Malaria as well as the Immune System
Approximately 300 million of the world’s population is suffering from a quiet life threatening parasitic disease (Roll Back Malaria, 2001). Between 1 and 1.5 million people, most of whom are children, die from this disease every year (World Health Organization, 2003). While female mosquitoes of the Anopheles genusare not aware that they are accomplices to this disease, they carry the culprits responsible for the epidemic we recognize as malaria. Malaria is an acute and chronic disease caused by protozoa of the genus Plasmodium. There are four species that cause human malaria: P. vivax, P. malariae, P. ovale, and P. falciparum (Roll Back Malaria, 2001).

Among the four species, plasmodium vivax is the most common malaria parasite as it is the most geographically widespread of the species. It is not as severe as the others but relapses can occur for up to 3 years with debilitating effects in chronic disease. Plasmodium malariae on the other hand, produces typical malaria symptoms characterized by spells of fever, chills, and weakness, and can persist in the blood for decades without ever producing symptoms. As for plasmodium ovale, it is rarest form and generally occurs in West Africa. The most notorious species of them all is plasmodium falciparum. This is the most lethal form of malaria infection and is responsible for most malaria deaths (National Institutes of Health, 2003). Researchers everywhere turn to this species to learn everything they can about malaria and its devastating impact on immunity. If left untreated, plasmodium falciparum can lead to death by anemia through infection and destruction of red blood cells, or by clogging capillaries that carry blood to the brain and other vital organs, ultimately resulting in cerebral malaria (Roll Back Malaria, 2001).

Infection & Malaria Lifecycle:

Malarial infection takes place when an Anopheles mosquito carrying the malaria parasite takes a blood meal. Once injected into the human host in the form of sporozoites, the plasmodium parasite circulates in the bloodstream finding its way into the liver where it can begin to multiply furiously without being detected. During this period, the parasite prolongs its survival by quickly attaching to and entering red blood cells (Malaria Vaccine Initiative, 2003). Malaria-infected red blood cells disable dendritic cells and prevent them from launching an effective attack against the infection. While hiding inside the red blood cell host, they are protected and shielded from detection by the human host’s immune system and continue to form daughter parasites, known as merozoites, without causing any detectable symptoms. Finally, after 48 hours the infected red blood cells burst releasing the merozoites into the bloodstream (Marsh, 2003) where they wait for another mosquito to transfer them to their next human host to repeat the whole cycle once again.

Malaria’s Impact on Immunity:

Once a person is bitten and infected, it is only a matter of time before the individual experiences the parasite’s wrath. Symptoms usually appear in three stages: chills, followed by fever, and then sweating. Signs of malaria first begin to emerge 10 to 16 days after the mosquito bite, the same time which red blood cells are bursting. The infected person starts to experience chills, along with headache, nausea, and vomiting. Within an hour or two, the person’s temperature rises, and the skin feels hot and dry. Then, as the body temperature falls, drenching sweat begins. Eventually, the person grows tired and weak and is likely to fall asleep (National Institutes of Health, 2003).

Malaria symptoms can reappear at regular time periods. With P. vivax malaria and P. ovale malaria, attacks recur about every two days, and for P. malariae they recur every three days. In between attack from P. vivax malaria, it is actually not surprising for patients to appear in good health and show no symptoms. Even without treatment, the symptoms can subside in a few weeks. A person with P. falciparum malaria, however, is likely to feel miserable even between attacks and, without treatment, may die. The reason why P. falciparum malaria is so powerful is due to the parasite’s ability to infect red blood cells in all stages of development. As a result, very high parasite levels are found in the blood. In contrast, P. vivax parasites infect only young red blood cells, leading to lower parasite levels in the blood that do not reach the same high levels as seen in P. falciparum infection (National Institutes of Health, 2003).

With advancements of the electron microscope technology improving, we are able to carry out more extensive observations of the complicated life cycle and structure of malaria parasites. There is still a great deal of mystery left as to the impact and effect these parasites leave on the human immune system. We know that our immune system has an array of protective cells working to shield the body and attack any recognized foreign invaders; some of these protective cells work in the innate immune system functioning as the first line of defense, while others work in other parts of the immune system using powerful specific weaponry for combating the parasite.

Cell-Mediated Immunity (Inflammatory Mediators):

In attempts to combat disease, the human body has organized an army of neutrophils, mononuclear phagocytes, T cells, and natural killer (NK) cells. These cells all have certain roles in immunity which include use of NK cells for macrophage activation, inhibition of merozoite invasion of erythrocytes via antibodies, and phagocytosis of parasite-infected erythrocytes by means of the cytokine network (Perlmann & Troye-Blomberg, 2002, p. 230, 232, 235). When T cells produce Th1-derived interferon (IFN-) for phagocytosis, nitric oxide (NO) is released carrying anti-parasitic effects. In fact, high concentrations of nitric oxide appear to have deadly effects on P. falciparum parasites in vitro. However, at lower concentrations, after nitric oxide is depleted, the parasites survive and resume normal development. Nitric oxide has also been noted to interfere with neurotransmission, thus leading to cerebral malaria. Conversely, in vivo data seems to contradict these findings demonstrating no indication of nitric oxide in parasite eradication or initiation of cerebral malaria (Artavanis-Tsakonas, Tongren, & Riley, 2003, p. 145-146).

In severe cases of malaria, high levels of inflammatory cytokines such as tumor necrosis factor- (TNF- ), interleukin-1 (IL-1), and IL-6 are produced. Cytokines serve as the regulators of immune response. TNF- is a primary cytokine which serves in protection and malarial pathogenesis. The major sources of TNF- are found from activation of monocytes and macrophages by various parasite products. Recent evidence obtained from experimentation with mice suggests that overproduction of lymphotoxin-(LT- ) rather than TNF-leads to cerebral malaria. According to this study, deficiency in TNF- increases susceptibility to cerebral malaria while deficiency of LT- shows increased resistance. On a clearer note, the major role of TNF-lies in parasite killing. At low concentrations, TNF-is anti-parasitic and works collectively with IFN- to generate production of nitric oxide for cytotoxic functions. Therefore, this leads us to believe that overcoming malaria infection and its associated symptoms relies on acquiring an ideal level of TNF- in addition to other inflammatory cytokines (p.146).

In contrast to TNF- , IFN- is of pathologic significance due to its ability to activate macrophages and lyse infected host erythrocytes as well. Moreover, studies in mice have shown that IFN- is necessary for cerebral malaria to develop. Interestingly, researchers have learned that peripheral blood mononuclear cells (PBMC) are efficient producers of IFN- when triggered with sporozoite or merozoite (daughter parasite) antigen peptides taken from children with severe disease rather than children with mild disease. This reveals that there is a connection between antigen-specific IFN- production and reduced pathology (p. 146).

Susceptibility to Malaria Disease:

When non-immune, malaria-naïve, individuals travel to areas where malaria is endemic, the chances of infection increase with age. However, there is significant evidence point out that while adults develop anti-parasitic immunity faster than children (Taylor-Robinson, 2003), malaria seems to hit adults harder and so they are more prone to severe clinical pathology or even death (Riley, 2003). A likely explanation for this is that in these areas where mosquito-human transmission of P. falciparum is intense, almost all of the children there have parasites in their blood so their bodies have developed a type of “semi-immunity” allowing them to resist malaria without experiencing any of its associated illnesses. However, the fact that some children do become ill with malaria while others manage to resist suggests that some parasites are tolerated better than others. In some cases, resistance to malaria can take more than decades to reach maximal protection. Hence, this may indicate that malaria antigens which induce protective immune responses may be poorly immunogenic (Taylor-Robinson, 2003).

Studies reveal that T cells cultured in vitro with P. falciparum antigens respond by proliferation and secretion of cytokines as seen with the major histocompatibility complex (MHC) II (Taylor-Robinson, 2003). Proliferated cells are recognized as either TCR⁺ T cells or TCR⁺ T cells. The former responds to both live and dead parasite antigens while the latter responds only to live parasites. Despite differences, both cell types have been shown to secrete IFN-. In early phases of parasite infection, TCR ⁺ T cells expand and contribute to innate parasite control. TCR ⁺ T cells make considerable amounts of IFN-and although they do not function in protecting the human host from infection or disease, IFN-must be closely regulated in order to steer clear from infection and avoid detrimental effects (Artavanis-Tsakonas, Tongren, & Riley, 2003, p. 146-147).

Innate Immunity:

Glycosylphosphatidylinositol (GPI) anchors are forms of glycoprotein and glycolipids of merozoite membrane proteins. They are released as a consequence of the rupturing of erythrocytes and in turn, trigger macrophages to produce low levels of TNF- . However, in the presence of mononuclear cells such as CD3+ T cells, the levels of TNF- significantly rise. This change leads to the fact that in addition to GPI, macrophages need a secondary stimulus to become fully activated to product TNF- . This secondary stimulus has been identified as IFN-(p. 147).

P. falciparum can induce rapid IFN-and TNF-responses within 12 hours. TCR⁺ T cells may contribute to the early IFN-response. In many malaria-naïve individuals, IFN-production takes place within 18 hours of in vitro stimulation of PBMC with intact erythrocytes housing plasmodium. This early supply of IFN-is provided by NK cells which are also backed up by ⁺ T cells to release IFN-. There are some individuals who have trouble activating their NK cells to secrete little, if any, IFN-. Those who fall in this category also fail to produce IFN- by ⁺ and ⁺ cells, which means that NK cells seem to act as the designated cells that initiate inflammatory response (p. 147).

Initiating inflammatory response through NK activation requires receptors IL-12 and IL-18 from monocyte-macrophages or dendritic cells. There is data confirming that parasitized erythrocytes attach to immature dendritic cells. This in turn, causes inhibition of dendritic cell maturation, prevention of IL-12 production and switching to IL-10 production, and reduction of T cell reproduction response. This inhibition of inflammatory cytokine responses is most likely due to the parasites efforts to aid its own survival (p. 147).

Humoral Immunity:

Malaria infection generates strong immune responses brought about by the production of mainly IgM and IgG but includes other immunoglobulins as well. Even though most immunoglobulins carry no specificity to malaria, species-specific antibodies react with various types of parasite antigens. The significance here is that this enables parasites to use this variability to evade immune response (Perlmann & Troye-Blomberg, 2002, p. 231).

From what researchers already know, parasite antigens found on the surface of infected erythrocytes are encoded by highly variant gene products or polypeptides known as P. falciparum erythrocyte membrane protein 1 (PfEMP-1). These polypeptides hold numerous binding sites used for adhesion to infected erythrocytes. This adhesion serves to protect the parasites from detection and destruction in the spleen.

To neutralize parasites in vitro, the most protective and efficient antibodies that prevail are IgG. More specifically, IgG1 and IgG3 are the most frequent isotypes found to overcome parasites. However, there is notion that high levels of IgG2 antibodies may have some relation to decreased risk of malaria infection (p. 231-232). Furthermore, IgE and IgE anti-malarial antibodies also play a role in malaria infection. When IgE and IgE anti-malarial antibodies come into play, regulatory T cell activities cease Th1 and switch over to Th2 in cases where the immune system has already encountered the parasite before. Usually with Th1 and Th2, one functions to protect while the other promotes manifestation. However, it does not work that way with the malaria parasite (p. 232). In this case, both actually share the task of protecting the host using different mechanisms and each coming to play at a given time or stage of the infection (Taylor-Robinson, 2003) Nevertheless, IgE increase is dependent on other factors such as genetic control. Research shows that patients with severe or cerebral malaria have higher IgE levels which are also linked to higher blood concentration, than seen in those with less severe or uncomplicated malaria. One proposed reason for this IgE effect is from the overproduction of TNF-and nitric oxide which result from immune complexes containing IgE. Despite this, researchers have not excluded the possibility of protective functions in IgE antibodies (Perlmann & Troye-Blomberg, 2002, p. 232).

Combating Inflammation:

The severity of infection with malaria depends heavily on the levels of IFN- and TNF- . As long as the immune system is capable of properly regulating the production of pro-inflammatory cytokines at a moderate level while avoiding severe pathology, then clinical immunity is achieved. Studies indicate that certain antibodies to malarial GPI block TNF- generation from macrophages in order to regulate inflammatory response. Two recent studies with mice had very limited evidence that naturally obtained antibody responses for anti-GPI contribute to resistance. On the other hand, another supported hypothesis suggests that pro-inflammatory (Th1/ IFN-) response would switch to an anti-inflammatory response via cytokines TGF-or IL-10. However, some infected mice were observed to produce large amounts of TGF-and managed to completely suppress inflammatory cytokine response. This ultimately led to parasite growth and death resulting from anemia. The same would come about from administering high doses of TGF- externally. Therefore, the role of TGF-, and IL-10, response is critical and its timing and levels determine the results. High levels achieved too early in infection would compromise cell-mediated effector mechanisms while low levels that are delayed in infection would risk failure in regulating inflammatory cytokine response (Artavanis-Tsakonas, Tongren, & Riley, 2003, p.147-148, 150).

There is strong evidence emphasizing the importance of cytokine stability and balance in order to fight malaria infections without causing severe damage to the human host. A procedure performed on the brain tissue of a patient who died from cerebral malaria showed localized build up of TNF- , IFN-, and IL-1 possibly related to parasite-infected erythrocytes, lymphocytes, and monocytes. Reports on Vietnamese adults diagnosed with severe malaria imply a link with organ failure due to increased plasma concentration of inflammatory cytokines. Conversely, those who died showed lower plasma concentration levels. In another study involving the correlation of pro-inflammatory and anti-inflammatory cytokine responses, researchers of learned that that elevated ratio’s of IFN-, IL-12 or TNF- , to TGF- reduce the risk of infection. Overall, these facts suggest that anti-inflammatory cytokines are essential in controlling the concentration of pro-inflammatory cytokines in order to avoid the detrimental effects of high concentrations. Equilibrium must be achieved between the pro-inflammatory cytokines working to contain the parasite and inhibit its growth and development, and the anti-inflammatory cytokines working to control disease manifestation (p. 150).

Anti-Malarial Immunity:

One interesting hypothesis states that infants living in endemic populations and are malaria infected produce low levels of IFN- and TNF- . This in turn results in nominal clinical symptoms and removal of the parasite via immunologically or as a consequence of the parasites inability to thrive in the infected host. If re-infected, T cells that have been previously exposed with malaria would generate greater amounts of IFN- which would collaborate with malarial GPI to increase TNF- production and consequently escalating the risk of cerebral malaria. Clinically immune individuals would be able to remove the infection without having to worry about the dangers of inflammatory cytokine overproduction. Therefore, the chances of severe disease rely on the swiftness of anti-malarial immune response to develop and launch their different components to attack (p. 150).

On the other hand, individuals who are not immune and travel to an endemic population where they end up contracting malaria have no outlet. Their immune response is weak and so they wouldn’t have any control over their infections. The most they can probably do is rely on their innate immune response to provide some measure of protection and relief (p. 150). When taking all relevant factors into consideration, it is apparent that there are several implications that prevent proper vaccine development. Thus far, the malaria parasite has been advantageous in resisting current drug treatments thanks to its complex lifecycle. Even so, Th1-derived IFN- producing T cells are clearly important for phagocytosis and elimination of the malaria parasite, but they must be induced in a controlled, stable, site-specific manner in order for them to overcome the parasite.

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