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T
he malaria parasite has a complex, multistage life cycle occurring
within two living beings, the vector mosquitoes and the vertebrate
hosts. The survival and development of the parasite within the
invertebrate and vertebrate hosts, in intracellular and extracellular
environments, is made possible by a toolkit of more than 5,000 genes and
their specialized proteins that help the parasite to invade and grow
within multiple cell types and to evade host immune responses.[1,2] The
parasite passes through several stages of development such as the
sporozoites (Gr. Sporos = seeds; the infectious form injected by the
mosquito), merozoites (Gr. Meros = piece; the stage invading the
erythrocytes), trophozoites (Gr. Trophes = nourishment; the form
multiplying in
erythrocytes), and gametocytes (sexual stages) and all these stages have
their own unique shapes and structures and protein complements. The
surface proteins and metabolic pathways keep changing during these
different stages, that help the parasite to evade the immune clearance,
while also creating problems for the development of drugs and
vaccines.[2]
Sporogony Within the Mosquitoes:
Mosquitoes are the definitive hosts for the malaria
parasites, wherein the sexual phase of the parasite's life cycle occurs.
The sexual phase is called sporogony and results in the
development of innumerable infecting forms of the parasite within the
mosquito that induce disease in the human host following their injection
with the mosquito bite.
When the female Anopheles draws a blood meal from
an individual infected with malaria, the male and female gametocytes of
the parasite find their way into the gut of the mosquito. The molecular and cellular changes in the gametocytes
help the parasite to quickly adjust to the insect host from the
warm-blooded human host and then to
initiate the sporogonic cycle. The male and female gametes fuse in the
mosquito gut
to form zygotes, which subsequently develop into actively moving
ookinetes that burrow into the mosquito midgut wall to develop into oocysts.
Growth and division of each oocyst produces thousands
of active haploid forms called sporozoites. After the sporogonic phase
of 8–15 days,
the oocyst bursts and releases sporozoites into the body cavity
of the mosquito, from where they travel to and invade the
mosquito salivary glands. When the mosquito thus loaded with sporozoites takes another
blood meal, the sporozoites get injected from its salivary
glands into the human bloodstream, causing malaria infection in the
human host. It has been found that the infected mosquito and the
parasite mutually benefit each other and thereby promote transmission of the
infection. The Plasmodium-infected mosquitoes have a better
survival and show an increased rate of blood-feeding, particularly from
an infected host.[3-5]
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Coloured TEM of malaria oocysts in the gut of Anopheles
mosquito |
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Coloured TEM of a malarial oocyst in the gut of Anopheles
mosquito |
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A false-colored
electron micrograph showing a malaria sporozoite migrating through
the midgut epithelia (Above)
Coloured TEM of malaria sporozoites in a Anopheles mosquito gut
(left) |
Schizogony in the
Human Host:
Man is the intermediate host for malaria, wherein the
asexual phase of the life cycle occurs. The sporozoites inoculated by
the infested mosquito initiate this phase of the cycle from the liver,
and the latter part continues within the red blood cells, which results
in the various clinical manifestations of the disease.
Pre-erythrocytic
Phase - Schizogony in the Liver:
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With
the mosquito bite, tens to a few hundred invasive sporozoites are
introduced into the skin. Following the intradermal deposition, some
sporozoites are destroyed
by the local macrophages, some enter the lymphatics, and
some others find a blood vessel.[6–8] The sporozoites that enter a lymphatic vessel reach the draining lymph node
wherein some of the sporozoites partially develop into
exoerythrocytic stages[6] and may also prime the T cells to
mount a protective immune response.[9]
The sporozoites that find a blood vessel reach the liver
within a few hours. It has recently been shown that the sporozoites travel by a
continuous sequence of stick-and-slip motility, using the thrombospondin-related anonymous protein
(TRAP) family and an actin–myosin motor.[7,10,11][See
video from ref.10] The sporozoites then
negotiate through the liver sinusoids, and migrate into a few hepatocytes,
and then multiply and
grow within parasitophorous vacuoles. Each sporozoite develop into a schizont
containing 10,000–30,000 merozoites (or more in case of P. falciparum).[12–14]
The growth and development of the parasite in the liver cells is
facilitated by a a favorable environment created by the The circumsporozoite protein of the
parasite.[15,16] The entire pre-eryhrocytic phase lasts about
5–16 days depending on the parasite species:[17] on an average 5-6 days
for P. falciparum, 8 days for P. vivax, 9 days for P.
ovale, 13 days for P. malariae and 8-9 days for P.
knowlesi.[Also
See] The pre-erythrocytic phase remains a
“silent” phase, with little pathology and no symptoms, as only a few hepatocytes are affected.[6]
This phase is also a single cycle, unlike the next, erythrocytic stage,
which occurs repeatedly.
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A Plasmodium
sporozoite entering a liver cell
[Source] |
The merozoites that develop within the hepatocyte
are contained inside host cell-derived vesicles called
merosomes that
exit the liver intact, thereby protecting the merozoites from phagocytosis by Kupffer cells. These
merozoites are eventually released into the blood stream at the lung
capillaries and initiate the blood
stage of infection thereon.[8]
In P. vivax and
P. ovale malaria, some of the sporozoites
may remain dormant for months within the liver. Termed as hypnozoites,
these forms develop into
schizonts after some latent period, usually of a few weeks to months. It
has been suggested that these late developing hypnozoites are genotypically different
from the sporozoites that cause acute infection soon after
the inoculation by a mosquito bite,[18,19] and in many patients cause relapses
of the clinical infection after weeks to months.
Erythrocytic Schizogony - Centre Stage in
Red Cells Red blood cells are the 'centre stage' for the asexual development
of the malaria parasite. Within the red cells,
repeated cycles of parasitic development occur with precise periodicity,
and at the end of each cycle, hundreds of fresh daughter parasites
are released that invade more number of red cells. The merozoites
released from the liver recognize, attach, and enter the red blood
cells (RBCs) by multiple receptor–ligand interactions in as little as 60
seconds. This quick disappearance from the circulation into the red
cells minimises the exposure of the antigens on the surface of the parasite,
thereby protecting these parasite forms from the host immune
response.[1,8,20]
The invasion of the merozoites into the red cells is facilitated by molecular
interactions between distinct ligands on the merozoite and host
receptors on the erythrocyte membrane. P. vivax invades
only Duffy blood group-positive red cells, using the Duffy-binding
protein
and the reticulocyte homology protein, found mostly on the
reticulocytes. the more virulent P. falciparum uses several
different receptor families and alternate invasion pathways that are
highly redundant. Varieties of Duffy binding-like (DBL)
homologous proteins and the reticulocyte binding-likehomologous proteins of
P. falciparum recognize
different RBC receptors other than the Duffy blood group or
the reticulocyte receptors. Such redundancy is helped by the fact that
P. falciparum has four Duffy binding-like erythrocyte-binding
protein genes, in comparison to only one gene in the DBL-EBP family
as in the case of P. vivax, allowing P. falciparum to invade any red cell.[21,22]
The process of attachment, invasion, and establishment of the
merozoite into the red cell is made possible by the specialized apical secretory organelles of the
merozoite, called the micronemes, rhoptries, and dense granules. The initial
interaction between the parasite and the red cell stimulates a rapid “wave” of deformation
across the red cell membrane, leading to the
formation of a stable parasite–host cell junction. Following this,
the parasite pushes its way through the
erythrocyte bilayer with the help of the actin–myosin motor, proteins of the
thrombospondin-related anonymous protein family (TRAP)
and aldolase, and creates a parasitophorous vacuole
to seal itself from the host-cell cytoplasm, thus creating a hospitable
environment for its development within the red cell. At this stage,
the parasite appears as an intracellular “ring”.[20,23,24]
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Process of
Invasion of Red Cells by Merozoites [© 2009
QIAGEN, all rights reserved] |
Within the red cells, the parasite numbers expand rapidly with a
sustained cycling of the parasite population. Even though the red cells provide some
immunological advantage to the growing parasite, the
lack of standard biosynthetic pathways and intracellular
organelles in the red cells tend to create obstacles for the fast-growing intracellular parasites. These
impediments are overcome by the growing ring
stages by several mechanisms: by restriction of the nutrient to the
abundant hemoglobin, by dramatic expansion of the
surface area through the formation of a tubovesicular network,
and by export of a range of remodeling and virulence
factors into the red cell.[8] Hemoglobin from the red cell, the
principal nutrient for the growing parasite, is
ingested into a food vacuole and degraded. The
amino acids thus made available are utilized for protein biosynthesis
and the remaining toxic
heme is detoxified by heme polymerase and sequestrated
as hemozoin (malaria pigment). The parasite
depends on anaerobic glycolysis for energy, utilizing enzymes
such as pLDH, plasmodium aldolase etc. As the parasite grows and
multiplies within the red cell, the membrane permeability and cytosolic composition of
the host cell is modified.[25,26] These new permeation pathways induced by the parasite
in the host cell membrane help not only in the uptake of solutes
from the extracellular medium but also in the disposal of
metabolic wastes, and in the origin and maintenance of
electrochemical ion gradients. At the same time, the premature hemolysis of the
highly permeabilized infected red cell is prevented by the
excessive ingestion, digestion, and detoxification of the
host cell hemoglobin and its discharge out of the infected
RBCs through the new permeation pathways, thereby
preserving the osmotic stability of the infected red cells.[25,26]
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Credit for Images Below:
LONDON SCHOOL OF HYGIENE / SCIENCE
PHOTO LIBRARY |
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False-colour transmission electron micrograph
of two merozoites of P. falciparum (blue & pink) parasitising
a red blood cell (Above)
Coloured TEM of a
human red blood cell infected with merozoites (green) (Right) |
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Coloured scanning
electron micrograph (SEM) of a malaria
infected
red blood cell |
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Coloured SEM of a dendritic cell
(orange) surrounded by red blood cells infected with P. falciparum |
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Coloured TEM of a
malaria trophozoite in a red blood cell |
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TEM of P. falciparum
schizont (X2810)
[Credit: Dennis Kunkel Microscopy, Inc./Visuals Unlimited, Inc.] |
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SEM of
red cell infected with P. falciparum (X4,000)
[Credit: Dennis Kunkel Microscopy, Inc./Visuals Unlimited, Inc.] |
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Merozoites
of the malaria parasite bursting out of the red blood cell |
The erythrocytic cycle occurs every 24 hours in case of P.
knowlesi, 48 h in cases of P. falciparum, P. vivax and
P. ovale and 72 h in case of P. malariae. During each
cycle,
each merozoite grows and divides within the vacuole
into 8–32 (average 10) fresh merozoites, through
the stages of ring, trophozoite, and schizont. At the end of the cycle,
the infected red cells rupture, releasing the new
merozoites that in turn
infect more RBCs. With sunbridled growth, the parasite
numbers can rise rapidly to levels as high as 1013 per host.[1]
A small proportion of asexual parasites do not undergo
schizogony but differentiate into the sexual stage gametocytes. These
male or female gametocytes are extracellular and
nonpathogenic and help in transmission of the infection to others through
the female
anopheline mosquitoes, wherein they continue the sexual phase of the
parasite's life cycle. Gametocytes of P. vivax develop
soon after the release of merozoites from the liver, whereas
in case of P. falciparum, the gametocytes develop much later with peak densities of the sexual stages typically occurring 1
week after peak asexual stage densities.[27,28]
Further Reading:
- Brian M. Greenwood, David A. Fidock, Dennis E. Kyle, Stefan
H.I. Kappe, Pedro L. Alonso, Frank H. Collins, Patrick E. Duffy.
Malaria: progress, perils, and prospects for eradication. J.
Clin. Invest. 2008;118:1266–1276. doi:10.1172/JCI33996 Full
Text at
http://www.jci.org/articles/view/33996/files/pdf
- Laurence Floren, Michael P. Washburn, J. Dale Raine et al. A
proteomic view of the Plasmodium falciparum life cycle
Nature October 2002;419:520-526. Full text at
http://www.nature.com/nature/journal/v419/n6906/pdf/nature01107.pdf
- Carolina Barillas-Mury, Sanjeev Kumar. Plasmodium –mosquito
interactions: a tale of dangerous liaisons. Cellular Microbiology
2005;7(11):1539–1545 doi:10.1111/j.1462-5822.2005.00615.x. Full text at
http://www3.interscience.wiley.com/cgi-bin/fulltext/118714410/PDFSTART
- Hill AVS. Pre-erythrocytic malaria vaccines: towards
greater efficacy. Nature Reviews Immunology January 2006;6:21-32
- Heather M Ferguson, Andrew F Read. Mosquito appetite for blood
is stimulated by Plasmodium chabaudi infections in
themselves and their vertebrate hosts. Malaria Journal
2004;3:12 doi:10.1186/1475-2875-3-12 Full text at
http://www.malariajournal.com/content/pdf/1475-2875-3-12.pdf
- Ashley M. Vaughan, Ahmed S. I. Aly, Stefan H. I. Kappe. Malaria
parasite pre-erythrocytic stage infection: Gliding and Hiding. Cell Host
Microbe. 11 September 2008;4(3):209–218. Full Text at
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2610487/pdf/nihms69860.pdf
- Lucy Megumi Yamauchi, Alida Coppi, Georges Snounou, Photini Sinnis.
Plasmodium sporozoites trickle out of the injection site. Cell Microbiol.
1 May 2007;9(5):1215–1222. Full Text at
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1865575/pdf/cmi0009-1215.pdf
- Olivier Silvie, Maria M Mota, Kai Matuschewski, Miguel Prudêncio.
Interactions of the malaria parasite and its mammalian host. Current
Opinion in Microbiology 2008;11:352–359. Full Text at
http://www.mpiib-berlin.mpg.de/research/Mat_2008_Silvie_etal_COM.pdf
- Michael F Good, Denise L Doolan. Malaria's journey through the lymph
node. Nature Medicine 2007;13:1023-1024.
- Sylvia Münter, Benedikt Sabass, Christine Selhuber-Unke et al.
Plasmodium Sporozoite Motility Is Modulated by the Turnover of Discrete
Adhesion Sites Cell Host & Microbe. December 2009;6(17):551-562. Full
text at
http://download.cell.com/cell-host-microbe/pdf/PIIS1931312809003849.pdf?intermediate=true
- Jake Baum, Dave Richard, Julie Heale et al. A Conserved Molecular
Motor Drives Cell Invasion and Gliding Motility across Malaria Life
Cycle Stages and Other Apicomplexan Parasites. The Journal of Biological
Chemistry. February 2006;281:5197-5208. Full text at
http://www.jbc.org/content/281/8/5197.full.pdf+html
- Kebaier C, Voza T, Vanderberg J. Kinetics of Mosquito-Injected
Plasmodium Sporozoites in Mice: Fewer Sporozoites Are Injected into
Sporozoite-Immunized Mice. PLoS Pathog 2009;5(4):e1000399. Full text at
http://www.plospathogens.org/article/info:doi%2F10.1371%2Fjournal.ppat.1000399
- Amino R, Thiberge S, Martin B et al. Quantitative imaging of
Plasmodium transmission from mosquito to mammal. Nat Med. Feb
2006;12(2):220-224.
- Malcolm K Jones, Michael F Good. Malaria parasites up close.
Nature
Medicine 2006;12:170-171 Full text at
http://ecofog.cirad.fr/actualites/documents/JCP20060224.pdf
- Miguel Prudêncio , Ana Rodriguez, Maria M. Mota. The silent path to
thousands of merozoites: the Plasmodium liver stage. Nature Reviews
Microbiology 2006;4:849–856
- Agam Prasad Singh, Carlos A. Buscaglia, Qian Wang et al. Plasmodium
Circumsporozoite Protein Promotes the Development of the Liver Stages of
the Parasite. Cell 2007;131:492–504.
- Malaria: Life Cycle of the Malaria Parasite. At
http://www3.niaid.nih.gov/topics/Malaria/lifecycle.htm
- William E. Collins. Further Understanding the Nature of Relapse of
Plasmodium vivax Infection. The Journal of Infectious Diseases
2007;195:919–920. Full Text at
http://www.journals.uchicago.edu/doi/pdf/10.1086/512246
- Frank B. Cogswell. The Hypnozoite and Relapse in Primate Malaria.
Clinical Microbiology Reviews. Jan. 1992;5(1):26-35. Full Text at
http://cmr.asm.org/cgi/reprint/5/1/26.pdf
- Alan F. Cowman, Brendan S. Crabb. Invasion of Red Blood Cells by
Malaria Parasites. Cell. 24 February, 2006;124:755–766. Full Text at
http://download.cell.com/pdf/PIIS0092867406001814.pdf
- Ghislaine Mayera DC, Joann Cofiea, Lubin Jiangb, Daniel L. Hartlc,
Erin Tracya, Juraj Kabatd, Laurence H. Mendozaa, Louis H. Millera.
Glycophorin B is the erythrocyte receptor of Plasmodium falciparum
erythrocyte-binding ligand, EBL-1. PNAS 31 March, 2009;106(13):5348–5352
Full text at
http://www.pnas.org/content/106/13/5348.full.pdf+html
- David J. Weatherall, Louis H. Miller, Dror I. Baruch, Kevin Marsh,
Ogobara K. Doumbo, Climent Casals-Pascual, David J. Roberts. Malaria and
the Red Cell. Haematology 2002;1:35-57. Full Text at
http://asheducationbook.hematologylibrary.org/cgi/reprint/2002/1/35
- Kasturi Haldar, Narla Mohandas. Erythrocyte remodeling by malaria
parasites. Curr Opin Hematol 2007;14:203–209. Full Text at
http://www.nd.edu/~haldarlb/pubs/article007.pdf
- Jürgen Bosch, Carlos A. Buscaglia, Brian Krumm, Bjarni P. Ingason,
Robert Lucas, Claudia Roach, Timothy Cardozo, Victor Nussenzweig, Wim G.
J. Hol. Aldolase provides an unusual binding site for thrombospondin-related
anonymous protein in the invasion machinery of the malaria parasite. PNAS 24 April, 2007;104(17):7015–7020. Full text at
http://www.pnas.org/content/104/17/7015.full.pdf
- Virgilio L. Lew, Teresa Tiffert, Hagai Ginsburg. Excess hemoglobin
digestion and the osmotic stability of Plasmodium falciparum-infected
red blood cells. Blood. 15 May 2003;101(10):4189-4194. Full Text at
http://bloodjournal.hematologylibrary.org/cgi/reprint/101/10/4189
- Kiaran Kirk. Membrane Transport in the Malaria-Infected Erythrocyte.
Physiological Reviews April 2001;81(2):495-537. Full Text at
http://physrev.physiology.org/cgi/reprint/81/2/495
- Sasithon Pukrittayakamee, Mallika Imwong, Pratap Singhasivanon,
Kasia Stepniewska, Nicholas J. Day, Nicholas J. White. Effects of
Different Antimalarial Drugs on Gametocyte Carriage in P. vivax Malaria.
Am. J. Trop. Med. Hyg., 2008;79(3):378-384. Full Text at
http://www.ajtmh.org/cgi/reprint/79/3/378
- Louis H. Miller, Dror I. Baruch, Kevin Marsh, Ogobara K. Doumbo. The
pathogenic basis of malaria. Nature February 2002;415(7):673-679. Full
Text at
http://www.doh.gov.za/issues/malaria/red_reference/cross_cutting/cross20.pdf
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