Pathogenesis

Individuals with malaria typically acquired the infection in an endemic area following a mosquito bite. Cases of airport malaria and infection secondary to transfusion of infected blood are extremely rare. The risk of infection depends on the intensity of malaria transmission and the use of precautions such as bed nets, diethyl-meta-toluamide (DEET), and malaria prophylaxis. Pathogenesis of Malaria can be divided into 2 cycles in human which are exo-erythrocytic and erythrocytic schizogony.

i) Exo-erythrocytic schizogony: 

Sporozoites are injected into the subcutaneous tissue

travel to the liver either directly or through lymphatic channels. 

 They reach the liver in 30-40 minutes by brisk motility conferred by 

Circum Sporozoite Protein (CSP)

 

Approximately 8-15 (up to 100) sporozoites are injected 

and thus only a few hepatocytes are infected, 

therefore this stage of the infection causes no symptoms 

The co-receptor on the sporozoites which involve for invasion are the 

thrombospondin domains on the circumsporozoite protein 

and on thrombospondin-related adhesive protein (TRAP). 

These domains bind specifically to heparin sulfate proteoglycans on hepatocytes in the region in apposition to sinusoidal endothelium and Kuppfer cells. 

Within the hepatocyte, each sporozoite divides into

10000-30000 merozoites. 

This phase is called pre-erythrocytic schizogony (development of schizoint 

forms of the parasite before reaching the red blood cells) 

and takes about 10 - 15 days in P. vivax malaria 

and about 7-10 days in P. falciparum malaria.

 Following rupture of their host cells, escape into the blood and infect red blood cells, thus beginning the erythrocytic stage of the life cycle. The parasite escapes from the liver undetected by wrapping itself in the cell membrane of the infected host liver cell

Some P. vivax and P. ovale sporozoites produce hypnozoites that remain dormant for periods ranging from several months (6–12 months is typical) to as long as three years. After a period of dormancy, they reactivate and produce merozoites. Hypnozoites are responsible for long incubation and late relapses in these two species of malaria.

The parasite is relatively protected from attack by the body's immune system because for most of its human life cycle it resides within the liver and blood cells and is relatively invisible to immune surveillance. However, circulating infected blood cells are destroyed in the spleen. 

To avoid this fate, the P. falciparum parasite displays 

• adhesive proteins on the surface of the infected blood cells, causing the blood cells to stick to the walls of small blood vessels, thereby sequestering the parasite from passage through the general circulation and the spleen. 
• This "stickiness" is the main factor giving rise to hemorrhagic complications of malaria. 
• High endothelial venules (the smallest branches of the circulatory system) can be blocked by the attachment of masses of these infected red blood cells. 
• The blockage of these vessels causes symptoms such as icerebral malaria. In cerebral malaria the sequestrated red blood cells can breach the blood brain barrier possibly leading to coma.

ii) Erythrocytic schizogony:

 

At the completion of the pre-erythrocytic schizogony, 

the mature schizonts rupture the liver cells 

and millions of mature merozoites escape into the blood, 

wherein they infect the red blood cells. 

These merozoites continue to multiply within the red blood cells 

and mature into trophozoite and then erythrocytic schizont.

The matured schizonts will rupture and release millions of merozoites.

Haemolysis of the RBCs will lead to anaemia. 

Besides that, the release of the merozoites, parasites debris 

and endogenous pyrogens into the blood circulation 

will cause the malarial fever

Some merozoites turn into male and female gametocytes. 

Since the gametocytes are formed in the blood of the vertebrate host,

the vertebrate host is the definitive host of the disease

If a mosquito pierces the skin of an infected person, 

it potentially picks up gametocytes within the blood. 

Fertilization and sexual recombination of the parasite

occurs in the mosquito's gut

New sporozoites develop and travel to the mosquito's salivary gland, 

completing the cycle 

 Immunological basis of Malarial infections