Malaria

            Human malaria is caused by one or a combination of four species of Plasmodia:  Plasmodium falciparum, P. vivax, P. malariae, and P. ovale.  The disease caused by each species is different in terms of the way the species responds to drugs, behaves in the mosquito phase and behaves once inside the human (Kreier, 1980).  P. falciparum causes malignant tertian malaria, which causes death more often than the other species.  However, P. vivax remains in the body longer than P. falciparum, causing a more gradual health deterioration.  The course of vivax malaria, however, is more predictable than falciparum malaria.  P. malariae causes the third most common type of malaria in the world, although it grows slower than the other three species.  P. ovale causes the least common and least pathogenic malaria of the four human malaria species (Kreier, 1980).

            Other Plasmodia species cause malaria in other vertebrates.  In general, the species, and therefore the diseases caused by them, are different enough between humans and other vertebrates such that there is almost no transmission between humans and animals.  P. malariae can be found in chimpanzees, however, and although laboratory tests have proven that humans can be infected with simian malaria species, this has only been known to have occurred four times in nature (Kreier, 1980).

            Although there are different species of the malaria parasite, the basic life cycle of each follows the same basic pathway described below.  The life cycle of the malaria parasite begins in a female Anopheline mosquito where two gametocytes (sexually differentiated Plasmodium parasites) that were ingested by the Anopheline mosquito from the human host fuse to form the ookinete or egg.  The ookinete develops in the midgut of the mosquito and eventually breaks open, releasing sporozoites, which circulate through the mosquito, eventually arriving at the salivary glands where they can then be injected into a host when the mosquito next feeds.  This stage, which occurs within the mosquito, is called the extrinsic cycle. 

Once injected into the human host, the sporozoites move to the liver and enter liver cells where they asexually reproduce to form merozoites, which then spread through the blood and invade red blood cells.  Inside the red blood cells, the merozoites synthesize all the necessary components for the multiplicative production of more merozoites.  When full of merozoites, the red blood cell breaks open, causing fevers and the other symptoms of malaria.  Some of the merozoites differentiate into gametocytes that can start the cycle over again when another female Anopheline feeds on the infected host (Oaks et al., 1991).

            The human suffers from symptoms of malaria when the red blood cells that are infected with the parasites rupture and release merozoites into the human’s bloodstream.  The main symptom experienced by the malaria-infected human host is a fever or paroxysm which involves one-half to two hours of a cold shivering stage, a few hours of a hot stage and then two or more hours of sweating as the body temperature falls.  The length of the incubation period, the time between being bitten by an infected mosquito and experiencing a fever, depends on the species of the parasite.  For P. falciparum, the average incubation period is 11 days, whereas for P. vivax 14 days is average (Pampana, 1969).  The symptoms of malaria, in addition to fever, are chills, headache, malaise, weakness, hepatomegaly (enlarged liver), splenomegaly (enlarged spleen), and dehydration.  Malaria can also cause anemia, anorexia, nausea, vomiting, abdominal pain and diarrhea.  Deaths from malaria are normally caused by cerebral, renal, or pulmonary failure, or a combination of the three (Strickland, 1982).

            After the first fever attack, relapses occur with a pattern dependent on the species of the parasite.  Falciparum malaria has frequent relapses during the first few months, whereas vivax malaria has two patterns of relapse, the first period involves short-time relapses for two months beginning two weeks after the primary attack, followed by a latency period, and then, six to nine months later, long-term relapses.  This creates what appear to be two outbreaks of vivax malaria in the year, but the second is just the long-term relapse from the infections caused six to nine months earlier (Pampana, 1969).  The vivax parasite can therefore survive the winter in the human host, becoming active again when the mosquito vectors are likely to be alive and circulating (McMichael, 2000, personal communication).

            Morbidity and mortality from malaria also depends on the species.  P. falciparum causes the shortest infections, lasting ten months or less on average, but if not treated these infections can lead to death in up to 25% of cases.  Occasionally deaths due to P. vivax do occur, especially during epidemics and when infections are left untreated, and P. vivax causes death less frequently.  These infections last about two to four years on average (Pampana, 1969).

            Some individuals have genetic resistance to malaria.  In individuals who are heterozygous for sickle-cell hemoglobin, the internal environment of the red blood cells does not allow for the development of the merozoites (Wakelin, 1996).  Therefore red blood cells don’t rupture, thus  limiting transmission because more merozoites are not created in the red blood cells.  This person, although infected with malaria, does not suffer from its symptoms nor can the disease be spread from this person.  The Duffy antigen, which is expressed on the surface of the red blood cell, is necessary for P. vivax to enter the red blood cell and therefore people without this antigen are protected from vivax malaria.  The fact that many people in endemic areas are infected with the parasite but do not have the disease gives evidence to the existence of acquired immunity (Wakelin, 1996).  Much research is being conducted currently into the mechanisms of this acquired immunity to malaria in order to create a malaria vaccine.  It is this acquired immunity to malaria that limits the correlation between rates of morbidity and mortality, and malaria transmission rates (Brewster, 1999).

Acquired immunity does not last forever, because the parasites have a large diversity of antigens that vary between species, strains, stages, and during the course of an infection.  This means that a person may gain acquired immunity to one type of malaria, but can be infected by other strains that the immune system will not recognize (Wakelin, 1996).  By continued exposure to the malaria present in a population, a person can gain and maintain acquired immunity to changing strains, whereas people who leave a location and then return to it are no longer immune (Bradley et al., 1987).  Only by “exposure to multiple parasite variants circulating in the community” (Kabilan, 1997) can a person form an immunity across strains of the malaria parasite.

The ability of parasites to mutate, which limits the power of acquired immunity in humans, also gives the parasites the ability to resist anti-malarial drugs.  Once a parasite mutates into a form that can resist the effects of the drug, that form is naturally selected for as it rapidly multiplies and spreads from host to host (Oaks et al., 1991).  P. falciparum has become resistant to chloroquine in many parts of the world and there are now strains of multi-drug resistant P. falciparum  that were first discovered in Asia and may be spreading around the world (Kidson and Indaratna, 1998).  Malaria vectors have also proven to be resistant to many insecticides, including DDT (Sharma, 1996a).