Invited Review
Harbouring in the brain: A focus on immune evasion mechanisms and their deleterious effects in malaria and human African trypanosomiasis

https://doi.org/10.1016/j.ijpara.2006.02.001Get rights and content

Abstract

Malaria and human African trypanosomiasis represent the two major tropical vector-transmitted protozoan infections, displaying different prevalence and epidemiological patterns. Death occurs mainly due to neurological complications which are initiated at the blood–brain barrier level. Adapted host-immune responses present differences but also similarities in blood–brain barrier/parasite interactions for these diseases: these are the focus of this review. We describe and compare parasite evasion mechanisms, the initiating mechanisms of central nervous system pathology and major clinical and neuropathological features. Finally, we highlight the common immune mediated mechanisms leading to brain involvement. In both diseases neurological damage is caused mainly by cytokines (interferon-gamma, tumour necrosis factor-alpha and IL-10), nitric oxide and endothelial cell apoptosis. Such a comparative analysis is expected to be useful in the comprehension of disease mechanisms, which may in turn have implications for treatment strategies.

Introduction

Malaria and human African trypanosomiasis (HAT or sleeping sickness) are two major killers in tropical countries. Every year, more than 1 million people, primarily children, die from malaria due to severe anaemia, multi-organ system failure or cerebral complications (Anonymous, 2000). The figures are more difficult to evaluate in African trypanosomiasis since people die from opportunistic infections, meningoencephalitis or drug-related encephalopathy. This disease, affecting remote rural populations, is often misdiagnosed and under-diagnosed, as out of the total of 500,000 suspected cases, only 40,000 are detected yearly (Anonymous, 1998). Malaria affects tropical populations worldwide and consequently is 200 times more frequent than HAT. On the other hand, using the disability-adjusted-life years lost (DALY) estimations from the World Bank, trypanosomiasis represents 10 million DALY, placing it second only to malaria in the global burden of parasitic diseases (Anonymous, 1993).

The geographic range of these vector-transmitted diseases (mosquito for malaria and tsetse fly for HAT) overlap in sub-Saharan African countries and clinical signs may be confused in those regions. Fever, headaches, polyarthralgia, dizziness are common signs at the onset of both infections, as are psychiatric symptoms and coma at the stage of CNS involvement. In malaria, the rapid onset of symptoms and the presence of numerous parasites on a blood smear make diagnosis easier than in sleeping sickness. Malaria progresses in acute attacks with progressive development of premunition and cerebral malaria (CM) occurs mainly in children (0–5 years) and in previously non-immune subjects from areas of low endemicity. Clinical patterns vary widely around the world because of strain variations in parasite pathogenicity and/or differences in patient immune status (Turner, 1997, Artavanis-Tsakonas et al., 2003b). Recent immunological studies confirm similar variability for trypanosomiasis (MacLean et al., 2004, Sternberg, 2004), however acquired immunity has not been studied properly in HAT (Khonde et al., 1995). It is common practice to avoid co-infection of sleeping sickness patients with malaria (via systematic pre-treatment of patients with anti-malarial drugs) but the reasons for this are not clearly documented and the details of the interactions between the two protozoan diseases (exacerbation/attenuation of symptoms or pathogenicity) are not yet known.

In both diseases, research has been conducted in human and diverse animal models: mouse and monkey in malaria (Lou et al., 2001, de Souza and Riley, 2002), mouse, rat, sheep and monkey in HAT (Bouteille et al., 1999). Animal models are, of course, imperfect in representing the human diseases. However, they allow studies on basic mechanisms involved in the development of immune and neuropathological reactions.

This review deals with Plasmodium falciparum and Trypanosoma brucei gambiense/Trypanosoma brucei rhodesiense as they interact with the blood–brain barrier (BBB). Our aim was to focus on the strategies utilized by both parasites to escape the host's immune system and the resulting neuropathological differences and similarities during host-BBB interactions, using both man and animal studies to help piece together the fragmentary data (see Table 1). Dissecting the mechanisms of those interactions offers insights into the dynamics of host membranes and intracellular trafficking that could potentially lead to the development of new control strategies.

Section snippets

Mechanisms of parasite survival in the host

Both parasites have developed sophisticated means to evade destruction by the immune system. Three main mechanisms can be identified: (i) hiding sites from host immunity or from destruction processes; (ii) antigenic variation; and (iii) parasite production of host-like molecules or metabolic deviations that favour their survival either directly or through immunosuppression.

Mechanisms initiating CNS invasion in CM and HAT meningoencephalitis

P. falciparum and T. brucei parasites interact with the BBB, the physical and metabolic barrier between the CNS and the periphery. Two different structures separate the blood from the CNS: the BBB and the blood–cerebrospinal fluid barrier (BCSFB). The BBB is composed of specialized capillary ECs. This endothelium differs from others through the presence of intercellular tight junctions, the presence of pericytes within the capillary basement membrane and the fact that astrocyte foot processes

Malaria

Neurological manifestations of malaria include headache, agitation, prostration, frank psychosis, seizures and impaired consciousness (Newton and Warrell, 1998). Cerebral malaria is the most severe neurological complication and is defined as an acute encephalopathy with seizures and loss of consciousness in an individual with P. falciparum infection in whom other causes of coma have been excluded (Anonymous, 2000). CM is defined on the Glasgow coma scale ≤9 or Blantyre coma scale ≤2, for adults

Neuropathology in CM and HAT meningoencephalitis

The cerebral pathology of the two diseases differs, as trypanosomes penetrate the CNS while malaria parasites induce pathology through contact with cerebral ECs (Fig. 1a and b). However, the diseases are similar, in that they cannot be distinguished by identification of systematic brain lesions capable of explaining clinical signs and evolution. Cerebral malaria leads to very poorly defined pathological lesions, while African trypanosomiasis does not show any specific alteration.

Common immune mediated mechanisms of brain pathology

The CNS is no longer considered an ‘immune-privileged’ site: constant immune interactions occur with the blood compartment, with the intact CNS regularly containing small numbers of T cells (Ransohoff et al., 2003). Protein antigens in the CNS can readily access lymphoid tissues through the CSF and cervical lymphatics and, after appropriate processing and presentation, can stimulate antigen-specific responses of naïve or memory T cells that express cognate receptors. The CSF may be considered

Concluding remarks

Understanding cross-talk between BBB and CNS in health and different disease states provides important insights to explain neuropathogenesis and develop new treatment options. Cerebral malaria is an acute partially ischemic-related pathology whereas HAT meningoencephalitis is a neurodegenerative-type pathology. The latter may be used as a model for studies on neurodegenerative processes. Recent findings concerning laminin α4 and treatment strategies for multiple sclerosis open the field to new

Acknowledgements

This work benefited from several grants or funding sources: (i) Programme PAL +(2002) du Ministère de la Jeunesse, de l'Education Nationale et de la Recherche ‘Analyse du rôle des molécules de transduction du signal dans la pathogenèse du neuropaludisme humain. Application à la compréhension de la pathogénicité des isolats de P. falciparum et à l'identification de nouvelles cibles thérapeutiques’ (ii) Contrat d'objectif 03CO001 08 de la Délégation ministérielle pour l'armement ‘Lutte contre le

References (132)

  • A.M. Dondorp et al.

    Reduced microcirculatory flow in severe falciparum malaria: pathophysiology and electron-microscopic pathology

    Acta Trop.

    (2004)
  • J.E. Donelson et al.

    Multiple mechanisms of immune evasion by African trypanosomes

    Mol. Biochem. Parasitol.

    (1998)
  • B. Engelhardt et al.

    The ins and outs of T-lymphocyte trafficking to the CNS: anatomical sites and molecular mechanisms

    Trends Immunol.

    (2005)
  • M.L. Gatton et al.

    Switching rates of plasmodium falciparum var genes: faster than we thought?

    Trends Parasitol.

    (2003)
  • M. Girard et al.

    In vitro induction of microglial and endothelial cell apoptosis by cerebrospinal fluids from patients with human African trypanosomiasis

    Int. J. Parasitol.

    (2003)
  • M. Girard et al.

    Endothelial cell activation in the presence of African trypanosomes

    Mol. Biochem. Parasitol.

    (2005)
  • B.M. Greenwood et al.

    The pathogenesis of sleeping sickness

    Trans. R. Soc. Trop. Med. Hyg.

    (1980)
  • K.L. Hill et al.

    T lymphocyte-triggering factor of african trypanosomes is associated with the flagellar fraction of the cytoskeleton and represents a new family of proteins that are present in several divergent eukaryotes

    J. Biol. Chem.

    (2000)
  • N.H. Hunt et al.

    Cytokines: accelerators and brakes in the pathogenesis of cerebral malaria

    Trends Immunol.

    (2003)
  • P. Imbert et al.

    Severe falciparum malaria in children: a comparative study of 1990 and 2000 WHO criteria for clinical presentation, prognosis and intensive care in Dakar, Senegal

    Trans. R. Soc. Trop. Med. Hyg.

    (2002)
  • M. Keita et al.

    Inducible nitric oxide synthase and nitrotyrosine in the central nervous system of mice chronically infected with Trypanosoma brucei brucei

    Exp. Parasitol.

    (2000)
  • N. Khonde et al.

    Epidemiological evidence for immunity following Trypanosoma brucei gambiense sleeping sickness

    Trans. R. Soc. Trop. Med. Hyg.

    (1995)
  • V. Lejon et al.

    Interleukin (IL)-6, IL-8 and IL-10 in serum and CSF of Trypanosoma brucei gambiense sleeping sickness patients before and after treatment

    Trans R. Soc. Trop. Med. Hyg.

    (2002)
  • J.D. Lonsdale-Eccles et al.

    Trypanosome hydrolases and the blood–brain barrier

    Trends Parasitol.

    (2002)
  • B.K. Lopansri et al.

    Low plasma arginine concentrations in children with cerebral malaria and decreased nitric oxide production

    Lancet

    (2003)
  • R. Lucas et al.

    A role for TNF during African trypanosomiasis: involvement in parasite control, immunosuppression and pathology

    Res. Immunol.

    (1993)
  • C.L. Mackintosh et al.

    Clinical features and pathogenesis of severe malaria

    Trends Parasitol.

    (2004)
  • K. Marsh et al.

    Plasmodium falciparum: the behavior of clinical isolates in an in vitro model of infected red blood cell sequestration

    Exp. Parasitol.

    (1988)
  • J.D. Mhlanga et al.

    Neurobiology of cerebral malaria and African sleeping sickness

    Brain Res. Bull.

    (1997)
  • G.W. Morgan et al.

    The kinetoplastida endocytic apparatus. part I: a dynamic system for nutrition and evasion of host defences

    Trends Parasitol.

    (2002)
  • T. Owens et al.

    Cytokine and chemokine inter-regulation in the inflamed or injured CNS

    Brain Res. Brain Res. Rev.

    (2005)
  • E. Pays

    Regulation of antigen gene expression in Trypanosoma brucei

    Trends Parasitol.

    (2005)
  • M.O. Abolarin et al.

    Cryptic stage of sleeping-sickness trypanosome developing in choroid plexus epithelial cells

    Br. Med. J.

    (1982)
  • V. Amani et al.

    Involvement of IFN-gamma receptor-medicated signaling in pathology and anti-malarial immunity induced by Plasmodium berghei infection

    Eur. J. Immunol.

    (2000)
  • M.D. Amevigbe et al.

    Human African trypanosomiasis: presence of antibodies to galactocerebrosides

    Am. J. Trop. Med. Hyg.

    (1992)
  • Anonymous

    World Development Report 1993—Investing in Health

    Commun. Dis. Rep. CDR Wkly

    (1993)
  • Anonymous

    Control and surveillance of African trypanosomiasis. Report of a WHO Expert Committee

    World Health Organ. Tech. Rep. Ser.

    (1998)
  • Anonymous

    Severe falciparum malaria. World Health Organization, communicable diseases cluster

    Trans. R. Soc. Trop. Med. Hyg.

    (2000)
  • K. Artavanis-Tsakonas et al.

    Activation of a subset of human NK cells upon contact with Plasmodium falciparum-infected erythrocytes

    J. Immunol.

    (2003)
  • K. Artavanis-Tsakonas et al.

    The war between the malaria parasite and the immune system: immunity, immunoregulation and immunopathology

    Clin. Exp. Immunol.

    (2003)
  • Z. Ayed et al.

    Detection and characterization of autoantibodies directed against neurofilament proteins in human African trypanosomiasis

    Am. J. Trop. Med. Hyg.

    (1997)
  • M. Bakhiet et al.

    A trypanosoma brucei brucei-derived factor that triggers CD8+ lymphocytes to interferon-gamma secretion: purification, characterization and protective effects in vivo by treatment with a monoclonal antibody against the factor

    Scand. J. Immunol.

    (1993)
  • B. Bouteille et al.

    Experimental models for new chemotherapeutic approaches to human African trypanosomiasis

  • H. Brown et al.

    Evidence of blood–brain barrier dysfunction in human cerebral malaria

    Neuropathol. Appl. Neurobiol.

    (1999)
  • H. Brown et al.

    Cytokine expression in the brain in human cerebral malaria

    J. Infect. Dis.

    (1999)
  • H. Brown et al.

    Blood–brain barrier function in cerebral malaria in malawian children

    Am. J. Trop. Med. Hyg.

    (2001)
  • A. Buguet et al.

    NO is a cornerstone in sleeping sickness: voltametric assessment in mouse and man

  • J.A. Carter et al.

    Developmental impairments following severe falciparum malaria in children

    Trop. Med. Int. Health

    (2005)
  • Q. Chen et al.

    Developmental selection of var gene expression in Plasmodium falciparum

    Nature

    (1998)
  • G.A. Cross

    Antigenic variation in trypanosomes: secrets surface slowly

    Bioessays

    (1996)

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