Plasmodium species (Malaria)

Malaria is an infection that can be caused by a few different types of Plasmodium species, which are single-celled parasites that get spread around by mosquitoes.

Once the plasmodium gets into the bloodstream, it starts to infect and destroy mainly liver cells and red blood cells, which causes a variety of symptoms and sometimes even death.

Malaria is a serious global health problem that affects millions of people, particularly young children under the age of 5, pregnant women, patients with other health conditions like HIV and AIDS, and travelers who have had no prior exposure to malaria.

Tropical and subtropical regions are hit the hardest, together the most affected regions form the malaria belt, which is a broad band around the equator that includes much of latin america, sub-saharan africa, south asia, and southeast asia.

There are hundreds of types of Plasmodium species, but only five cause malarial disease in humans, and those are Plasmodium falciparum, Plasmodium vivax, Plasmodium malariae, Plasmodium ovale, and Plasmodium knowlesi.

Plasmodium vivax uses a specific erythrocyte surface receptor called the Duffy antigen.

And some individuals, particularly those with sickle-cell anemia lack this receptor, meaning that Plasmodium vivax cannot get into their cells.

In other words, having sickle cell anemia is genetically related to having relative protection from Plasmodium vivax.

Other diseases, like thalassemia and G6PD deficiency make the parasite-infected erythrocyte more susceptible to dying from oxidative stress.

So despite the obvious downside to having any of these diseases, they do offer an upside when it comes to warding off a malaria infection.

In fact, because malaria has historically circulated in Africa, the genes underlying these diseases are thought to have conferred a natural selection advantage and therefore become more common in the genetic pool.

Now, malaria begins when a plasmodium-infected female Anopheles mosquito hunts for a blood meal in the evening and through the night.

Like a tiny flying vampire, the mosquito is drawn to carbon dioxide that get breathed out as well as bodily smells, like foot odor.

At this point, the Plasmodium is in a stage of development called a sporozoite, waiting patiently in the mosquito’s salivary gland.

When the mosquito pierces a person’s skin with its long and needle-shaped tusk, called a proboscis, the tiny, worm-like sporozoites spill out of the mosquito’s saliva and make it into the bloodstream.

Within minutes, the sporozoites reach the liver and mount an attack on hepatic parenchymal cells where they begin asexual reproduction also known as schizogony.

At this point, the plasmodium species vary a bit.

Over the next 1-2 weeks, Plasmodium falciparum, Plasmodium malariae, and Plasmodium knowlesi sporozoites multiply asexually and mature into merozoites, while host hepatic parenchymal cells die.

In contrast, over the next few months to years, Plasmodium vivax and Plasmodium ovale sporozoites enter into a dormant hepatic phase, where they are called hypnozoites.

Hypnozoites don’t divide - instead they snooze for a period of time before entering the process of schizogony, causing a long delay between the initial infection and symptoms from the disease.

This is called the exoerythrocytic phase because it happens outside of the erythrocyte or red blood cell, and it’s generally asymptomatic.

The merozoites are then released into the blood, and each one binds to a surface receptor and invades a red blood cell.

Plasmodium ovale and Plasmodium falciparum invade red blood cells of all ages, whereas Plasmodium vivax prefers to invade reticulocytes which are young, immature red blood cells, and Plasmodium malariae and Plasmodium knowlesi prefer to invade older red blood cells.

Once inside the red blood cell, the merozoite undergoes asexual reproduction and a series of transformational changes.

This phase is known as the erythrocytic phase of malaria, because it happens inside of the red blood cell and generally lasts 2 to 3 days.

In the first stage of the erythrocytic phase the merozoite looks like a tiny ring within the red blood cell and is called an early trophozoite or a ring form.

In the second stage, the ring form trophozoite grows and is referred to as a late trophozoite.

In the third and final stage, the parasite grows some more by digesting hemoglobin and leaves behind hemozoin, which under a microscope looks a little like a brown feces smudge on the red blood cell, and at this point the parasite is called a schizont.

This is the actual replicative phase in which the parasite undergoes mitosis and differentiates into lots of merozoites which can get released into the blood.

Now, instead of going into the erythrocytic phase again, some of the merozoites undergo gametogony which is where they divide and give rise to gametocytes which are little sausage-shaped sexual forms that can be either male or female.

These gametocytes remain inside of a red blood cell, and can get sucked up by another female Anopheles mosquito that might take a blood meal from the infected person.

The gametocytes can then reach the mosquito's gut where they mature a bit more and then fuse together to form a zygote.

This part of the plasmodium life cycle is called sporogony, and it’s sexual reproduction, as opposed to the schizogony or asexual reproduction that happened in the liver and red blood cells.

The zygote then goes on to develop further, it becomes an ookinete and then an oocyst that ruptures in the mosquito’s gut, releasing thousands of sporozoites which navigate their way into the mosquito's salivary gland, in order to repeat the cycle all over again.

Now, the incubation time, which is the period of time between infection and symptom onset, varies depending on the plasmodium species.

Plasmodium falciparum incubates for a few days, whereas Plasmodium malariae incubates for a few weeks.

The release of tumor necrosis factor alpha and other inflammatory cytokines, causes fevers that typically occur in paroxysms or short bursts, and correspond to the rupture of the infected red blood cells, which happens in waves of reproductive cycles unique for each plasmodium species.

For Plasmodium malariae, fevers happen every 72 hours, and is called quartan fever.

For Plasmodium vivax and Plasmodium ovale, fevers happen every 48 hours, and these are called tertian fever.

For Plasmodium knowlesi, the fever happens every 24 hours, and for Plasmodium falciparum, the pattern can vary - sometimes following the pattern of tertian fever, while other times the fevers happen daily, earning it the name malignant tertian fever.