Why Plasmodium berghei Is a Model for Human Malaria

Plasmodium berghei is a single-celled protozoan parasite belonging to the genus Plasmodium. It is one of four Plasmodium species known to naturally infect murine rodents in specific regions of Africa. The others include P. yoelii, P. vinckei, and P. chabaudi.

The parasite was first identified in 1948 by scientists Ignace Vincke and Marcel Lips. They discovered the organism in the blood of a thicket rat (Grammomys surdaster) in what is now the Democratic Republic of the Congo. The species was named in honor of Louis van den Berghe, who was the director of the Institute for Scientific Research in Central Africa at the time.

The Plasmodium berghei Life Cycle

The life cycle of Plasmodium berghei requires two hosts to complete its development: a rodent and a female Anopheles mosquito. The cycle begins when an infected mosquito takes a blood meal from a rodent, injecting parasites called sporozoites from its salivary glands into the rodent’s bloodstream.

Once the sporozoites reach the liver, they invade liver cells, known as hepatocytes, initiating the asymptomatic liver stage of infection. Inside a single hepatocyte, the parasite undergoes intense asexual replication over approximately 47 to 52 hours. This process transforms a single sporozoite into a structure called a liver schizont, which is filled with 1,500 to 8,000 merozoites.

At the conclusion of the liver stage, the host hepatocyte ruptures, releasing the merozoites into the bloodstream. This event marks the beginning of the erythrocytic, or blood stage. Each merozoite is equipped to invade a red blood cell. Inside the erythrocyte, the parasite develops from a ring stage into a trophozoite, consuming hemoglobin and growing larger before replicating its genetic material to form a blood-stage schizont.

This asexual blood-stage cycle in P. berghei is rapid, taking about 22 to 24 hours to complete. The mature schizont eventually bursts the red blood cell, releasing a new generation of merozoites that go on to invade more erythrocytes, amplifying the infection. Instead of continuing this asexual replication, a small fraction of the parasites in the blood will differentiate into sexual forms known as male and female gametocytes. The development of these transmissible forms takes about 26 to 30 hours.

The cycle is completed when a different Anopheles mosquito feeds on the infected rodent, ingesting blood that contains these gametocytes. Inside the mosquito’s midgut, the gametocytes are activated to form male and female gametes, which then fuse to create a zygote. The zygote matures into a motile ookinete that penetrates the mosquito’s midgut wall and develops into an oocyst on the exterior surface. Within the oocyst, thousands of new sporozoites are produced, which eventually migrate to the mosquito’s salivary glands, positioning the insect to infect another rodent.

Rodent Malaria

In its natural rodent hosts, Plasmodium berghei infection causes a disease known as rodent malaria. Laboratory mice infected with the parasite exhibit a range of symptoms that reflect the systemic nature of the illness.

One of the most prominent pathological features is severe anemia. In severe infections, the reduction in the total number of red blood cells can exceed 70%, leading to a decreased oxygen-carrying capacity of the blood. This loss contributes to the general lethargy and weakness observed in infected animals.

An enlarged spleen, or splenomegaly, is a characteristic finding. The spleen is involved in filtering blood and removing old or damaged red blood cells, and its enlargement is a response to the high load of parasitized and destroyed erythrocytes. Similarly, hepatomegaly, or an enlarged liver, is also commonly observed.

Beyond these specific organ enlargements, infected mice often display general signs of sickness such as weight loss, piloerection (hair standing on end), and reduced locomotor activity. Depending on the strain of P. berghei, such as the ANKA strain, the infection can progress to a more severe state. This can involve the sequestration of parasitized red blood cells in the microvasculature of vital organs, including the brain, lungs, and kidneys.

A Model for Human Malaria

While Plasmodium berghei does not naturally infect humans, its use as a laboratory model is valuable for studying human malaria, particularly the form caused by Plasmodium falciparum. This utility stems from the biological and genetic similarities between the rodent and human parasites.

The disease it causes in mice, rodent malaria, presents pathologies that parallel severe human malaria, including anemia and organ damage. Certain parasite strains, like P. berghei ANKA, can be used to study specific severe syndromes, such as the neurological complications associated with cerebral malaria.

A primary reason for its widespread use is the high degree of genetic similarity to P. falciparum. The genomes of both species have been sequenced and show considerable conservation in structure and gene content. Many of the core biochemical pathways and housekeeping genes are nearly identical, meaning that what is learned about a gene’s function in P. berghei can often be informative about its counterpart in P. falciparum.

The P. berghei-mouse model also offers practical advantages over studying human malaria parasites. Working with mice is less expensive and has a much faster timeline, as the parasite’s life cycle is shorter. Furthermore, P. berghei is more amenable to genetic modification than P. falciparum, which is difficult to manipulate. The availability of numerous inbred and transgenic mouse strains also makes it possible to study how specific host immune genes affect the course of infection, an approach not possible in human studies.

Research Applications and Discoveries

The P. berghei model is a workhorse for the initial screening of candidate antimalarial drugs and vaccines. Compounds or vaccine strategies can be tested in mice to assess their effectiveness at clearing or preventing infection before they are considered for more complex and costly human trials.

One application involves the genetic modification of the parasite itself. Scientists have engineered P. berghei lines that produce fluorescent proteins, such as Green Fluorescent Protein (GFP), or bioluminescent enzymes like luciferase. These transgenic parasites glow, allowing researchers to use advanced microscopy to track the parasites in real time inside a living mouse. This technology makes it possible to visualize the parasite’s journey from the skin to the liver and its accumulation in different organs.

Researchers can create “knockout” parasites by deleting a single gene and then observing the consequences. For instance, studies deleting genes for enzymes involved in hemoglobin digestion revealed that parasites could survive without this function but were restricted to developing in young red blood cells.

The model has been used in developing novel vaccine strategies. Research with genetically modified P. berghei led to the creation of genetically attenuated parasites (GAPs). These are parasites that have had genes deleted, causing them to be arrested during the liver stage. They are able to provoke a protective immune response in the host without ever progressing to the disease-causing blood stage, making them a promising platform for next-generation malaria vaccines.