EPIDEMIOLOGY

Malaria is an internationally devastating disease, producing nearly 600 million new infections and 3 million deaths each year.  The burden of this disease falls heaviest among children below the age of five in sub-Saharan Africa. Nearly 30% of the annual mortality in this population is attributable to malaria. Malaria is caused by four species of Plasmodium, a unicellular protozoan. Of these species, P. falciparum accounts for the preponderance of morbidity and mortality globally. The protozoan is transmitted through the bite of the female Anopheles mosquito (WHO).

1Pre-erythrocytic cycle: period that starts when parasite is first introduced to the bloodstream until merozoites are released by liver schizont, and infect erythrocytes.
²Pre patent period: The interval between infection and the time that the malaria parasites are detectable in the peripheral blood.
³Incubation period: The interval between infection and the time that symptoms first appear.
⁴ Exo-erythrocytic cycle: After merozoites are produced in a hepatic schizont, merozoites reinfect liver cells and repeat schizogony.
⁵Erythrocytic cycle: The amount of time necessary for merozites to invade an erythrocyte, asexually reproduce inside of the erythrocyte, and burst the erythrocyte releasing more merozoites.
⁶Febrile paroxysm: One of the symptoms of malaria is periodic bouts of fever. The fever is related to the time of the rupture of a sufficient number of mature schizonts and subsequent discharge of merozoites into the bloodstream.
⁷ Recurrence: Plasmodium have been known to incubate inside of the victim's tissue for extended periods of time, causing disease months after infection with no symptoms in the interim.

Malaria is a multi-stage parasite that is spread through the female Anopheles mosquito vector. When a carrier female mosquito takes a blood meal, malaria sporozoites are released into the bloodstream from the mosquito's salivary glands. From the bloodstream, the sporozoites enter liver parenchymal cells. Because few sporozoites are transmitted to the host, they must quickly and efficiently target hepatocytes. While some evidence indicates that sporozoites are first trapped by Kupffer cells and then transported to hepatocytes, other findings suggest that sporozoites home to hepatocytes directly. Circumsporozoite (CS) protein, the primary protein antigen found on the surface of sporozoites, binds to the basolateral domain of hepatocytes. Other sporozoite surface proteins, such as sporozoite surface protein (SSP2), are believed to be involved in hepatocyte invasion. It is estimated that the blood circulation is clear of sporozoites in less than 60 minutes.  In the hepatocytes, the sporozoites undergo asexual amplification. In 1 to 2 weeks, a single sporozoite can give rise to 30,000 merozoites.  During this pre-erythrocytic stage, no illness is induced by malaria.

The liver schizont bursts, releasing the merozoites into the bloodstream where the beginning of the erythrocytic phase begins. The merozoites are extracellular for only 1-2 minutes before they rapidly invade erythrocytes. In the erythrocyte the merozoite goes through ring, trophozoite, and schizont stages. Again, asexual amplification occurs with as many as 36 merozoites being produced within one erythrocyte. When the erythrocytic schizont ruptures, the merozoites spill into the blood once again; it is during this phase that malaria-associated morbidity and mortality occurs. The merozoites continue in a repeated cycle of infecting erythrocytes, multiplying, and bursting the erythrocytes.

During this repeated cycle, some merozoites differentiate into male and female gametocytes. It is in this form where they can be taken up by the mosquito vector during a blood meal. Inside the mid-gut of the mosquito, fertilization occurs, producing zygotes, which develop into ookinetes. The ookinetes form oocysts which then grow and divides and rupture to give rise to sporozoites which migrate to the salivary glands. Then the infectious cycle of malaria can repeat itself.

 

PATHOLOGY

Much of the morbidity and mortality associated with malaria is caused by the rupture of iRBCs (infected red blood cells) during the asexual reproductive stages of the parasite. Intense fever, occurring in 24-72 hour intervals, is accompanied by nausea, headaches, and muscular pain among other symptoms. The characteristic fever spike has been correlated with incremental rises in serum levels of TNF-a associated with the release of parasite proteins during erythrocytic rupture. Furthermore, a variety of potentially fatal symptoms, including liver failure, renal failure, and cerebral disease are associated with untreated P. falciparum. These symptoms are consequences of the unique ability of the parasite to bind to endothelial surfaces; this adherence inhibits circulation and causes localized oxygen-deprivation and sometimes hemorrhaging. It has been proposed that ICAM-1, E-selectin, VCAM-1, and chondroitin sulfate A (CSA), and CD36 are some of the surface molecules responsible for parasite-endothelial adherence.

 

Marked edema of face and neck secondary to nephrosis. (M. King)  

 

 

IMMUNE RESPONSE

The immune response to malaria is not well understood. The presence of serum antibodies in individuals living in regions where malaria is endemic indicates that the immune system mounts a humoral response against the parasite. This immunity is strain-specific and can be lost if the individual migrates to a region where malaria is not endemic. Furthermore, the efficacy of the humoral response is limited by the intracellular tendencies of the parasite as well as its ability to alter its surface molecules through various maturational stages. The humoral response is bolstered by a variety of non-specific effector mechanisms. The presence of excess type-1 cytokines, including IFN-g , IL-2, IL-12, and TNF-a , has been confirmed in infected individuals. However, the ability of the infected to generate CTL activity is severely limited; the infected hepatocytes are the only cellular targets expressing the requisite class I MHC molecule.