Immunopathology

Apicomplexa: Malaria

3.7 Immunopathology

Malaria is a complex multisystem disorder, with many similarities to bacterial sepsis. Disease can manifest as a heterogeneous set of symptoms, varying from person to person but broadly defined as mild and severe malaria. The vast ma- jority of cases of malaria are mild in nature, but severe life-threatening malaria occurs mostly in children under five years of age infected with P. falciparum. Ex- cessive inflammatory immune responses against the erythrocytic asexual cycle stages of malaria results in pathogenesis of malaria infection but this can be counteracted by the induction of the immunoregulatory cytokines IL-10 and transforming growth factor (TGF)-␤, which down-regulate production of IFN-

␥in malaria infection.

3.7.1 Thermoregulation

Malaria is associated with fevers that coincide with rupture of infected RBCs upon schizont rupture (Figure 3.1), with the concomitant release of inflam- matory parasite products such as GPI anchors, uric acid and parasite DNA (Table 3.1). Stimulation of macrophages, and other antigen presenting cells harbouring the relevant PRRs, results in an acute phase reaction and the release of cytokines such as TNF-␣. Fever is caused by the interaction of acute phase response cytokines with the hypothalamus in the brain. Neutralisation of TNF-␣via monoclonal antibody treatment can reduce fevers in P. falciparum infection.

3.7.2 Severe malarial anaemia

Severe malarial anaemia (SMA) is often associated with chronic and repeated infections of malaria, and it can lead to a drop in haemoglobin in the blood to ⬍5 g/dl (normal values are between 10–15 g/dl for humans). Anaemia in malaria infection can be due to loss of RBCs during parasite replication, as well as removal of infected RBCs as part of immune-mediated clearance mech- anisms. In addition, increased phagocytic mechanisms in the spleen lead to

premature clearance of uninfected RBCs; around ten times more uninfected RBCs are removed from the circulation that infected RBCs.

RBC loss is normally compensated for by the development and release of new RBCs from progenitor cells in a process known as erythropoiesis. Parasite prod- ucts such as haemozoin, and anti-malarial immune responses to these prod- ucts, can depress normal haematopoietic mechanisms in the bone marrow and spleen.

The amount of TNF in children infected with malaria is positively correlated with the severity of malarial anaemia, in particular when levels of the im- munoregulatory cytokine IL-10 are low. In addition, the TNF-238A promoter al- lele, controlling expression of TNF, is correlated with the development of SMA.

The production of haematopoietic stimulant proteins (such as erythropoietin produced from the kidneys) is also depressed in malaria infection.

3.7.3 Metabolic acidosis and respiratory distress

The development of metabolic acidosis, whereby the pH of the blood lowers due to increased production of hydrogen in the body or defective removal of bicarbonate from the body by the kidneys, is often accompanied by respiratory distress and is strongly correlated with fatal malaria infection. Metabolic aci- dosis is exacerbated by the lack of circulating RBCs in patients with SMA, due to a reduction in the amount of oxygen delivered to the tissues and anaerobic metabolism. Hypovolaemia, whereby the volume of circulating blood decreases (presumably volume loss is partially due to lost RBC mass), is associated with severe anaemia, and this also exacerbates metabolic acidosis.

3.7.4 Cerebral malaria

This has a high case fatality and is a pathological condition resulting from infec- tion with P. falciparum. A number of hypotheses have been proposed to explain the phenomenon of cerebral malaria, but in general it is thought to stem from immune responses against sequestered infected RBCs. Without the adhesive properties of P. falciparum, cerebral malaria does not generally occur.

Sections of brain tissue from fatal P. falciparum infections reveal microvas- cular obstruction in the brain due to the accumulation of sequestered in- fected RBCs, autoagglutinates (whereby infected RBC adhere to each other) and rosettes of infected RBCs, as well as infiltrates of lymphocytes. Brain-resident macrophages, or macrophage/monocyte populations that migrate to the brain tissue as a result of inflammatory immune responses against sequestered in- fected RBCs, directly contribute to the pathogenesis of cerebral malaria.

Secretion of chemokines such as macrophage inflammatory protein (MIP)-1␣ and MIP-1␤by macrophages augments the migration of lymphocytes to the brain, in turn magnifying the pro-inflammatory response already under way.

The release of pore-forming molecules such as perforin from CD8+ T cells and NK cells that have migrated to the brain tissue contributes to disruption of the

blood-brain barrier (BBB). Release of inflammatory molecules such as TNF-␣ up-regulates the expression of adhesion molecules such as ICAM-1 and VCAM- 1 on the endothelium of the brain tissue, in turn amplifying the sequestration of infected RBC via Pf EMP-1.

REFERENCES FOR FURTHER READING

Malaria

World Health Organisation (2010).World Malaria Report 2010. Can be accessed at URL:

www.who.int/malaria/world malaria report 2010/en/index.html

The malaria life cycle

Cooke, BMet al. (2001). The malaria-infected red blood cell:

structural and functional changes.Advances in Parasitology50, 1–86.

Haase, S & de Koning-Ward, TF (2010). New insights into protein export in malaria parasites.Cellular Microbiology12(5), 580–7.

Mouse models of malaria

De Souza, JBet al. (2010). Cerebral malaria: why experimental murine models are required to understand the pathogenesis of disease.Parasitology137(5), 755–72

Lamb, TJet al. (2006). Insights into the immunopathogenesis of malaria using mouse models.Expert Reviews in Molecular Medicine 8(6), 1–22.

Langhorne, Jet al. (2002). Mouse models of blood-stage malaria infections: immune responses and cytokines involved in protection and pathology.Chemical Immunology80, 204–28.

Recognition of malaria parasites

Couper, KNet al. (2010). Parasite-derived plasma microparticles contribute significantly to malaria infection-induced inflammation through potent macrophage stimulation.PLoS Pathogens6(1), e1000744.

Lamb, Tet al. (2010). How do malaria parasites activate dendritic cells?Future Microbiology5(8), 1167–71.

Innate immunity to malaria

Roetynck, Set al. (2006). Natural killer cells and malaria.

Immunological Reviews214, 251–63.

Stevenson, MM & Riley, EM. (2004). Innate immunity to malaria.

Nature Reviews Immunology4(3), 169–80.

Urban, BCet al. (1999).Plasmodium falciparum-infected erythrocytes modulate the maturation of dendritic cells.Nature 400(6739), 73–7.

Adaptive immunity to malaria liver-stages

Charoenvit, Yet al. (1999). CD4(+) T-cell- and gamma interferon-dependent protection against murine malaria by immunization with linear synthetic peptides from aPlasmodium yoelii17-kilodalton hepatocyte erythrocyte protein.Infection and Immunity67(11), 5604–14.

Doolan, DL & Hoffman, SL (2000). The complexity of protective immunity against liver-stage malaria.Journal of Immunology165(3), 1453–62.

Frevert, U & Nardin, F (2008). Cellular effector mechanisms againstPlasmodiumliver stages.Cellular Microbiology10 (10), 1956–1967

Overstreet, MGet al. (2008). Protective CD8 T cells against Plasmodiumliver stages: immunobiology of an ‘unnatural’ immune response.Immunological Reviews225, 272–83.

Vanderberg, Jet al. (2007). Assessment of antibody protection against malaria sporozoites must be done by mosquito injection of sporozoites.The American Journal of Pathology171(4), 1405–6; author reply 1406.

Weiss, WRet al. (1988). CD8+ T cells (cytotoxic/suppressors) are required for protection in mice immunized with malaria sporozoites.Proceedings of the National Academy of Sciences of the USA85(2), 573–6.

White, KLet al. (1996). MHC class I-dependent presentation of exoerythrocytic antigens to CD8+ T lymphocytes is required for protective immunity againstPlasmodium berghei. Journal of Immunology156(9), 3374–81.

Adaptive immunity to malaria erythrocytic stages

Cohen, Set al. (1961). Gamma-globulin and acquired immunity to human malaria.Nature192, 733–7.

Langhorne, Jet al. (1998). A role for B cells in the development of T cell helper function in a malaria infection in mice.Proceedings of the National Academy of Sciences of the USA95(4), 1730–4.

Langhorne, Jet al. (2008).Immunity to malaria: more questions than answers. Nature Immunology9(7) pp725–732

O’Donnell, RAet al. (2001). Antibodies against merozoite surface protein (MSP)-1(19) are a major component of the invasion-inhibitory response in individuals immune to malaria.The Journal of Experimental Medicine193(12), 1403–12.

Sabchareon, Aet al. (1991). Parasitologic and clinical human response to immunoglobulin administration in falciparum malaria.

The American Journal of Tropical Medicine and Hygiene45(3), 297–

308.

Memory responses

Weiss, GEet al. (2010). ThePlasmodium falciparum-specific human memory B cell compartment expands gradually with repeated malaria infections.PLoS Pathogens6(5), e1000912.

Scheller, LF & Azfad, AF (1995). Maintenance of protective immunity against malaria by persistent hepatic parasites derived from irradiated sporozoites.Proceedings of the National Academy of Sciences of the USA92(9), 4066–8.

Mount, AMet al. (2004). Impairment of humoral immunity to Plasmodium falciparummalaria in pregnancy by HIV infection.

Lancet363(9424), 1860–7.

Immune evasion

Casares, S & Richie, TL (2009). Immune evasion by malaria parasites: a challenge for vaccine development.Current Opinion in Immunology21(3), 321– 30.

Steers, Net al. (2005). The immune status of Kupffer cells profoundly influences their responses to infectiousPlasmodium

bergheisporozoites.European Journal of Immunology35(8), 2335–46.

Torcia, MGet al. (2008). Functional deficit of T regulatory cells in Fulani, an ethnic group with low susceptibility toPlasmodium falciparummalaria.Proceedings of the National Academy of Sciences of the USA105(2), 646–51.

Urban, BCet al. (2001). Peripheral blood dendritic cells in children with acutePlasmodium falciparummalaria.Blood98(9), 2859–61.

Walther, Met al. (2005). Upregulation of TGF-␤, FOXP3, and CD4+CD25+ regulatory T cells correlates with more rapid parasite growth in human malaria infection.Immunity23(3), 287–96.

Immunopathogenesis

Mackintosh, CLet al. (2004). Clinical features and pathogenesis of severe malaria.Trends in Parasitology20(12), 597–603

McGuire, Wet al. (1999). Severe malarial anemia and cerebral malaria are associated with different tumor necrosis factor promoter alleles.The Journal of Infectious Diseases179(1), 287–90.

4