Malaria

Malaria is an acute febrile illness caused by Plasmodium parasites, which are spread to people through the bites of infected female Anopheles mosquitoes

Malaria is one of the most common debilitating infections worldwide.

The WHO estimated that in 2015 there were 214 million new cases of malaria worldwide and more than 400,000 malaria related deaths, more than 90% occurring in Africa, and most of whom were children.

 Malaria is caused by

 five species of Plasmodium parasites that infect humans :

P. falciparum, P. vivax, P. ovale, P. malariae, P. knowlesi  

(a simian parasite that causes human malaria primarily in Malaysia), although two species account for the most cases and deaths.

Plasmodium falciparum is the most prevalent in Africa and accounts for most fatalities.

P. vivax is the primary cause of malaria outside of Africa it's Symptoms are severe flulike in nature and with less morbidity and mortality than observed with P.falciparum.

The signs and symptoms of Malaria

§  severe chills

§  high fever

§  sweating

§  headache

§  muscle pains

§  vomiting

§  Fatigue

§  severe anemia

§  Rapid breathing

§  Rapid heart rate

§  Cough

All forms of malaria are characterized by paroxysm (cyclic chills followed by fever).

 Cycles range from every 2 days for P. vivax to 36 hours for P. falciparum.

Complications of Malaria

Neurologic complications may result from infected red blood cells (RBCs)

adhering to endothelium in capillaries of the brain causing hypoxia and degradation of neural tissue.3 The most severely affected individuals may develop cardiovascular collapse, shock, coma, and death.

Pathophysiology of Malaria

The life cycle of Plasmodium requires two hosts:

Mosquito and human.

The parasite undergoes a sexual reproductive cycle in the salivary gland of the female Anopheles mosquito and is transmitted to humans during a blood meal.

The infectious form (sporozoite) enters the tissue and migrates to the bloodstream.

The sporozoite has the capacity to traverse through cells in the tissue, mediated by a variety of parasitic proteins that bind to specific substance on the cell surface and facilitate entry.

4 The parasite enters hepatocytes using sporozoite proteins that bind to sulfated molecules on endothelial cells and Kupffer cells.

Protection against malaria

 may occur by means of stage-specific immune responses against different phases of the life cycle:

Invasive stage, hepatic stage, pre-erythrocyte stage, erythrocyte stage, and sexual stages.

Phagocytic cells, like Kupffer cells, are the primary means of protection against the prehepatic invasive stage and hepatic stage. Traversal of phagocytic cells results in modulation of the cell's cytokine profile, causing decrease  regulation of proinflammatory cytokines and increase regulation of antiinflammatory cytokines blocked production of reactive oxygen species, and reduced expression of class I MHC to suppress antigen presentation.

The parasite in the blood avoids destruction by phagocytes in the spleen by expressing adhesion proteins that cause adherence and sequestration along the walls of

the small vessels.

Sequestration in the liver begins an asymptomatic stage during which several rounds of multiplication occur.

P. vivax and P. ovale can remain dormant in the liver for years, protected from the

immune system by intracellular residence. In the hepatocytes, the parasites transform to the merozoite form, thousands of which are released into the blood during hepatocyte rupture and infect erythrocytes.

The blood-borne phase and infection of erythrocytes begin the

symptomatic stage of the disease P. falciparum uses a  variety of parasite surface proteins (e.g., merozoite surface protein-1 [MSP-1]) for adhesion to erythrocyte membrane glycophorins and entrance into the cell.

Symptoms of malaria occur after an approximate 2-week period from the initial mosquito bite and are the result of asexual multiplication in the erythrocytes and cell lysis upon the release of daughter parasites that reinfect other erythrocytes. During this erythrocytic cycle, the merozoites mature into male and female gametocytes within the erythrocyte, which after another blood meal can establish another cycle of further sexual multiplication in the mosquito vector. The erythrocytic cycle will resolve, but many relapses will occur upon new cycles of merozoite release from infected hepatocytes

P. vivax seems to use the erythrocyte Duffy antigen for adhesion. Thus individuals who are negative for the Duffy blood group antigen are naturally resistant to P. vivax malaria.

During the erythrocytic cycle, the infected individual produces protective antibodies against antigens expressed on the surface of infected erythrocytes. Plasmodium expresses several families of antigens on the erythrocyte's surface and uses antigen variation through gene switching diversity to mitigate the effects of antibody. 

Other antigen-directed responses contribute to protection of the parasite. Antibodies against P. falciparum asparagine-rich protein enhance merozoite invasion of erythrocytes, which is further facilitated by the addition of complement. The PfEMP1 antigen also can protect the infected erythrocyte by epitope masking. The antigen contains Fc binding sites where IgM antibody, regardless of specificity, is bound by its Fc region, thus masking the PfEMP1 epitopes. Parasites also can bind complement regulator factor, factor H, which protects the parasite from damage by activated complement factors.

Malarial infection also may induce immune suppression by inhibiting macrophage and dendritic cell phagocytosis, as well as inducing apoptosis of antigen-presenting cells. Phagocytic cell function is diminished by a malarial pigment (hemozoin), which is taken up and reduces the ability to phagocytize merozoites or infected erythrocytes. Numbers of CD4 and CD8 T-cells are diminished by apoptosis combined with induction of immunosuppressive Treg cells. Malarial parasites have developed broad drug resistance including against chloroquine, the previous mainstay of the preventive and therapeutic arsenal of antimalarial drugs. Drug resistance appears to result from increased activity of drug transporters that eliminate the drugs from the parasitic microorganism.