachusetts Institute of Technology
Studying the Hypnozoite's Transcriptome
One exciting announcement from the MIT researchers is the fact that they've identified the specific components of the RNA transcriptome made by hypnozoites (or, in biological terms, that they've sequenced the RNA).
Plasmodium, human, and other cells contain a chemical called DNA (deoxyribonucleic acid). This contains a code that controls many of the organism's characteristics via the manufacture of proteins. DNA is located inside the nucleus of a cell and can't leave this location. Proteins are made outside the nucleus. The cell has a solution for this problem. It copies the information in the part of the DNA that codes for a required protein and stores it in a molecule called messenger RNA (or mRNA). The mRNA leaves the nucleus and goes to the site of protein manufacture in the cell, where the protein is made.
The production of mRNA is known as transcription. The complete set of mRNA molecules made from the DNA of a cell is called a transcriptome. The fact that the MIT researchers have identified the components of the hypnozoite's transcriptome is significant in several ways. First, it indicates that transcription is still occurring, even though the hyponozoite appears to be dormant. Secondly, the researchers have discovered that a different subset of genes is being transcribed in the hypnozoite compared to the situation in other forms of the parasite. (A gene is a section of a DNA molecule that codes for a protein). Other potential benefits of the discovery are that it may lead to a better way to identify the presence of hypnozoites as well as better methods of disease treatment.
P. vivax Parasites in Bone Marrow
P. vivax studies have focused on the parasite in the liver and the blood. They may not be all that is needed to fight the parasite, however. Scientists at the Harvard School of Public Health have reported the discovery of gametocytes of P. vivax in the bone marrow of humans and of at least some other primates. They say that the gametocytes mature rapidly in the marrow, which appears to act as a reservoir for the parasites.
The team has made another interesting discovery. When they studied tissue from infected primates, they found antibodies that could potentially fight the parasites in the liver, bone marrow, and lungs, but not in the intestine, subcutaneous fat, or brain. This suggests that the first three locations had been exposed to the parasites and that their relationship to malaria should be studied further.
A Plasmodium vivax infection is like an iceberg: It's dangerous, in part, because much of it hides out of view.— EurekAlert news service, American Association for the Advancement of Science
Dealing With the Parasite
All of the recent discoveries about P. vivax described above were reported in 2018. They offer hope for the future, although the benefits of the research are uncertain at the moment. Further research is required before new medical treatments are created and their effectiveness assessed. Malaria has been a serious and difficult problem to solve for a long time. Hopefully this situation will change soon.
Information about malaria from the CDC (Centers for Disease Control and Prevention)
Malaria facts from the Mayo Clinic
Stopping Plasmodium vivax from entering red blood cells from the Walter and Eliza Hall Institute of Medical Research
Hypnozoites grown in the lab for the first time from MIT (Massachusetts Institute of Technology
Malaria parasite accumulates undetected in bone marrow from the EurekAlert news service
Questions & Answers
© 2018 Linda Crampton