|
All
the manifestations of malarial illness are caused by the infection
of the red blood cells by the asexual forms of the malaria parasite
and the involvement of the red cells makes malaria a potentially
multisystem disease, as every organ of the body is reached by the
blood.[1,2] All types of malaria manifest with common symptoms such
as fever, some patients may progress into severe malaria. Although
severe malaria is more often seen in cases of P. falciparum
infection, complications and even deaths have been reported in non-falciparum malaria
as well.
| |
Induction of
fever by malaria parasites [Source]7 |
At
the completion of the schizogony within the red cells, each cycle
lasting 24-72 hours depending on the species of the infecting
parasite, newly developed merozoites are released by the lysis of infected
erythrocytes and along with them, numerous known and unknown waste
substances, such as red cell membrane products,
hemozoin pigment, and other toxic factors such as
glycosylphosphatidylinositol (GPI) are also released into the
blood. These products, particularly the GPI, activate macrophages and
endothelial cells to secrete cytokines and inflammatory
mediators such as tumor necrosis factor, interferon-γ,
interleukin-1, IL-6, IL-8, macrophage colony-stimulating factor,
and lymphotoxin, as well as superoxide and nitric oxide(NO). Many
studies have implicated the GPI tail, common to several merozoite surface
proteins such as MSP-1, MSP-2, and MSP-4, as a key parasite
toxin.[3,4] The systemic manifestations of malaria such as headache,
fever and rigors, nausea and vomiting, diarrhea, anorexia,
tiredness, aching joints and muscles, thrombocytopenia,
immunosuppression, coagulopathy, and central nervous system
manifestations have been largely attributed to the various cytokines released in
response to these parasite and red cell membrane products.[5] In
addition to these factors, the plasmodial DNA is also highly
proinflammatory and can induce cytokinemia and fever. The plasmodial DNA is presented by
hemozoin (produced during the parasite development within the red
cell) to interact intracellularly with the Toll-like
receptor-9, leading to the release of proinflammatory
cytokines that in turn induce COX-2-upregulating
prostaglandins leading to the induction of fever.[6,7] Hemozoin has
also been linked to the induction
of apoptosis in developing erythroid cells in the bone marrow,
thereby causing anemia.[8,9]
Pathogenesis of Severe Malaria
The
infection of the red cells by malaria parasites, particularly P.
falciparum, results in progressive and dramatic structural,
biochemical, and mechanical modifications of the red cells that can
worsen into life-threatening complications of malaria. While the
vast majority of severe malaria and related mortality
are caused by P. falciparum infection, complications can
occur in non-falciparum infections as well. In recent years, several cases of
severe infection and even deaths have been reported following
infections with P. vivax and P. knowlesi
infections.[10-18] Several pathophysiological factors such as the parasite biomass;
'malaria toxin(s)' and inflammatory response; cytoadherence,
resetting and sequestration; altered deformability and
fragility of parasitized erythrocytes; endothelial activation,
dysfunction and injury; and altered thrombostasis have been found to
be involved in the development of severe malaria. All these
phenomena are more profound and wide spread in P. falciparum infection
compared to non-falciparum infections. As a result, except for severe anemia, complications
such as cerebral malaria, hypoglycemia, metabolic
acidosis, renal failure, and respiratory distress are
more commonly seen in P. falciparum infections[16,19,20]
| |
Schematic
representation of pathogenesis of severe malaria
[Louis
Schofield, Georges E. Grau. Immunological processes in malaria
pathogenesis. Nature Reviews Immunology September
2005;5:722-735][Source] |
Parasite Biomass
With its wide array of
receptor families and highly redundant, alternate invasion
pathways,[21] P. falciparum has the ability to invade RBCs of all ages,
and with repeated cycles of development within the red cells, the
parasite numbers exponentially grow into very high parasite burdens if
the infection is uninhibited by
treatment or host immunity. On the contrary, P. vivax
preferentially infects only young RBCs, thus limiting its
reproductive capacity and resultant parasite loads. Thus, the
parasite load in P. falciparum infections can be very high,
even exceeding 20-30%, whereas in vivax malaria it rarely exceeds
2%, even in case of severe disease.[16,19]
Role of
Cytokines in Severe Malaria
The cytokines of the proinflammatory cascade like tumor
necrosis factor, interleukins, interferon-γ, and nitric oxide
act as double-edged swords in the pathogenesis of malaria. Cytokines
act as homeostatic agents and an early proinflammatory
cytokine response helps in limiting the
infection, with the cytokines inhibiting the growth of
malarial parasites in lower concentrations. On the other, failure to down-regulate this inflammatory
response results in progressive immune pathology, leading to complications.
Excessive levels of cytokines can lead to decreased mitochondrial
oxygen use and enhanced lactate production; increased
cytoadherence that in turn causes microvascular obstruction and
more hypoxia; disturbed auto-regulation of local blood
flow leading to poor circulation and further tissue
hypoxia; dyserythropoiesis, poor red cell deformability
and multifactorial anemia; reduced gluconeogenesis
and hypoglycemia; myocardial depression and cardiac
insufficiency; loss of endothelial integrity and vascular
damage in the lungs and brain; selective upregulation of
vascular and intercellular adhesion molecules (ICAMs),
particularly in the brain and placenta leading to
cerebral malaria and placental dysfunction; and activation
of leukocytes and platelets, promoting procoagulant
activity.[2-5,20,22-28] It can therefore be said that the outcome of
malaria infection is determined by the balance between the pro- and anti-inflammatory
cytokines.[2,5,22]
Some of the
complications seen in P. vivax malaria may be related to cytokine-mediated
injury. P. vivax has been reported to induce a greater
inflammatory response than P. falciparum (with equal or greater parasite
load), resulting in higher levels of cytokine release. The pyrogenic
threshold is also lower in P. vivax infections, resulting in
fever at lower levels of parasitemia. Structural differences in the
P. vivax GPI that MAY make it more pyrogenic and/or
greater concentrations of Toll-like receptor-9-stimulating
motifs within P. vivax hemozoin may be responsible for this greater
pyrogenicity.[16] A cholesterol/triglyceride(s)-containing
lipid, that has greater activity than GPI-like phospholipids, has
also been proposed as a putative malaria toxin unique to P. vivax,
and that may also contribute to the pyrogenicity of P. vivax.[29]
Cytoadherence, Sequestration, and Rosetting
Structural changes in the infected red cells and the resulting
increase in their rigidity and adhesiveness are major contributors
to the virulence for P. falciparum malaria. Owing to the
increased adhesiveness, the red cells infected with late stages
of P. falciparum (during the second half of the 48 hour life
cycle) adhere to the capillary and postcapillary
venular endothelium in the deep microvasculature (cytoadherence).
The infected red cells also adhere to the uninfected red cells,
resulting in the formation of red cell rosettes (rosetting).
Cytoadherence leads to sequestration of the parasites in
various organs such as the heart, lung, brain, liver, kidney,
intestines, adipose tissue, subcutaneous tissues, and
placenta. Sequestration of the growing P. falciparum
parasites in these deeper tissues provides them the microaerophilic venous environment
that is better suited for their maturation and the adhesion to
endothelium allows them to escape clearance by the
spleen and to hide from the immune system. These factors help the
falciparum parasites to undergo unbridled multiplication, thereby
increasing the parasite load to very high numbers. Due to the
sequestration of the growing parasites in the deeper vasculature,
only the
ring-stage trophozoites of P. falciparum are seen circulating in the peripheral
blood, while the more mature
trophozoites and schizonts are bound in the deep microvasculature,
hence seldom seen on peripheral blood examination. If the
cytoadherence-rosetting-sequestration of infected and uninfected erythrocytes in
the
vital organs goes on uninhibited, it ultimately blocks blood flow, limits the local oxygen
supply, hampers mitochondrial ATP synthesis, and
stimulates cytokine production - all these factors contributing to
the development of severe
disease.[5,16,19,20,26,30-33]
| |
Cytoadherence
and rosetting in postcapillary vasculature [Source]20 |
Certain proteins expressed on the surface of the infected red cells
mediate the adhesion of parasitized RBCs to the endothelium and to
uninfected red cells. The most important of such proteins is the
P. falciparum erythrocyte membrane protein 1 (PfEMP1),
an antigenically diverse protein family that is expressed
on the thousands of knob-like excrescences on the
surface of red cells infected with P. falciparum trophozoites and schizonts.
PfEMP1 is anchored at the red cell membrane skeleton by the
knob-associated histidine-rich protein. PfEMP1 appears on the
surface of the P. falciparum-infected red cells about 16
hours after the invasion and that heralds the cytoadherence.[19,32] PfEMP1
can bind to several adhesion
receptors expressed on the endothelial cells such as thrombospondin, CD36, ICAM-1, vascular cell adhesion
molecule 1, platelet/EC adhesion molecule)/CD31, neural
cell adhesion molecule, P-selectin and E-selectin, integrin
αvβ3, globular C1q receptor (gC1qR)/hyaluronan binding
protein 1/p32, chondroitin sulfate A (CSA), and
hemagglutinin, and such binding can proceed synergistically.[4,20,26]
Whereas ICAM-1 and CD36 are more commonly
used receptors, CSA acts as the receptor for binding in the
placenta. Activation of endothelial cells by cytokines as well as by the parasitized RBCs increases
the expression of adhesion-promoting molecules and further promotes
cytoadherence.[34] Differences in binding to these receptors (CD36
and ICAM-1) may determine the virulence of P. falciparum
isolates from different parts of the world.[19,33]
Rosetting is
mediated by binding of PfEMP1-DBLα on the surface
of infected red cells to complement receptor 1, CD31, and
heparan sulfate-like glycosaminoglycans of uninfected RBCs.[31,33,35] Rosetting is
found to be lesser in blood group O
erythrocytes compared with groups A, B, and AB, and thus patients
with blood group O may be protected from
severe malaria.[36,37]
Cytoadherance, sequestration, rosetting and aggregation of
leukocytes have been reported in P. vivax infections as well.
However, these are lesser in magnitude and extent in comparison to
P. falciparum infections and their roles in pathophysiology
of complications remain unclear.[16]
Red
Cell Membrane Rigidity and Deformability
Altered red cell membrane rigidity and
deformability also contribute to the pathogenesis of severe malaria.
In patients with severe
falciparum malaria, the entire red cell mass, comprising mostly of
unparasitized red cells and also parasitized red cells, becomes
rigid.[38-40] Several mechanisms such as hemin-induced oxidative damage
of the red cell membrane, alterations in the phospholipid
bilayer and attached spectrin network by the proteins
transported to the red cell membrane, thermally driven
membrane fluctuations due to fever, and inhibition of the
Na+/K+ pump on the red cell membrane, possibly by nitric oxide (NO)
may be responsible for the increase in rigidity and reduction in deformability of the red cells in
falciparum malaria.[5,39,40] Reduced red cell deformability leads to increased splenic
clearance and loss of red cells, causing anemia. Hemolysis, suppression
of erythropoeisis by cytokines, and hemozoin-induced
apoptosis in developing erythroid cells also contribute to the
development of anemia in severe malaria.[5,8,40] Compared to
infection with P. falciparum,
in which red cell deformability is reduced, the red cell deformability
is increased in P. vivax infection. While this may enable P. vivax
infected red cells to survive the passage through the splenic sinusoids,
the accompanying increase in fragility of both
infected and noninfected red cells may contribute to severe
anemia in P. vivax malaria. Increased deformability of P. vivax
infected red cells also makes sequestration and obstruction to blood flow
unlikely.[16,41]
The pathogenesis of severe malaria
therefore involves a cascading interaction between parasite and red
cell membrane products, cytokines and endothelial receptors, leading
to inflammation, activation of platelets, hemostasis, a procoagulant
state, microcirculatory dysfunction and tissue hypoxia, resulting in
various organ dysfunctions manifesting in severe malaria.[23]
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. 118:1266–1276 (2008). doi:10.1172/JCI33996 Full
Text at http://www.jci.org/articles/view/33996/files/pdf
- Fakhreldin M. Omer, J. Brian de Souza, Eleanor M. Riley.
Differential Induction of TGF-{beta} Regulates Proinflammatory
Cytokine Production and Determines the Outcome of Lethal and
Nonlethal Plasmodium yoelii Infections J. Immunol.
2003;171;5430-5436 Full Text at
http://www.jimmunol.org/cgi/reprint/171/10/5430.pdf
- Claire L.
Mackintosh, James G. Beeson, Kevin Marsh. Clinical
features and pathogenesis of severe malaria. Trends in Parasitology
December 2004;20(12):597-603
- Srabasti J. Chakravorty, Katie R. Hughes, Alister G. Craig. Host
response to cytoadherence in Plasmodium Falciparum. Biochem. Soc.
Trans. 2008;36:221–228; doi:10.1042/BST0360221 Full text at
http://www.biochemsoctrans.org/bst/036/0221/0360221.pdf
- Ian A Clark,
Alison C Budd, Lisa M Alleva, William B Cowden.
Human malarial disease: a consequence of inflammatory cytokine
release. Malaria Journal 2006;5:85. doi:10.1186/1475-2875-5-85. Full
Text at
http://www.malariajournal.com/content/pdf/1475-2875-5-85.pdf
- Peggy Parroche, Fanny N. Lauw, Nadege Goutagny, Eicke Latz,
Brian G. Monks, Alberto Visintin, Kristen A. Halmen, Marc Lamphier,
Martin Olivier, Daniella C. Bartholomeu, Ricardo T. Gazzinelli,
Douglas T. Golenbock. Malaria hemozoin is immunologically inert but
radically enhances innate responses by presenting malaria DNA to
Toll-like receptor 9. PNAS. 2007;104:1919–1924. Full Text at
http://www.pnas.org/content/104/6/1919.full.pdf+html
- Ralf R. Schumann. Malarial fever: Hemozoin is involved but
Toll-free. PNAS 6 February, 2007;104(6):1743-1744. Full text at
http://www.pnas.org/content/104/6/1743.full.pdf+html
- Lamikanra AA, Theron M, Kooij TWA, Roberts DJ Hemozoin (Malarial
Pigment) Directly Promotes Apoptosis of Erythroid Precursors. PLoS
ONE 2009;4(12):e8446. doi:10.1371/journal.pone.0008446. Full Text at
http://www.plosone.org/article/info:doi%2F10.1371%2Fjournal.pone.0008446
- Gordon A. Awandare, Yamo Ouma, Collins Ouma et al. Role of Monocyte-Acquired Hemozoin in Suppression of
Macrophage Migration Inhibitory Factor in Children with Severe
Malarial Anemia. Infection And Immunity. Jan. 2007;75(1):201–210.
Full Text at http://iai.asm.org/cgi/reprint/75/1/201.pdf
-
Ric N. Price, Emiliana
Tjitra, Carlos A. Guerra, Shunmay Yeung, Nicholas J. White,
Nicholas M. Anstey. Vivax Malaria: Neglected and Not Benign. In J
G Breman, M S Alilio, Nicholas J White. (Editors) Defining and
Defeating the Intolerable Burden of Malaria: III. Progress and
Perspectives. In Breman, Joel G, Alilio, Martin S, Mills, Anne,
White, Nicholas J. (Editors). The Intolerable Burden of Malaria: A
Collection from the American Journal of Tropical Medicine and
Hygiene. Boca Raton (FL): CRC Press, Taylor & Francis Group;
c2001-2007. Full Text at
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Nicholas M. Anstey,
Tjandra Handojo, Michael C. F. Pain, Enny Kenangalem, Emiliana
Tjitra, Ric N. Price, Graeme P. Maguire. Lung Injury in vivax
Malaria: Pathophysiological Evidence for Pulmonary Vascular
Sequestration and Posttreatment Alveolar-Capillary Inflammation.
The Journal of Infectious Diseases 2007;195:589–596. Full
Text at
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Tjitra E, Anstey NM,
Sugiarto P, Warikar N, Kenangalem E, et al. Multidrug-Resistant
Plasmodium vivax Associated with Severe and Fatal Malaria: A
Prospective Study in Papua, Indonesia. PLoS Med 2008;5(6):e128.
Full Text at
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Kochar DK, Saxena V,
Singh N, Kochar SK, Kumar SV, Das A. Plasmodium vivax
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Kochar DK, Shubhakaran,
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S H Yale, A Adlakha, T
J Sebo and J H Ryu. Bronchiolitis obliterans organizing pneumonia
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Nicholas M. Anstey,
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Janet Cox-Singh,
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Cyrus Daneshvar,
Timothy M. E. Davis, Janet Cox-Singh, Mohammad Zakri Rafa’ee, Siti
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Laboratory Features of Human Plasmodium knowlesi Infection.
Clinical Infectious Diseases 2009;49:852–860
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Doumbo. The pathogenic basis of malaria. Nature February
2002;415(7):673-679. Full Text at
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the Red Cell. Haematology 2002;1:35-57. Full Text at
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Henri C. van der Heyde, John Nolan, Valéry Combes, Irene
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Jayakumar S. Poovassery, Demba Sarr, Geoffrey Smith, Tamas Nagy,
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Evelien Dekker, Marc K. Hellerstein, Johannes A. Romijn, Richard
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