Malaria is caused by the parasite Plasmodia,

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Evolution of Disease (Pathophysiology)

Malaria is caused by the parasite Plasmodia, and it is spread by the

vector, the female anopheles mosquito.

 

 

 

Host factors:

 

Some patients are at special risk for developing malaria. These

include patients with no immunity against malaria - infants and

unexposed individuals and patients who have lost the acquired immunity

like pregnant ladies, elderly and people who have left the area of

transmission. Also it has been observed that certain inborn defects in

the blood hemoglobin offer some sort of a protection against either

clinical attacks of malaria or its complications. The exact mechanism

of this protection is not well understood. However, many possibilities

have been suggested.

 

1.

 

People of West African origin are strikingly non-susceptible to

P. vivax infections. It has been found that P. vivax merozoites

penetrate the red cells after binding to the Fya and Fyb receptors,

which are the Duffy blood group antigen alleles. In the West African

population, this blood group antigen is an extreme rarity and this

explains the phenomenon.

2.

 

The sickle cell trait (heterozygous state) has been found to

confer protection against the complications of P. falciparum malaria

(at a ratio of 1:10 compared to non-sickle cell children, in a

controlled study). Decreased availability of oxygen in the presence of

abnormal hemoglobin, faster clearance of sickled cells by the spleen,

decrease in the intracellular pH, leakage of potassium, rigidity of

cell membrane in the presence of Hb S may all contribute to the

resistance.

3.

 

Hemoglobin F also has protective effects against severe malaria.

In beta thalassemia, fetal hemoglobin levels are high.

4.

 

In Melanasian ovalocytosis, the rigid membrane of the red cells

prevents entry of the parasites.

 

Pathophysiology:

 

Pre-erythrocytic schizogony: Sporozoites are injected by the mosquito

into the subcutaneous tissue (less frequently directly into the

bloodstream) and 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 therefore only a few

hepatocytes are infected, therefore this stage of the infection causes

no symptoms (rarely however a prodromal illness characterised by vague

aches and pains, headache, nausea etc. may be present). Recent

evidence indicates that sporozoites pass through several hepatocytes

before invasion. The co-receptor on sporozoites for invasion involves,

in part, 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, meaning

development of schizoid forms of the parasite before reaching the red

blood cells. This phase takes about 10 - 15 days in P. vivax malaria

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

 

Erythrocytic schizogony: At the completion of the pre-erythrocytic

schizogony, the mature schizonts rupture the liver cells and escape

into the blood, wherein they infect the red blood cells. These

infective forms are called merozoites and they continue their growth

and multiplication within the red blood cells. In P. vivax malaria,

the young red blood cells are predominantly infected, while in P.

falciparum malaria, red blood cells of all ages are affected. Thus the

infective load and severity of infection are more in case of P.

falciparum malaria.

 

The sequence of invasion into red cells

 

Engage receptors on RBC for binding: Duffy for P. vivax, many for P.

falciparum

 

dnar.gif (1209 bytes)

Apical re-orientation

dnar.gif (1209 bytes)

 

Junction formation

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Signaling

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Vacuole formed from the RBC plasma membrane

dnar.gif (1209 bytes)

Enters the vacuole by a moving junction

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?Cleavage of a RBC surface protein by a parasite serine protease

 

 

The sequence of invasion is probably similar for all Plasmodium spp.

The merozoite first attaches to red cells. In P. falciparum,

Erythrocyte Binding Antigen 175 and Merozoite Surface Protein 1, 2

with sialoglycoproteins have been identified as the ligands and in P.

vivax, Duffy antigen on RBC is the site of binding. After the

attachment to the red cell, the merozoite reorientates itself so that

apposition of apical end occurs. This is followed by localized

invagination and interiorization of the merozoite. The entire process

is completed in 30 seconds.

 

The growth and multiplication cycle within the RBCs (Erythrocytic

schizogony) takes about 48 hours for one cycle (72 hours in case of P.

malariae). Each merozoite divides into 8-32 (average 10) fresh

merozoites. The merozoites grow in stages into rings - trophozoites

(trophos = nourish) and divide in a Schizont(=split) to release more

merozoites (mero = separate). At the end of this cycle, the mature

schizonts rupture the RBCs and release the new merozoites into the

blood, which in turn infect more RBCs.

 

The parasite has complex metabolic processes: It utilises amino acids

from hemoglobin and detoxifies heme; pLDH, Plasmodium aldolase have

been identified as enzymes of anerobic glycolysis. It has been found

that the parasites increase the permeability of RBC to get nutrients,

yet maintain the RBC structure for 48 hours. strengthened by RESA,

allowing tthe immature parasite to survive. At the end, RBC ruptures

and each schizont releases 6-36 merozoites

 

Merozoite's Nutrition in RBC: The parasite ingests hemoglobin from RBC

to form a food vacuole where it is degraded and heme is released. The

toxic heme is in turn detoxified by heme polymerase and sequestrated

as hemozoin (malaria pigment). (Many of the antimalarial drugs act by

inhibiting heme polymerase thereby causing accumulation of toxic heme).

 

All the clinical features of malaria are caused by these developments

in the blood. The growing parasite progressively consumes and degrades

intracellular proteins, principally hemoglobin, resulting in formation

of the 'malarial pigment' and hemolysis of the infected red cell. This

also alters the transport properties of the red cell membrane, and the

red cell becomes more spherical and less deformable. The rupture of

red blood cells by merozoites releases certain factors and toxins

(such as lycosylphosphotidylinositol anchor of a parasite membrane

protein, phospholipoprotein, RBC membrane products, protease sensitive

components with hemozoin, ? malarial toxins etc.), which could

directly induce the release of cytokines such as TNF and interleukin-1

from macrophages, resulting in chills and high grade fever. This

occurs once in 48 hours, corresponding to the erythrocytic cycle. In

the initial stages of the illness, this classical pattern may not be

seen because there could be multiple groups (broods) of the parasite

developing at different times, and as the disease progresses, these

broods join and the synchronous development cycle results in the

classical pattern of alternate day fever. It has been observed that in

primary attack of malaria, the symptoms may appear with lesser degree

of parasitemia or even with submicroscopic parasitemia. However, in

subsequent attacks and relapses, a much higher degree of parasitemia

is needed for onset of symptoms. Further, there may be great

individual variations with regard to the degree of parasitemia

required to induce the symptoms.

 

pvgr.jpg (14524 bytes)

 

 

The progeny from a single parasite in the liver could destroy all the

host's RBCs within 12-14 days!

 

In case of P. vivax infection, the parasitemia is limited by

exhaustion of suitable red cells, specific and non-specific immune

response, destruction of meronts by high fevers and splenic clearance.

 

Limited parasitemia in P. vivax

 

 

In P. falciparum infection, the available red cell numbers are higher

as red cells of all ages are infected and the parasitised red cells

escape from destruction by sequestration. The P. falciparum has better

skills for attack and can enter most RBCs, has plenty of redundant

receptors and pathways and hence higher parasitemia. It also has

better skills for survival: the parasite constantly changes itself

with 2% antigenic variation, it changes the RBC structure by producing

sticky Knobs on the surface, it changes the immune response by numbing

the dendritic cells and hides in deeper tissues by sequestration.

 

 

pfgr.jpg (18843 bytes)

Higher parasitemia in P. falciparum

 

P. falciparum malaria is characterised by development of sticky knobs

on the surface of red cells, adhesion of red cells to the endothelial

cells of post-capillary venules and formation of rosettes with

uninfected cells.

 

Cytoadherence is mediated by strain specific, high MW P. f Erythrocyte

Membrane Protein 1 (PfEMP 1) that is exported to the surface of

infected erythrocyte and anchored through the membrane to a

sub-membranous accretion of parasite derived histidine rich protein

(Pf HRP). These accretions cause humps or knobs on the surface of the

red cell and these are the points of attachment to vascular

endothelium. Some parasites are knob negative and yet show

cytoadehrence. A protein called sequestrin has also been identified

recently. Altered red cell membrane components may also play a role.

Cytoadherence may be modulated by the spleen and cytoadherence does

not occur after splenectomy.

 

On the endothelium, Leukocyte differentaiting antigen CD36,

intercellular adhesion molecule 1 (ICAM1), Thrombospondin, VCAM and

ELAM have been idenbtified as binding proteins. TNF upregulates

binding to ICAM 1 (not CD36) and binding is higher at low pH and high

calcium levels. ICAM 1 is abundant in brain microcirculation and CD36

elsewhere.

 

Rosetting is adherence of parasitised red cells with uninfected red

cells. It is independent of venular cytoadherence and exhibits 5 times

stronger adhesion than cytoadherence. Rosetting causes higher

microvascular obstruction than cytoadherence and is associated with

cerebral malaria (cytoadherence with other vital organ damage).

Rosetting reduces blood flow, encourages cytoadherence to endothelium,

enhances anerobic glycolysis and reduces the pH.

 

As the parasite matures, flexible biconcave disc becomes progressively

more spherical and rigid. Reduced membrane fluidity, increasing

sphericity, enlarging and relatively rigid intra-erythrocytic

parasites make the red cells less filtrable and cause obstruction at

mid capillary level itself.

 

Unbridled cytoadherence-rosetting-sequestration results in poor tissue

perfusion, organ dysfunction, anerobic glycolysis in tissues and

lactic acidosis, malfunctioning of dendritic cells and T cells due to

CD36 binding. While low levels of cytokines may be beneficial, high

levels are found to be harmful, contributing to placental dysfunction,

suppression of erythropoeisis, inhibition of gluconeogenesis and

increased cytoadherence.

 

Exo-erythrocytic schizogony: In P. vivax and P. ovale, some

exo-erythrocytic forms remain as single celled dormant forms called

hypnozoites. This helps them to survive in temperate countries. These

hypnozoites can get re-activated once in 3-6 months to cause

`relapses'. This phase of the infection is called as exo-erythrocytic

schizogony. In P. falciparum and P. malariae infections, relapses from

the liver do not occur; however, the blood infection may remain

chronic and, if untreated, may remain for years in case of P.

falciparum and decades in case of P. malariae.

 

Some of the merozoites in the blood transform into sexual forms,

called as gametocytes. These appear in the peripheral blood after 7-10

days of the infection in P. vivax and 10-20 days in P. falciparum

infection. When anopheles mosquito bites an infected individual, these

gametocytes enter the mosquito and continue their sexual phase of

development within the gut wall of the mosquito. This completes the

asexual - sexual cycle of the malarial parasite.

 

See Weatherall DJ, Miller LH, Baruch DI et al. Malaria and the Red

Cell. Hematology 2002. Available at

http://www.asheducationbook.org/cgi/content/full/2002/1/35

 

 

 

 

Life Cycle

 

 

Pathology

 

 

Dr. B.S. Kakkilaya's Malaria Web Site

Last Updated: April 14, 2006

 

B. S. Kakkilaya 2006-2008

malariasite.com 2006-2008