Malaria

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What causes malaria?    

Picture: Plasmodium Source

Answer:

A protistan parasite (Genus: Plasmodium)

What is the vector for human parasitization?

Picture: Anopheles Source

Answer:

The female Anopheles mosquito

Plasmodium

Four species cause malaria in humans

P. falciparum (80% of infections; 90% of deaths)

P. vivax

P. ovale

P. malariae

Plasmodium Life Cycle                

Picture Source

When a mosquito wants a blood meal it penetrates the host’s skin, injects saliva, anticoagulant and 10-100 sporozoites.  Within 30 minutes, the sporozoites travel to the liver and enter the liver cells.  There, the sporozoites undergo schizogony, asexual division (lasts 2-10 days), and generate merozoites (10s of 1000s of these).  The merozoites invade other liver cells, enter bloodstream, and invade erythrocytes (RBCs).

In RBCs, merozoites enlarge into a uninucleate cell called a ring trophozoite.  The nucleus asexually divides to produce a schizont.  The schizont divides and produces 20-30 new multi-nucleated merozoites. 

The merozoites use an aspartic acid protease (plasmepsin) to degrade hemoglobin.  This causes the RBCs rupture and release toxins – resulting in the characteristic waves of fever/chills. Some merozoites develop into gametocytes which produce gametes; those RBCs do not rupture.  Finally, the gametocytes are extracted by mosquito.  Gametes are produced in the gut of the mosquito (they cannot be formed in humans).  The diploid zygotes develop in intestinal walls and differentiate into oocysts.  The subsequent mitotic divisions in oocysts produce many sporozoites.  The sporozoites migrate to salivary gland of mosquito, and the cycle continues...

Picture: RBCs infected with P. vivax  Source                                                                                             

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How is the immune system evaded?

Trojan Horse Mechanism

• merozoites hide in merosomes (dead liver cells) and release “cloaking chemicals” so that the body doesn’t clean up those dead cells like it should

 Adhesive surface proteins (PfEMP1)

• P. falciparum displays 60+ variations of PfEMP1 on surface of infected RBCs

• PfEMP1 stick to walls of vessels and prevents travel to spleen (where they would have been destroyed)

 Anopheles mosquito

• 400 species

• 30-40 transmit the four Plasmodium species

• Anopheles gambiae best known

  • transmits P. falciparum

  • infects large proportion of RBCs (10x others) adheres to walls of blood vessels

 Anopheles and malaria transmission

Anopheles is innately susceptible to Plasmodium.  Anopheles is also anthropophilic, which means they prefer to feed on humans.

A. gambiae and A. funestus

Anopheles survive longer than required Plasmodium incubation period

Current Research

A. gambiae

In lab, strains are selected that have an immune response to parasites.  That mechanism involves the mosquito encapsulating and killing the parasites once in the mosquito’s intestinal wall.  Scientists are studying this mechanism with the thought of replacing wild mosquitoes.

Evolutionary pressure of malaria on human genes

High levels of mortality/morbidity especially associated with P. falciparum

Sickle-cell anemia

Picture: Sickle-cell on left, normal RBC on right Source

• mutation in a gene (HBB) that codes for a hemoglobin subunit (valine for glutamate)

• normal allele = HbA; Sickle-cell = HbS

• heterozygotes (HbA/HbS) have malaria protection

• 10% sustained frequency of allele

 Duffy antigens

• chemokine receptor on RBCs

• carriers completely immune to P. vivax

Picture: Duffy antigen's resistance cycle Source

• carriers lack receptor on RBC membrane

• rarely found in white populations

• found in 68% of black people

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