Immunity

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 (TCR^int) 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]

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/]

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.

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:

1. 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
2. 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
3. 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.
4. 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
5. 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
6. Mary M. Stevenson, Eleanor M. Riley. Innate immunity to malaria. Nature Reviews Immunology March 2004;4:169-180. doi:10.1038/nri1311
7. 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
8. 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
9. 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
10. Hajime Hisaedaa, Koji Yasutomob, Kunisuke Himeno. Malaria: immune evasion by parasites. The International Journal of Biochemistry & Cell Biology. April 2005;37(4):700-706
11. 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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