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During its complex, multi-stage life cycle, the malaria
parasite not only expresses a great variety of proteins at different stages,
but these proteins also keep changing often. As a
result, a natural infection with malaria parasites leads to of only a partial and short lived
immunity that is unable to protect the individual against a new
infection. The complex interplay of parasite proteins with the
immune system of the host has also made it difficult or even
impossible to develop an effective vaccine against the disease until
now.
Immunity against malaria can be
classified into natural or innate immunity and acquired or
adaptive immunity.
Natural or innate immunity to malaria is an inherent
refractoriness of the host that prevents the establishment of the infection or
an immediate inhibitory response against the introduction of
the parasite. The innate immunity is naturally present in the host
and is not dependent on any previous infection. Alterations in the
structure of hemoglobin or in certain enzymes have been found to
confer protection against either the infection or
its severe manifestations and these traits are often found in areas
of high malaria transmission. Duffy negativity in red cells
protects against P. vivax infection. It is found to be widely
prevalent in Africa and this may be responsible for the virtual
elimination of this parasite from the continent. Certain
thalassemias (50% reduction in infection), homozygte hemoglobin C
(90% reduction), hemoglobin E, and ovalocytosis carrier
status hav ebeen reported to confer protection against P. falciparum
or P. vivax. Glucose 6
phosphate dehydrogenase deficiency (50% protection)
and sickle cell hemoglobin (90% protection) confer protection
against severe malaria and related mortality.[1,2]
Acute malarial infection also induces immediate, non-specific immune
response that tends to limit the progression of disease. The humoral
and cellular mechanisms of this ‘nonspecific’ defense are poorly
defined. Primordial, extrathymic T Cells [Natural Killer (NK) 1.1-,
intermediate TCR (TCRint) cells] and autoantibody
producing B-1 cells have been considered as the prime movers of this
response. Natural killer (NK) cells are found in blood, in secondary
lymphoid organs as well as in peripheral non-lymphoid tissues.
Related cell types probably playing a role in innate malaria
immunity are the NKT cells which in mice carry both the NK1.1
surface marker and T-cell receptors (TCR). NK cells have been shown
to increase in numbers and to be able to lyse P. falciparum-infected
erythrocytes in vitro. NK cells in peripheral blood produce
Interferon-gamma in response to Plasmodium infected
erythrocytes, leading to parasiticidal macrophage activation, and
this may be of greater importance for innate malaria immunity than
their potential to lyse infected host erythrocytes. These cells are
also important in the initiation and development of adaptive immune
responses. NK cells induce the production of the proinflammatory
chemokine Interleukin-8, that in turn plays its role in the
recruitment and the activation of other cells during malaria
infection. Dendritic cells, macrophages, gamma delta T cells and NKT
cells also sense the presence of the parasite and participate in the
immune response. NKT cells are potent inhibitors of liver-stage
parasite replication in mouse malaria systems in vitro. NK1.1 CD4
murine T cells have been reported to regulate IgG antibody responses
to glycosylphosphatidyl inositol-anchored P. falciparum
protein, and this may be important for a rapid, specific but major
histocompatibility complex (MHC) unrestricted parasite control.
Malaria infection gives rise to strongly elevated blood
concentrations of non-malaria-specific immunoglobulin, but the
importance of the underlying polyclonal B-cell activation for innate
immunity is not known.[3-7]
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Antibody-independent (T-cell) immunity against malaria:
Activation of CD4+ T cells by mature dendritic cells leading to
macrophage activation, phagocytosis of parasitized red blood
cells (pRBC), and elaboration of cytokines and small
inflammatory molecules (such as nitric oxide and oxygen redicals)[Source: Michael F. Good. Towards a blood-stage vaccine for
malaria: are we following all the leads? Nature Reviews
Immunology November 2001;1:117-125. doi:10.1038/35100540.
Available at
http://www.nature.com/nri/journal/v1/n2/fig_tab/nri1101-117a_F4.html] |
Acquired or adaptive immunity against malaria
develops after infection and its protective efficacy varies
depending on the characteristics of the host, place of stay, number
of infections suffered etc. It has been graded as anti-disease immunity (that protects against clinical
disease), anti-parasite immunity (protects against
high parasitemia), and sterilizing immunity (protects
against new infections by maintaining a low-grade,
asymptomatic parasitemia; also called premunition), with a considerable overlap between
these. Following infection with malaria parasites, a nonimmune individual
commonly develops an acute clinical illness with very low levels of
parasitemia and the infection may progress to severe disease
and death. After a couple of more infections, anti-disease immunity
develops and causes suppression of
clinical symptoms even in the presence of heavy parasitemia and also reduces the risk of
severe disease. Frequent and multiple infection slowly lead to the
development of anti-parasite immunity that results in very low
or undetectable parasitemia. Sterilizing immunity, though never
fully achieved, results in
a high degree of immune responsiveness, low levels of
parasitemia, and an asymptomatic carrier status. Premunition
suggests an immunity mediated directly by the presence of the
parasites themselves and not as much the result of previous
infections.[1,2]
The presence of genetically and
antigenically distinct strains of the parasites in a given locality
and the occurrence of clonal antigenic variation during the course
of an infection force the host to mount immune response against these
different strains and antigenic variants. The acquisition of
immunity against malaria is, therefore, very slow and not very
effective and remains
species specific and strain specific. However, in areas with stable endemic
malaria and intense malaria transmission, such as sub-Saharan Africa and forest areas in
the Indian states like Orissa, Chhattisgarh, Jharkhand,
southern Madhya Pradesh, and northeastern states etc.,
acquired immunity develops at a very early age. In these areas,
children born to immune mothers are protected against disease during
their first half year of life by maternal antibodies. This passive
immunity is followed by 1 or 2 years of increased susceptibility
before acquisition of active immunity. The risk of clinical disease
increases from birth to about 6 months of age, depending on the
transmission rate, and beginning at around 3 to 4 months of age,
infants become susceptible to severe disease and death. The risk of
cerebral malaria increases with age in children 2 to 4 years old. At
about 2 to 5 years of age, due to repeated and frequent infections,
the frequency of clinical disease begins to diminish and the risk of
mortality sharply decreases, and by
adulthood, most inhabitants generally possess sterilizing immunity.
On the other, people living in unstable endemic areas tend to
acquire only partial immunity.[1,2,4,8] Thus, the level of antimalaria
immunity influences the clinical outcome of the disease in different
locations and age groups.
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Regulation
of adaptive immunity to blood-stage malaria by cytokines
produced by cells of the innate immune response: In response to
parasite ligands recognized by pattern-recognition receptors (PRRs),
such as Toll-like receptors (TLRs) and CD36, or inflammatory
cytokines, such as interferon- (IFN-γ), dendritic cells (DCs)
mature and migrate to the spleen — the primary site of immune
responses against blood-stage Plasmodium parasites. Maturation
of DCs is associated with the upregulation of expression of MHC
class II molecules, CD40, CD80, CD86 and adhesion molecules and
the production of cytokines including interleukin-12 (IL-12).
IL-12 activates natural killer (NK) cells to produce IFN- γ and
induces the differentiation of T helper 1 (TH1) cells. The
production of cytokines, particularly IFN-γ, by NK cells results
in DC maturation and enhances the effect of parasite-derived
maturation stimuli, facilitating the clonal expansion of
antigen-specific naive CD4+ T cells. IL-2 produced by
antigen-specific TH1 cells further activates NK cells to produce
IFN-γ, which induces DC maturation and activates macrophages,
further amplifying the adaptive immune response. Cytokines such
as IL-10 and transforming growth factor-β (TGF-β) negatively
regulate both innate and adaptive responses. NO, nitric oxide; TCR, T-cell receptor; TNF, tumour-necrosis factor.[Source: Mary M. Stevenson, Eleanor M. Riley. Innate immunity to
malaria. Nature Reviews Immunology March 2004;4:169-180.
doi:10.1038/nri1311. Available at
http://www.nature.com/nri/journal/v4/n3/fig_tab/nri1311_F3.html] |
The
underlying mechanisms and antigenic specificity of protective
immunity against malaria are not well understood. The acquired anti
malaria immunity has been demonstrated to be strain specific and
stage specific, with cross reactivity. Immune response have been
documented against the various parasite antigens in pre-erythrocytic
(sporozoite), asexual erythrocytic (merozoite) and sexual stages
(gametocyte). Natural exposure
to sporozoites does not induce complete (sterilizing) antiparasite
and antidisease immunity but only limit the density of parasitemia
and thereby decrease the malaria-associated morbidity and mortality.
The acquired immunity is directed predominantly against the asexual
erythrocytic stage, the primary targets being the extracellular
merozoites in circulation. Although the preerythrocytic stage is
also targeted by protective immune responses, it does not
effectively block sporozoite invasion or intrahepatic development of
the parasite.[2]
Malaria infection induces both polyclonal and specific
immunoglobulin production, predominately IgM and IgG but also of
other immunoglobulin isotypes. Of these, 5% or more represent
species- as well as stage-specific antibodies reacting with a wide
variety of parasite antigens. Passive transfer of IgG from immune
donors may be protective by reducing parasitemia and clinical
disease. Malaria infections of both humans and experimental animals
are also associated with elevations in total IgE and IgE
anti-malarial antibodies, reflecting a switch of regulatory T cell
activities from Th1 to Th2 due to repeated exposure of the immune
system to the parasites. IgE levels are significantly higher in
patients with cerebral or other forms of severe disease than in
those with uncomplicated malaria and the pathogenic effect of IgE is
probably due to local overproduction in microvessels of tumor
necrosis factor (TNF) and nitric oxide (NO) caused by IgE-containing
immune complexes.[4]
Antibodies may protect against malaria by a variety of mechanisms.
They may inhibit merozoite invasion of erythrocytes and intra-erythrocytic
growth or enhance clearance of infected erythrocytes from the
circulation by binding to their surface, thereby preventing
sequestration in small vessels and promoting elimination by the
spleen. Opsonization of infected erythrocytes significantly
increases their susceptibility to phagocytosis, cytotoxicity and
parasite inhibition by various effector cells such as neutrophils
and monocytes/macrophages. Interaction of opsonized erythrocytes
with these effector cells induces release of factors such as TNF
which may cause tissue lesions but which are also toxic for the
parasites.[4]
Cell-mediated immune responses induced by malaria infection may
protect against both pre-erythrocytic and erythrocytic parasite
stages. CD4 T cells are essential for immune protection against
asexual blood stages in both murine and human malaria. However the
role of CD8 T cells, which have important effector functions in pre-erythrocytic
immunity and which contribute to protection against severe malaria,
is less clear. It has been proposed that CD8 T cells may
regulate immunosuppression in acute malaria and down-modulate
inflammatory responses. As human erythrocytes do not express MHC
antigens, lysis of infected erythrocytes by CD8 cytotoxic T
lymphocytes has no role in the defense against blood-stage
parasites.[4]
Malaria parasites not only escape the host's
immune response, owing to their antigenic diversity and clonal antigenic
variation, but also modulate the
immune response and cause significant immune suppression. The parasitized
red cells, with the deposited hemozoin inside, have been found to inhibit the maturation of antigen presenting dendritic cells,
thereby reducing their interaction with T cells, resulting in
immunosuppression. Immune suppression in malaria increases the risk
of
secondary infections (such as nontyphoidal Salmonella,
herpes zoster virus, hepatitis B virus, Moloney leukemia
virus and nematode infections and reactivation of
Epstein-Barr virus) and may also reduce the immune response to
certain vaccines.[9,10]
The acquired anti malaria immunity does not
last long. In the absence of re-infection for
about 6 months or 1 year, as may happen when the person
leaves the malarious area, the acquired immunity turns ineffective
and the individual becomes vulnerable to the full impact of a
malarial infection once again. The immunity is also rendered less
effective during pregnancy, particularly during the first and second
pregnancies, due to
the physiological immunosupression as well as the cytoadherence of erythrocytes
to the newly available Chondroitin Sulfate A receptors on the
placenta. Such loss of acquired immunity makes the pregnant woman
more susceptible to malaria and its complications.[1,2] Immunosuppression in HIV/AIDS also increases the risks of clinical
malaria, its complications and death.[11]
Further Reading:
- Richard Carter, Kamini N. Mendis. Evolutionary and Historical
Aspects of the Burden of Malaria. Clinical Microbiology Reviews.
October 2002;15(4):564-594. Full text at
http://cmr.asm.org/cgi/content/full/15/4/564
- Denise L. Doolan, Carlota Dobaño, J. Kevin Baird. Acquired
Immunity to Malaria. Clinical Microbiology Reviews. Jan
2009;22(1):13–36. Full text at
http://cmr.asm.org/cgi/reprint/22/1/13
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Mannoor MK, Weerasinghe A, Halder RC, Reza S, Morshed M, Ariyasinghe
A, Watanabe H, Sekikawa H, Abo T. Resistance to malarial infection
is achieved by the cooperation of NK1.1(+) and NK1.1(-) subsets of
intermediate TCR cells which are constituents of innate immunity.
Cell Immunol. 2001 Aug 1;211(2):96-104.
- Peter Perlmann, Marita Troye-Blomberg. Malaria and the Immune
System in Humans. In Perlmann P, Troye-Blomberg M (eds): Malaria
Immunology. Chem Immunol. Basel, Karger, 2002, vol 80, pp 229–242.
Available at
http://content.karger.com/ProdukteDB/Katalogteile/isbn3_8055/_73/_76/CI80-Perlmann.pdf
- Roetynck S, Baratin M, Vivier E, Ugolini S. NK cells and
innate immunity to malaria. Med Sci (Paris). 2006
Aug-Sep;22(8-9):739-44 Available at
http://www.medecinesciences.org/articles/medsci/pdf/2006/08/medsci2006228-9p739.pdf
- Mary M. Stevenson, Eleanor M. Riley. Innate immunity to
malaria. Nature Reviews Immunology March 2004;4:169-180.
doi:10.1038/nri1311
- Anoja Ariyasinghe, Sufi Reza M. Morshed, M. Kaiissar Mannoor
et al. Protection against Malaria Due to Innate Immunity Enhanced
by Low-Protein Diet. The Journal of Parasitology. Jun
2006;92(3):531-538
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Ashwani Kumar, Neena Valecha, Tanu Jain, Aditya P. Dash. Burden
of Malaria in India: Retrospective and Prospective View. Am. J.
Trop. Med. Hyg. 2007;77(6_Suppl):69-78. Full Text at
http://www.ajtmh.org/cgi/reprint/77/6_Suppl/69
- Owain R Millington, Caterina Di Lorenzo, R Stephen Phillips,
Paul Garside, James M Brewer. Suppression of adaptive immunity to
heterologous antigens during Plasmodium infection through hemozoin-induced
failure of dendritic cell function. Journal of Biology 2006;5:5.
Full text at http://jbiol.com/content/pdf/jbiol34.pdf
- Hajime Hisaedaa, Koji Yasutomob, Kunisuke Himeno. Malaria:
immune evasion by parasites. The International Journal of
Biochemistry & Cell Biology. April 2005;37(4):700-706
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Laith J. Abu-Raddad, Padmaja Patnaik, James G. Kublin. Dual
Infection with HIV and Malaria Fuels the Spread of Both Diseases in
Sub-Saharan Africa. Science 8 December
2006;314(5805):1603–1606
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