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Plasmodium vivax and Malaria: Infection, Dormancy, and Relapses

Linda Crampton is a writer and teacher with a first-class honors degree in biology. She often writes about the scientific basis of disease.

A colourized electron micrograph showing a malaria parasite entering a red blood cell

A colourized electron micrograph showing a malaria parasite entering a red blood cell

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 can become temporarily dormant in the liver and then become 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. Many of them 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.)

  1. 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.
  2. The sporozoites travel to the liver via the victim's bloodstream.
  3. The sporozoites enter the liver cells, or the hepatocytes.
  4. Inside a liver cell, a sporozoite produces a cell known as a schizont.
  5. The schizont makes and releases multiple merozoites, which break out of the liver cell and enter the blood.
  6. 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.
  7. 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.
  8. 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.

Stages in the life cycle of Plasmodium vivax

Stages in the life cycle of Plasmodium vivax

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 steps in sexual reproduction are shown in the illustration above and described below.

  • 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.
  • The ookinete becomes an oocyst.
  • The mature oocyst releases sporozoites.
  • The sporozoites travel to the mosquito's salivary glands, enabling the cycle to start again.

The video below summarizes the life cycle of Plasmodium.

Possible Symptoms and Treatment of Malaria

Symptoms

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:

  • headache
  • stomach pain
  • vomiting
  • diarrhea
  • muscle pain
  • fatigue
  • 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.

Treatment

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

Possible 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
  • seizures
  • 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

The recent discoveries about P. vivax are very interesting. 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.

References

  • 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

This content is accurate and true to the best of the author’s knowledge and does not substitute for diagnosis, prognosis, treatment, prescription, and/or dietary advice from a licensed health professional. Drugs, supplements, and natural remedies may have dangerous side effects. If pregnant or nursing, consult with a qualified provider on an individual basis. Seek immediate help if you are experiencing a medical emergency.

© 2018 Linda Crampton

Comments

Linda Crampton (author) from British Columbia, Canada on May 22, 2018:

That’s an interesting memory. I’ve never heard of such a relationship.

jonnycomelately on May 20, 2018:

I seem to remember that in Tanzania in the mid-70s it was regarded as correct treatment not to continue Chloroquin to the point of completely "curing" an African person of malaria.

Apparently residual malaria helps in some way to protect against the effects of Sickle Cell.

Linda Crampton (author) from British Columbia, Canada on May 20, 2018:

Hi, Natalie. The relationship between the sickle cell gene and malaria resistance is very interesting. It's certainly worth exploring. I appreciate your comment.

Natalie Frank from Chicago, IL on May 20, 2018:

Interesting article. I've been interested in the relationship between sickle cell anemia and malaria for a while and have often wondered at how certain diseases or conditions can protect against other conditions. So though people are protected from malaria on the one hand they may die from sickle cell on the other. So inheriting one gene provides protection yet inheriting two leads to significant problems. Yet at the same time in many communities the majority of the people surviving to adulthood have one of the genes. Malaria is one of those diseases it seems we should be able to counter more effectively than we do. Thanks for another great article

Linda Crampton (author) from British Columbia, Canada on May 20, 2018:

Thanks for sharing the information about Malarone, Manatita. I'd love to visit the area that you've seen. It does seem advisable to take steps to prevent malaria, though.

manatita44 from london on May 20, 2018:

Pretty serious organ to attack and the red cells as well.

I take Malarone, even after 6 weeks in Kenya. Some Europeans don't and they volunteer in slum areas. Tough. Nice video.

Linda Crampton (author) from British Columbia, Canada on May 18, 2018:

Thanks, Peggy. I'm glad that Bill Gates is using some of his money for such a good cause, too.

Peggy Woods from Houston, Texas on May 18, 2018:

Malaria is a sinister disease particularly because of sometimes lying dormant and then resurfacing. Hopefully continued research will discover how to eliminate it completely. It is great that Bill Gates is using some of his money towards eradicating malaria. That will surely help. Your article was informative as always.

Linda Crampton (author) from British Columbia, Canada on May 18, 2018:

Yes, I've heard about his work, too. I'm glad he's involved in the endeavour. Research into the eradication of malaria is important.

Liz Westwood from UK on May 18, 2018:

In the UK we hear a lot about Bill Gates and his efforts through his charitable foundation to eradicate malaria.

Linda Crampton (author) from British Columbia, Canada on May 17, 2018:

Hi, Heidi. Thank you for the visit and the kind comment. It is sad that malaria still exists and is still such a major problem.

Heidi Thorne from Chicago Area on May 17, 2018:

We rarely hear about this in the U.S. But it's sad it still rages on. I agree, I hope a solution to the issue is found soon, too. Thanks, as always, for sharing your wealth of knowledge on biology!

Linda Crampton (author) from British Columbia, Canada on May 17, 2018:

I appreciate your comment, Liz. It's interesting to discover how many people have either had malaria or know people who have had the disease.

Liz Westwood from UK on May 17, 2018:

This is a very thorough and detailed article. Having had several family members who have traveled in Africa and two who contracted malaria, I have found it especially interesting to read.

Linda Crampton (author) from British Columbia, Canada on May 17, 2018:

Thank you for commenting, Devika. The parasites that mosquitoes carry can certainly be unpleasant. There are good reasons why the insects aren't liked!

Devika Primić from Dubrovnik, Croatia on May 16, 2018:

Mosquitoes affect people in most parts of the world. It is the most dangerous parasite. One should take the necessary precautions. An informative and well-formatted hub.

Linda Crampton (author) from British Columbia, Canada on May 16, 2018:

Thank you, Dora. The latest research does offer hope. Time will tell us whether it's helpful. I hope it is.

Dora Weithers from The Caribbean on May 16, 2018:

Thanks for these explanations on the seriousness of the disease and even the process by which the mosquito contaminates our blood. You always offer some hope, and that's great.

Linda Crampton (author) from British Columbia, Canada on May 15, 2018:

Hi, Alan. Thanks for an informative comment and for raising an interesting point about the food needed by the increased population. I certainly agree that the need for good science and technology is always present!

Linda Crampton (author) from British Columbia, Canada on May 15, 2018:

Thanks for the kind comment, Bede. The CDC website about malaria (the first reference above) has lots of information about where the disease is found. The website says that about 1,700 cases of malaria are diagnosed in the United States each year. Most of these appear in people who have returned from a visit to tropical and subtropical countries where malaria is common, but some cases are caused by mosquitoes within the United States. The CDC says that the risk of locally-transmitted disease is highest in the southern states.

jonnycomelately on May 15, 2018:

Thank you Linda. Most enlightening article. I did experience malaria first-hand in East Africa back in the early '70s. Very nasty fevers and rigors. Fortunately Chloroquin was still effective in those days and it cleared up with no complications except I was very debilitated for a couple of weeks.

If (and presumably when) there is wide spread effective treatment, we will need to provide much more food for the increased surviving population.

The need for good science and technology never ceases.

Bede from Minnesota on May 15, 2018:

Linda, I’m pleased to stay abreast of developments in the medical world, via your articles. I usually associate malaria with sub tropical countries such as Africa. Is there any real threat for those in the Midwest?

Linda Crampton (author) from British Columbia, Canada on May 15, 2018:

I hope you enjoy your trip to Peru, Flourish. It sounds like a wonderful opportunity, but I hope you don't get sick! The experiences of your friend and cousin sound horrible.

FlourishAnyway from USA on May 15, 2018:

A friend got antibiotic-resistant supermalaria when he traveled to Vietnam and he became quite sick. My cousin also became sick with malaria a couple years ago when he joined the Peace Corps, and he was so sick they sent him home. Now I’m headed to Peru this summer and am wary. Thus, I read your article with great interest!

Linda Crampton (author) from British Columbia, Canada on May 15, 2018:

Hi, Larry. Yes, the organism does have a big impact on the world. I hope the methods for dealing with it improve soon.

Larry Rankin from Oklahoma on May 15, 2018:

Very educational.

Certainly one of the most impactful microorganisms in the world.

Linda Crampton (author) from British Columbia, Canada on May 15, 2018:

Thirteen grandchildren is an impressive number, Paula! I think they will need a lot of insect repellent this summer.

Suzie from Carson City on May 15, 2018:

Educational, interesting and a little bit scary! I need gallons of repellent for 13 grandchildren!! Thanks for this awareness!

Linda Crampton (author) from British Columbia, Canada on May 15, 2018:

Hi, Bill. The name of the organism is interesting. I can understand why you think it sounds sinister! Thank you for the comment.

Bill Holland from Olympia, WA on May 15, 2018:

I'm being a bit silly right now, but those first two words just sound like a disease you wouldn't want to have. They sound sinister.

I've heard about malaria all my life, but really knew nothing about it until I read this article, so thank you, Linda!

Linda Crampton (author) from British Columbia, Canada on May 15, 2018:

Hi, Mary. It's interesting to hear that you've seen lots of people with malaria. I hope I never experience the disease myself. It has some very unpleasant symptoms.

Mary Norton from Ontario, Canada on May 15, 2018:

Mosquito season is back here in cottage country in Ontario. I have seen many malaria patients and I don't want this at all. Thank you for this information.

Linda Crampton (author) from British Columbia, Canada on May 14, 2018:

Thank you for such a kind comment, Jackie. I hope your mosquito repellent works well. Today is the first day of the year in which I've felt uncomfortable because of the heat in my home. Summer and probably mosquitoes are nearly here!

Jackie Lynnley from the beautiful south on May 14, 2018:

I have a recipe for a mosquito repellent for the patio and the lady claims it last three months. I was going to put it off awhile to make my month start at the first but this has changed my mind! Mosquitoes love me no matter what I do it seems so I sure hope it works for me.

Great informative article as always Linda. You truly are the smartest gal I know!

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