DƯỢC LÍ Goodman & Gilman's The Pharmacological Basis of Therapeutics 12th, 2010

1384 hepatocyte infection as a dormant form of the parasite
known as the hypnozoite. Consequently, P. vivax and
P. ovale can reinitiate symptomatic disease long after
the initial symptoms of malaria are recognized and
treated. Erythrocytic forms cannot reestablish infection
of hepatocytes.
Transmission of human-infecting malarial parasites
is maintained in human populations both by the
extended persistence of hypnozoites (lasting from
months to no more than a few years for P. vivax and P.
ovale), by antigenic variation in P. falciparum (probably
months), and presumably by antigen variation in P.
malariae (for as long as several decades) (Vinetz et al.,
1998).
The asexual erythrocytic stages of malarial parasites
are responsible for the clinical manifestations of
malaria. This part of the Plasmodium life cycle is initiated
by merozoite recognition of red blood cells, mediated
by cell surface receptors, followed by red blood
cell invasion. Once inside a red blood cell, the merozoite
develops into a ring form, which becomes a
trophozoite that matures into an asexually dividing
blood stage schizont. Upon rupture of the infected erythrocyte,
these schizonts release 8-32 merozoites that
can establish new infections in nearby red blood cells.
The erythrocytic replication cycle lasts for 24
hours (for P. knowlesi), 48 hours (for P. falciparum, P.
vivax, and P. ovale), and 72 hours (for P. malariae). As
such, infections due to P. vivax and P. ovale can produce
tertian fever patterns (48 hours), whereas those
due to P. malariae can result in quartan fever (72 hours,
as classically described in Hippocrates’ Epidemics).
Although most invading merozoites develop into schizonts,
a small proportion become gametocytes, the
form of the parasite that is infective to mosquitoes.
Gametocytes are ingested into the mosquito midgut during
an infectious blood meal and then transform into
gametes that can fertilize to become zygotes. Zygotes
mature into ookinetes, which penetrate the mosquito
midgut wall and develop into oocysts. Numerous rounds
of asexual replication occur in the oocyst to generate
sporozoites over 10-14 days. Fully developed sporozoites
rupture from oocysts and invade the mosquito
salivary glands, from which they can initiate a new
infection during subsequent mosquito blood meals
(Figure 49–1). Understanding the subtleties of the life
cycles of Plasmodium parasites is important for tailoring
drug therapies to the various species and geographic
contexts.
Mechanisms of erythrocyte invasion include initial binding by
merozoites to specific red blood cell surface ligands. P. falciparum
SECTION VII
CHEMOTHERAPY OF MICROBIAL DISEASES
Primary attack
ERYTHROCYTIC
CYCLE
Schizonts
Bite from
infected
mosquito
Relapse (due to P. vivax or P. ovale)
Erythrocytic
stage of infection
Merozoites
Figure 49–1. Life cycle of malaria parasites.
Infected
mosquito
Uninfected
mosquito
has a family of binding proteins that can recognize a variety of host
cell molecules. P. falciparum invades all stages of erythrocytes and
therefore can achieve high parasitemias. P. vivax selectively binds
to the Duffy chemokine receptor protein as well as reticulocytespecific
proteins. Thus, P. vivax does not establish infection in
Duffy-negative individuals and only invades reticulocytes. (However,
P. vivax has reportedly mutated in Madagascar to enable infection of
Duffy-negative individuals [Ménard et al., 2010].) Because of this
restricted subpopulation of suitable erythrocytes, P. vivax rarely
exceeds 1% parasitemia in the bloodstream. P. ovale is similar to
P. vivax in its predilection for young red blood cells, but the mechanism
of its erythrocyte recognition is unknown. P. malariae parasitizes
senescent red blood cells, maintains a very low parasitemia,
and typically causes an indolent infection.
P. falciparum assembles cytoadherence proteins (PfEMP1s,
encoded by a highly variable family of var genes) into structures
called knobs that are presented on the erythrocyte surface. Knobs
allow the P. falciparum-parasitized erythrocyte to bind to postcapillary
vascular endothelium, so as to avoid spleen-mediated clearance
and allow the parasite to grow in a low oxygen, high carbon dioxide