Plasmodium falciparum is a dangerous parasite that causes malaria, a severe disease affecting people worldwide. In 2020, there were around 241 million malaria instances in 85 countries, up from 227 million in 2019. Most cases were due to P. falciparum, a significant and lethal malaria parasite. It spreads through mosquito bites and causes severe malaria, responsible for about half of all cases.  

The way P. falciparum spreads are complex and affected by factors like genetics, immunity, mosquito behavior, and living conditions. Although it’s found in 84 countries worldwide, it used to be expected in Europe, but improved health measures led to its disappearance, making Italy malaria-free in 1970.  

In 2021, there were 247 million malaria instances globally, resulting in about 619,000 deaths. Most deaths happened in Africa, with kids under five facing the highest risk (67% of deaths). Sub-Saharan Africa carries 80% of the disease, and Nigeria and India have a significant share. Despite progress, around 2.4 billion people remain at risk.  

The African region is hit the hardest, with 95% of instances and 96% of deaths in 2021. Kids under five accounted for 80% of deaths there. COVID-19 increased the problem, causing 13 million malaria cases and 63,000 deaths in 2020-2021. The weight of P. falciparum, especially in Africa, shows the ongoing struggle needed to fight this potent parasite and its associated disease. 

Kingdom: Protista 

Phylum: Apicomplexa 

Class: Aconoidasida 

Order: Haemospororida 

Family: Plasmodiidae 

Genus: Plasmodium 

Species: Plasmodium falciparum   

Plasmodium falciparum, a protozoan parasite, exhibits diverse forms across its life cycle and stages within the host:   

Sporozoites: These are the infective stage transmitted by mosquitoes. They are spindle-shaped, around 10–15 μm long, and possess a complex structure aiding invasion into liver cells.   

Ring Forms: Immature trophozoites within RBCs with a ring-like appearance, including a central vacuole and peripheral cytoplasm with a nucleus, measuring about 1.25–1.5 μm.  

Trophozoites: Mature stage, feed on hemoglobin, and form granular pigment (hemozoin). Amoeboid and uninucleated, measuring about 4–5 μm.  

Schizonts: Undergo asexual division to create new merozoites. They occupy two-thirds of infected RBCs, containing 10–36 merozoites arranged in clusters, about 4.5–5 μm in diameter.  

Gametocytes: Sexual form infectious to mosquitoes. Elongated, crescent-shaped, 8–12 μm long, and 3–6 μm wide.   

Apicoplast: Plastid similar to plant chloroplasts, involved in lipid and compound synthesis, and a potential drug target. It aids in producing isoprenoid precursors via the MEP pathway during asexual blood infection.   

Apical Complex: Consisting of rhoptries and micronemes, essential for mobility, adhesion, host cell invasion, and vacuole formation. 

The primary antigen in Plasmodium falciparum, a protein called PfEMP1 (P. falciparum Erythrocyte Membrane Protein-1), is encoded by a family of genes referred to as “var” genes, short for “variable.” These var genes have evolved to exhibit high diversity, resulting in different parasites possessing distinct repertoires of approximately 50 to 60 var genes.

These genes are categorized into four main sub-groups based on semi-conserve upstream promoting sequences (ups) like groups C (upsC), A (upsA), E (upsE) & B (upsB). Group E comprises var2csa, a gene linked to placental malaria. Another significant protein is Plasmodium falciparum antigen 332, which resides in the peripheral membrane of Maurer’s clefts—a specific structure in the parasite.

During the invasion of erythrocytes (red blood cells), merozoites (parasite’s infective form) release various proteins, including merozoite cap protein-1 (MCP1), merozoite surface proteins (MSPs), erythrocyte-binding antigens (EBA), myosin A tail domain interacting protein (MTIP) & apical membrane antigen 1 (AMA1). Among these, MSP2 & MSP1 play pivotal roles in evading immune cells.  

Virulence in P. falciparum is orchestrated by erythrocyte membrane proteins produced by schizonts and trophozoites within erythrocytes, appearing on the erythrocyte membrane. Notably, PfEMP1 is of utmost importance as it serves as both an antigen and an adhesion molecule.  

The parasite employs a strategy of switching the expression of var genes, leading to the presentation of distinct forms of PfEMP1 on the surface of infected red blood cells. This phenomenon, termed antigenic variation, enables the parasite to elude host-produced antibodies directed against previous variants of PfEMP1.  

Additionally, the variant surface antigen RIFIN, encoded by approximately 150 to 200 var genes per parasite genome, plays a crucial role. Each parasite can express multiple RIFIN types simultaneously. RIFIN is situated on the surface of infected red blood cells and is responsible for their adherence to blood vessels, especially within the brain and lungs.  

Plasmodium falciparum strains exhibit varying responses to anti-malarial drugs. For instance, the NF54 strain is sensitive to chloroquine (CQs NF54) and was isolated from a patient in the Netherlands in 1975. In contrast, the K1 strain (CQr) is resistant to chloroquine and was obtained from a patient in Thailand.

Another strain, Pf7G8, isolated from a patient in Brazil in 1978, is resistant to chloroquine, mefloquine, and sulfadoxine-pyrimethamine. Similarly, the GB4 strain, isolated from a patient in Ghana in 1981, is chloroquine sensitive. This intricate interplay of antigenic variation and drug resistance underscores the complexity of Plasmodium falciparum‘s strategies for survival and adaptation in the human host. 

Plasmodium falciparum, as a causative agent of severe malaria, orchestrates a complex invasion into the human body, manifesting a series of intricate stages: 

Initiating from the bite of an infected female Anopheles mosquito, the parasite’s journey begins. Sporozoites, the infectious form of the parasite, are introduced into the bloodstream during the mosquito’s bite. These sporozoites navigate to the liver, where they replicate and mature into liver schizonts, each containing numerous merozoites.

These liver schizonts rupture after a brief incubation period, releasing merozoites into the bloodstream. This pivotal step marks the genesis of blood-stage infection, leading to the eventual onset of falciparum malaria characterized by the rupture and destruction of red blood cells (erythrocytes) by the merozoites, triggering pronounced symptoms including high fever known as paroxysm.  

Merozoites initiate a new phase within the red blood cells (RBCs). Transforming through ring forms, trophozoites, and schizonts, they metabolize hemoglobin and generate a toxic pigment called hemozoin. Schizonts eventually burst, liberating fresh merozoites that perpetuate the cycle of invasion and rupture, culminating in recurrent fever, chills, and anemia episodes. The insoluble β-hematin crystals, called hemozoin, emerge from hemoglobin digestion within RBCs.

This hemozoin contributes to sequestering infected RBCs within organs, evading the immune system’s phagocytes. Subsequently, these hemozoin-laden RBCs initiate inflammatory reactions, causing increased fever and impacting organs like the spleen, liver, kidneys, and lungs. It leads to their enlargement and discoloration, earning the name “malarial pigment.”  

Amidst this intricate progression, certain merozoites evolve into gametocytes, the sexual form of the parasite. When another mosquito feeds on an infected individual, it ingests these gametocytes. Inside the mosquito’s gut, gametocytes merge, forming ookinetes that infiltrate the gut wall and mature into oocysts. These oocysts generate sporozoites that migrate to the mosquito’s salivary glands, finalizing the life cycle.  

Its ability to cause severe malaria through a distinctive mechanism known as sequestration is unique to Plasmodium falciparum. Mature forms of the parasite reshape the surface properties of infected RBCs, inducing them to adhere to blood vessel walls, a process termed cytoadherence. This clever tactic prevents spleen clearance and shields the parasite from immune detection.

This clustering of sequestered infected RBCs leads to grave complications, clogging blood vessels, obstructing vital organ blood flow, and precipitating conditions like cerebral malaria, acute respiratory distress syndrome, renal failure, and severe anemia. In survivors, the reappearance of falciparum symptoms, known as recrudescence, is frequently observed. It induces hypoxia, inflammation, and tissue damage, signifying the severity of the impact. 

The host’s defense against Plasmodium falciparum involves a multifaceted immune response that targets different stages of the parasite’s life cycle. In the pre-erythrocytic stage, the initial encounter occurs at the skin, where sporozoites are introduced through mosquito bites. Sporozoites remain in the skin temporarily before transitioning to the liver.

Antibodies in the skin tissues inhibit sporozoite movement, with around half of the sporozoites remaining at the inoculation site. This early encounter presents a potential target for vaccine development. During the preerythrocytic stage, the immune response is directed against free sporozoites and infected hepatocytes. Antibodies, especially against the circumsporozoite protein (CSP), are crucial for preventing sporozoite invasion of hepatocytes.

These antibodies activate mechanisms like complement fixation, phagocytosis, and lysis mediated by cytotoxic NK and NKT cells. Additionally, CD8+ T cells producing interferon-γ contribute to the destruction of intrahepatic parasites. Other cell types, including NK, NKT, and γδT cells, also participate in this immune response.  

The erythrocytic stage of infection triggers an even more complex adaptive immune response. The release of merozoites from hepatocytes marks the initiation of this stage, where the targets include free merozoites and intraerythrocytic parasites (schizonts). Antibodies play a crucial role in controlling merozoites by opsonizing them for uptake or inhibiting their invasion of red blood cells (RBCs).

Antibodies also neutralize parasite toxins, prevent excessive inflammation, and facilitate cellular killing. This stage is characterized by a proinflammatory cytokine response that activates macrophages. While CD8+ T cell involvement is minimal, CD4+ T helper cells contribute by producing proinflammatory cytokines and facilitating B cell activation.  

The immune response against gametocytes, the sexual forms of the parasite, involves antibodies that mediate complement-mediated lysis. These antibodies also prevent gametocyte sequestration and maturation within the host. Antibodies acquired during mosquito blood meals significantly contribute to complement-mediated gametocyte killing and preventing gamete fusion within mosquitoes.

Macrophages contribute to the defense mechanism by producing nitric oxide, which aids in gametocyte elimination. Immunoglobulin M (IgM) serves the primary role of humoral defense against infection, activating the complement pathway to enhance the host’s immune response against Plasmodium falciparum. 

Plasmodium falciparum is responsible for causing malaria and leads to various clinical manifestations contingent on the disease stage, severity, and the host’s immune response. Symptoms and complications emerge from releasing toxins and products from the parasite and infected red blood cells into the bloodstream.   

Commonly encountered symptoms include fever, chills, headaches, muscle pain, weakness, nausea, vomiting, and diarrhea. A distinctive fever cycle comprises hot, cold, and sweating stages, arising every third day in sync with the 48-hour erythrocytic schizogony cycle. Referred to as tertian malignant fever, this cyclic pattern underscores the naming of the infection.   

Additional challenges encompass anemia, low platelet count, diminished blood sugar levels, and organ dysfunction. The parasite’s destruction of red blood cells and the sequestration of infected ones within vital organ blood vessels, like those in the brain, lungs, kidneys, and liver, contribute to these complications.   

Of particular concern is cerebral malaria, a life-threatening complication where brain blood flow is obstructed by infected red blood cells. It can lead to coma, seizures, neurological impairment, or even mortality. Notably, malaria relapses can occur months or years post initial infection due to dormant Plasmodium falciparum parasites in the liver reactivating. 

Microscopy: Microscopy is the “gold standard” for confirming malaria infection. In this method, a blood smear from the patient is stained with a dye (typically Giemsa) and examined under a microscope. Skilled personnel use visual criteria to detect and identify the parasite’s presence, species, and density. Microscopy can also reveal drug resistance and complications. However, it requires well-trained staff, quality reagents, and properly maintained equipment. A blood specimen is spread as a thick or thin blood smear, stained, and examined using high-magnification objectives. If Giemsa is unavailable, Wright’s stain can be used, but species determination might be more challenging.   

Rapid Diagnostic Test (RDT): RDTs are rapid and convenient tests that can be performed in the field or at the point of care. They involve using a test strip or cassette to detect specific parasite antigens in a drop of blood. Results can be obtained within about 15 minutes; these tests do not require complex equipment or electricity. However, the sensitivity and specificity of RDTs vary, and some may not accurately detect low-level infections or certain parasite species or strains.   

The Indirect Fluorescent Antibody (IFA) test: It is utilized for detecting antibodies against Plasmodium falciparum, the malaria-causing parasite. This serological test involves exposing a patient’s blood serum to blood-stage Plasmodium falciparum antigens, forming antigen-antibody complexes if specific antibodies are present. Subsequently, fluorescein-labeled anti-human antibodies are added, binding to the patient’s malaria-specific antibodies.

Under a fluorescence microscope, apple green fluorescence emitted by the bound antibodies indicates a positive reaction, signifying prior exposure to the parasite. While the IFA test is not routinely used for acute malaria diagnosis due to the time required for antibody development, it finds application in scenarios like blood donor screening and identifying specific conditions associated with repeated or chronic malaria infections. 

• Insecticide-Treated Bed Nets (ITNs): Distributing and promoting ITNs is one of the most effective strategies to prevent mosquito bites and malaria transmission. ITNs are treated with insecticides that repel or kill mosquitoes, reducing the risk of infection during nighttime when mosquitoes are most active. 

• Environmental Management: Modifying the environment to reduce mosquito breeding sites, such as stagnant water, can help control mosquito populations & prevent the spread of malaria. 

• Vaccination: The malaria vaccine, such as the RTS, S vaccine (Mosquirix), provides an additional tool for malaria prevention. While the vaccine’s effectiveness varies, it has shown promise in reducing severe malaria cases in children. 

Immune Response and Evasion Mechanisms of Plasmodium falciparum Parasites (hindawi.com)  

Plasmodium falciparum – an overview | ScienceDirect Topics