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39 Urdaneta, L. et al. (2001) Evidence for clonal
propagation in natural isolates of Plasmodium
falciparum from Venezuela. Proc. Natl. Acad. Sci.
U. S. A. 98, 6725–6729
40 Maynard Smith, J. and Haigh, J. (1974) The
hitch-hiking effect of a favorable gene. Genet. Res.
23, 23–35
41 Jongwutiwes, S. et al. (1994) Allelic variation in
the circumsporozoite protein of Plasmodium
falciparum from Thai field isolates. Am. J. Trop.
Med. Hyg. 51, 659–668
42 Rich, S.M. and Ayala, F.J. (2000)
Population structure and recent evolution
of Plasmodium falciparum. Proc. Natl.
Acad. Sci. U. S. A. 97, 6994–7001
43 Winzeler, E.A. et al. (1998) Direct allelic variation
scanning of the yeast genome. Science 281,
1194–1197
44 Desowitz, R.S. (1991) The Malaria Capers: More
Tales of Parasites and People, Research and
Reality, W.W. Norton

How protozoan parasites evade the

immune response
Sergio Zambrano-Villa, Disney Rosales-Borjas, Julio César Carrero and
Librado Ortiz-Ortiz

Protozoan pathogens such as Plasmodium, Leishmania, Trypanosoma and stages. During the very early stage of infection, the
Entamoeba are responsible for several of the most widespread and lethal host response is poor because of the relatively low
human diseases. Their successful survival depends mainly on evading the host density of sporozoites and their rapid migration to
immune system by, for example, penetrating and multiplying within cells, the liver. In order to survive, the parasite must reach
varying their surface antigens, eliminating their protein coat, and modulating the hepatocytes and transform into merozoites,
the host immune response. Immunosuppression is sometimes caused directly acquiring new biological features to confront the
by parasite products and sometimes involves antigenic mimicry, which often immune system. Once the Plasmodium parasite is
appears in association with parasitic diseases. However, one of the most established in the host, it evades the immune
sophisticated mechanisms of evasion is the selective activation of a subset response (IR) by changing its surface antigens
of T helper cells. as it passes through the stages of its life cycle.
Thus, each phase of the cellular cycle is associated
Parasites that cause malaria, sleeping sickness, with the expression of stage- and species-specific
Chagas disease, amoebiasis and leishmaniasis proteins, many of which are inserted into the
primarily affect the populations of developing membrane surface of the parasite or the red blood
countries, causing high rates of morbidity and cells they invade.
mortality [1]. The host’s mechanisms of defense range The development of an effective IR is hampered by
from primary barriers to the most elaborate devices, the fact that stage-specific proteins tend to be highly
which involve a wide variety of cells and molecules polymorphic or antigenically variable. Sequence
capable of the specific recognition and elimination of polymorphism is common in several Plasmodium
invasive agents. Parasites with extracellular stages proteins, especially in those with extensive repetitive
are the target of the humoral immune response, regions, such as the circumsporozoite protein (CSP),
whereas those with intracellular stages are an antigen with multiple tandem repeats and that is
Sergio Zambrano-Villa
Centro Universitario de susceptible to attack by the cell-mediated immunity. located on the surface of malaria sporozoites.
Ciencias Exactas e Despite the large amount of antigen presented by the Antigens with multiple repeats could downregulate
Ingenierías, Universidad parasite to the host and the host’s immune and antibody isotype maturation and the production of
de Guadalajara,
Guadalajara, Jalisco,
inflammatory response, parasites manage to survive high-affinity antibodies by acting as B-cell
México. within the host for long periods by using multiple superantigens and predominantly inducing a
evasion mechanisms that have been acquired during polyclonal thymus-independent humoral response
Disney Rosales-Borjas
Hospital Universitario Dr millions of years of evolution (Table 1). Parasites have [2]. Despite the short time of circulation of the
Miguel Oraá, Guanare, evasion mechanisms that depend on factors such as malaria extracellular phases, when an antibody
Edo. Portuguesa, their life-cycle stage, the route of penetration and the response does develop against sporozoites,
Venezuela.
microenvironment in which they are established plasmodia overcome the response by sloughing off
Julio César Carrero inside the host. their surface CSP coat, rendering the antibodies
Librado Ortiz-Ortiz*
Departamento de
ineffective. The versatility of CSP is also evident in its
Inmunología, Instituto de Malaria RNA-binding motifs, which block RNA translation in
Investigaciones In humans, malaria is caused by Plasmodium vivax, mammalian cells [3].
Biomédicas, UNAM, Plasmodium malariae, Plasmodium ovale and Other proteins, such as the P. falciparum
México.
*e-mail: librado@
Plasmodium falciparum. The infection involves a merozoite surface protein (MSP-1) 1, induce ‘blocking
servidor.unam.mx complex life cycle with intra- and extracellular antibodies’ that bind anywhere on MSP-1, preventing

http://parasites.trends.com 1471-4922/02/$ – see front matter © 2002 Elsevier Science Ltd. All rights reserved. PII: S1471-4922(02)02289-4
 Review TRENDS in Parasitology Vol.18 No.6 June 2002 273

Table 1. Comparison of main evasion mechanisms for selected protozoan parasitesa

Parasite (disease) Epidemiology of the Main strategies of evasion Result Refs
disease [1]
Plasmodium falciparum 300 million–500 million Antigenic variation and/or polymorphisms Evades the IR; infected cells are [2]
(malaria) infected per year prevented from being swept to the
1.5 million–2.7 million spleen
deaths per year Induction of blocking antibodies Blocks the binding of real inhibitory [4]
antibodies
Molecular mimicry Alters immune recognition and might [6,7]
induce autoimmune disease
Anergy of T cells Immunosuppression [10–14]
Altered peptide ligand Alters functions of memory T cells [15,16]
Trypanosoma brucei 15 000–20 000 new cases Antigenic variation by VSG Evades the previously established IR [17,18]
(African trypanosomiasis per year Alteration of T- and B-cell populations Immunosuppression [19]
or sleeping sickness) 55 million at risk Abnormal activation of macrophages Impairs macrophage functions [20]
Induction of changes in the pattern of cytokines Increases IFN-γ and decreases IL-2 and [21]
released by CD8+ T cells IL-2R; renders T cells unresponsive
Production of a gp63-like-protein Resists complement [22]
Trypanosoma cruzi 12 million–16 million Increased phagocytic activity More CD8+ T cells and reduced TDR [23]
(Chagas disease) infected and TIR
45 000 deaths per year Parasite mucin that binds to macrophage Impairs macrophage cytokine secretion [25]
90 million at risk Anergy of T cells Immunosuppression [26,27]
Production of blocking IgM antibodies Blocks the binding of real inhibitory [29]
antibodies
Turnover of surface molecules, phospholipases Resists complement [31–33]
and complement-regulating factors
Entamoeba histolytica 500 million infected Cytolytic capacity Damages host cells and tissues,
(Intestinal and liver 40 000–110 000 deaths interfering with IR
amoebiasis) per year Degradation of antibodies by proteases Evades humoral immunity [34]
Acquisition of complement-regulating factors, Resists complement and protects [36,37]
shedding of immune complexes by capping against the inflammatory response
and inactivation of C3a and C5a [38,39]
Anergy of T cells Immunosuppression [41–43]
Release of products (MLIF among others) that Impairs macrophage functions
act on macrophages; produces PGE2
Induction of IL-4 and IL-10 Modulates the Th1 response [45]
Leishmania parasites 12 million infected Inhibition of phagolysosome formation and Evades the macrophage proteolytic [46,47]
(leishmaniasis: 350 million at risk the proteolytic enzymes from lysosome processes
cutaneous, 1 million–1.5 million new [48]
mucocutaneous and cases per year of Abnormal activation of protein kinase C and Inhibits the respiratory burst [49]
visceral) cutaneous leishmaniasis scavenging of oxygen intermediates
500 000 new cases and Prevention of apoptosis of infected Extends the survival of the infected [50,51,
75 000–80 000 deaths macrophage macrophage 53]
per year owing to Inhibition of MHC-protein production, peptide Impairs macrophage antigen- [54,56]
visceral leishmaniasis loading and expression of co-stimulatory presenting function [57]
molecules
[58,59]
Induction of PGE2 and downregulation of TNF-αR Impairs macrophage function
Inhibition of macrophage and neutrophil Promotes survival of parasites once [61]
chemotaxis established
Shedding of MAC complex and inactivation of Resists complement
some MAC components
Suppression of transcription of the IL-12 gene Blocks the protective Th1 response
aAbbreviations: IFN-γ, interferon γ; IL-2, interleukin 2; IL-4, interleukin 4; IL-10, interleukin 10; IL-12, interleukin 12; IL-2R, IL-2 receptor; IR, immune response; MAC, membrane
attack complex; MHC, major histocompatibility complex; MLIF, monocyte locomotion inhibition factor; PGE2, prostaglandin E2; TDR, thymus-dependent response;
TIR, thymus-independent response; TNF-αR, tumor necrosis factor α receptor; VSG, variant surface glycoprotein.

the binding of antibodies with real inhibitory
capacity [4]. In addition, the P. falciparum protein
PfEMP-1, which is expressed at the surface of infected
erythrocytes, favors adherence to the vascular
endothelium via molecules such as CD36 and
ICAM-1. In this way, the infected cells are prevented
from being swept to the spleen, where they would be
recognized as altered and phagocytosed because of
their significantly altered morphology. To circumvent
the effect of anti-PfEMP-1 antibodies, the molecule
undergoes clonal variation at high frequency [5].
Molecular mimicry, which is common in human
malaria, can modulate the cellular IR and the release
of cytokines and is probably involved in some of
the pathological manifestations. Thus, the
glycosylphosphatidylinositol (GPI) moiety that

http://parasites.trends.com
274 Review TRENDS in Parasitology Vol.18 No.6 June 2002
anchors a range of MSPs appears to have a marked
insulin-mimetic effect, reducing the glucose levels in
rodents at the same time that it increases the
synthesis of tumor necrosis factor (TNF) α and
interleukin-1 (IL-1) in macrophages; this is
responsible for the typical malarial fevers and the
production of acute-phase proteins [6]. In the same
context, sequences homologous to 1-thymosin
(a thymic hormone that modulates the differentiation
of T cells) have been identified in two P. falciparum
proteins. Like the human hormone, synthetic peptides
from those sequences showed a similar effect on T-cell
maturation, suggesting that it might interfere with
the development of effective cellular immunity [7].
Moreover, molecular mimicry in combination with the
polyclonal B-cell activation (PBCA) could be
responsible for the raising of autoantibodies in
human malaria. Autoantibodies have been found
against single-stranded DNA, heat-shock protein 70
and polypeptide and carbohydrate epitopes from red
blood cells [8]. However, the association between
autoantibodies and malaria pathology is
controversial. Moreover, it has been suggested that
autoantibodies could have a role in immune protection
against malaria and other infectious diseases [9].
In comparison with these surface proteins, some
internal antigens are less variable and seem to be at
least partially conserved among Plasmodium species.
When the schizont bursts, some of the antigens
released in large quantities appear also to be involved
in triggering the cascade of cytokines responsible for
most of the symptoms and pathology of the infection.
Evidence suggests that acute malaria infection
induces a temporal reduction of the IR. During
infection with P. falciparum, circulating T cells are
reduced in number, accompanied by a decrease in
lymphoproliferative response and cytokine release by
peripheral blood mononuclear cells when stimulated
by malaria antigens [10]. This effect is partially
reverted by the addition of indomethacin to the cell
cultures, indicating that prostaglandin secreted by
activated macrophages might be responsible [11].
Alternatively, it might be caused by the release into
the serum of acute-phase proteins that bind to the
surface of lymphoid cells, inhibiting lymphocyte
proliferation [12]. However, it has also been
reported that some malaria antigens can directly
induce immunosuppression. A low molecular
weight glycoprotein has been isolated from
Plasmodium berghei that suppresses the primary
thymus-dependent humoral response (TDHR) to
antigens in mice [13] and a schizont extract from
P. falciparum suppresses the lymphoproliferative
response to malarial and other soluble antigens in vitro
[14]. The mechanisms responsible for suppression are
not well known, although it has been suggested that
parasite hemozoin accumulation in macrophages
might inhibit their accessory function. Recent analysis
of the IR against CSP suggests that some P. falciparum
strains contain CSP variants with T-cell epitopes that
http://parasites.trends.com
are closely related to those of the original CSP. These
variants prevent the binding of the original T-cell
epitopes to the major histocompatibility complex
(MHC) molecule, altering memory-T-cell effector
functions, such as lymphokine synthesis, cytotoxicity
and proliferation [15]. During the liver stage, CSP
participates in the binding of sporozoites to
hepatocytes and contains cytotoxic T-lymphocyte
(CTL) epitopes that bind common MHC-class-I
alleles. A pair of CSP variant epitopes have been
identified in parasites from The Gambia that did not
bind to the MHC-class-I allele HLA-B35 or induce
CTL responses [16], by contrast to the original epitopes.
This is particularly important if we consider that CTL
and the memory response appear to be essential for
protection and long-lasting immunity, respectively.
African trypanosomiasis
African trypanosomiasis (sleeping sickness) is
produced in humans by two African trypanosomes
(Trypanosoma brucei gambiense and T. brucei
rhodesiense) and in cattle by four (T. brucei brucei,
Trypanosoma vivax, Trypanosoma evansi and
Trypanosoma congolense). These trypanosomes live in
the blood and lack intracellular stages, so the parasite
is a target for antibody-mediated destruction.
Certainly, almost all trypanosomes are cleared from
blood by liver macrophages. However, the remaining
parasites survive and establish the infection thanks
to the antigenic variation of the so-called variant
surface glycoprotein (VSG). Each trypanosome
carries a large repertoire of VSG genes coding for
multiple VSG variants with different primary
sequence, particularly at the N termini [17].
Interestingly, each parasite expresses a single VSG
gene at any one time by replacing the previous gene at
the telomeric active site of transcriptional expression
with the new one [18]. In consequence, this repeated
antigenic change of VSG in trypanosomes allows
them to evade the TDHR, resulting in successive
surges of parasitemia, a situation similar to being
infected successively by related, but not identical,
pathogens. This phenomenon makes it difficult to
develop a vaccine against the disease.
Because pathogenesis is linked to the inability of the
untreated patient to eliminate the parasite, attempts
have been made to determine the way by which the
parasite interacts with the immune system and
disturbs the balance of cytokine and other mediators,
thus allowing the pathology to progress. During
parasitemia, several populations of B and T cells
are altered. The TDHR against the persistent
trypanosome antigens is depressed, although the
thymus-independent humoral response to the VSG
surface epitopes [19] can probably control subsequent
parasitemias. Trypanosome products also activate
macrophages and CD8+ T cells in a particular way that
causes changes in the pattern of cytokines they release.
Among these, the GPI moiety of VSG appears to
overactivate the macrophages, which become
Review TRENDS in Parasitology Vol.18 No.6 June 2002
suppressor macrophages that produce TNF-α [20] and,
similar to the parasite protein T-cell-triggering factor,
induce CD8+ (but not CD4+) T cells to secrete high levels
of interferon (IFN) γ [21]. In turn, the high levels of IFN-γ
result in the decrease of IL-2 receptor expression and
IL-2 synthesis, which impair the proliferative T-cell
response to avoid parasite elimination.
Recently, a set of experiments have shown that
trypanosomes have several homologous genes
encoding glycoprotein 63 (gp63)-like proteins, similar
to those from Leishmania [22]. Although their role in
trypanosomes has not yet been determined, the
correlation between the amounts of gp63-like-protein
on the surface of different stages of the parasite and
their susceptibility to complement-mediated lysis
suggests an important role in immune evasion at the
blood stage. Thus, the resistance of blood
trypanosomes, which contain a lot of gp63-like-
protein, contrasts with the susceptibility of procyclic
trypanosomes, which have less.
American trypanosomiasis
Infection by Trypanosoma cruzi, the agent that causes
American trypanosomiasis or Chagas disease, is often
lethal in children and infants. However, in adults, the
initial infection often turns into a chronic disease,
sometimes after a long interval, causing an illness
characterized by megacardia with megacolon,
mega-esophagus and degeneration of the central
and peripheral nervous systems. A range of
immune-system-evasion mechanisms operate
during the infection and contribute to both the
chronicity of the infection and the pathological
changes associated with it.
The disease is generally associated with
suppression of the IR that becomes more evident as
the parasitemia advances in blood and tissues.
Surprisingly, phagocytic activity is increased in
immunosuppressed animals [23], suggesting that the
immunosuppression is due to this increase and not to
the blocking of the mononuclear phagocytic system,
as has been observed in leishmaniasis and in African
trypanosomiasis. A similar phenomenon of increased
mononuclear phagocytic activity associated with
important immunosuppression was also noted in
experimental infections with Plasmodium vinckei
[24]. Moreover, T. cruzi evades destruction by
macrophages by escaping from the phagolysosome
and invading non-phagocytic cells as well as by
modulating the pattern of secreted cytokines at
the transcriptional level. In this sense, it has been
shown that a T. cruzi membrane GPI-anchored
mucin (AgC10) [25] can bind to the macrophage
surface and induce the secretion of IL-1β but not of
IL-12 or TNF-α, which are considered to be essential
in a protective response against Chagas disease.
The parasite also promotes the production of
IL-10 and transforming growth factor (TGF) β in
infected macrophages, which inhibit the induction
and effects of IL-12 (Ref. [26]).
http://parasites.trends.com
275
T-cell immunosuppression during experimental
infection by T. cruzi has been confirmed by various
authors. Parasite products interfere with various
components of the immune system, including a
decrease in the expression of lymphocyte receptors
(e.g. IL-2R) [27] and in the production of cytokines
involved in the effector phase of the IR [26]. The
mechanism is unknown but could involve suppressor
cells characterized as spleen non-adherent Thy-1+
Ly-2+ cells [28]. Trypanosoma cruzi, similar to other
protozoa, induces PBCA with subsequent
overproduction of IgM antibodies. These antibodies
bind to the trypomastigote surface, interfering with
the binding of IgG inhibitory antibodies and
consequently preventing the elimination of T. cruzi
parasites in mice [29]. Moreover, PBCA could activate
B cells specific for autoantigens, potentially inducing
the autoimmune disease that is characteristic of this
infection [30]. In the same context, T. cruzi produces
molecules that mimic those of host cells, inhibiting
immune recognition and eliciting autoimmunity.
The destruction of host cells is an autoimmune
phenomenon but whether it is initiated by antigens
of host or parasite origin or both is not at all clear.
Other strategies used by T. cruzi to extend its
survival in vertebrate blood include the production of
surface molecules with anti-complement properties,
such as T-DAF, gp58/68 and gp160 [31], and the
elimination of immune membrane complexes by
surface molecule turnover through the endocytic
pathway [32] and phospholipases that degrade the
anchoring glycoproteins [33].
Amoebiasis
Intestinal amoebiasis caused by Entamoeba histolytica
is a worldwide disease. The most relevant characteristic
of this parasite is its extensive cytolytic capacity.
Amoebic granules contain a battery of aggressive
components, such as hydrolytic enzymes and potent
cysteine proteases, whose secretion contributes to the
damage of host cells and tissues. The proteases can
also interfere with the humoral immune response by
degrading IgA and IgG antibodies [34]. This is
important if we consider that E. histolytica must
overcome the secretory IgA response during
intestinal colonization and the serum IgG antibodies
when it goes beyond the intestine. Even though
amoeba trophozoites activate the alternative
complement pathway [35], they escape the lytic
effect of complement and the inflammatory
response when they invade the host’s tissues by
acquiring complement-regulating molecules and
inactivating C3a and C5a mediators [36]. In addition,
E. histolytica has a sophisticated strategy to evade
antibodies and the antibody-dependent lytic effect
mediated by complement through a mechanism that
allows it to polarize the antibodies deposited on its
surface towards the uroid region, where they are
spontaneously eliminated as molecular aggregates
(capping) [37].
276 Review TRENDS in Parasitology Vol.18 No.6 June 2002
Tissue invasion by E. histolytica has been
associated with suppression of cell-mediated
immunity, suggested to be responsible for the acquired
protective immunity observed in convalescence
cases of extraintestinal amoebiasis, such as amoebic
liver abscess (ALA). Entamoeba histolytica exerts
different modulatory effects on macrophages and
T cells, especially on the T helper cell type-1 (Th1)
response. Cellular anergy accompanies the invasion
of the human liver by E. histolytica [38] and the
intestinal infection of mice [39]. The effect appears to
be produced by a soluble suppressor present in the
sera of the infected host that inhibits the production
of IL-2 even in cells from uninfected animals. It can
be reversed by adding exogenous IL-2 or phorbol
myristate acetate and ionomycin, indicating a defect
at the level of signal transduction [40].
The cytotoxic capacity of macrophages and their
potential as antigen-presenting and cytokine-
secreting cells are reduced during the acute phase of
ALA. Entamoeba histolytica trophozoites inhibit the
respiratory burst in human macrophages through a
monocyte locomotion inhibitory factor [41]. In
addition, the parasite exerts suppression that appears
to be a local event mediated by direct exposure of
macrophages to E. histolytica and its products. Thus,
the treatment of murine macrophages with amoebic
antigens in vitro reduces the production of molecules
associated to the I region of the MHC (Ia molecules)
induced by IFN-γ [42]. Because the effect was reversed
with cyclooxygenase inhibitor, it was suggested that it
is due in part to prostaglandin E2 (PGE2), probably
produced by E. histolytica or by the macrophage under
amoebic induction. PGE2 elevates cAMP levels in
macrophages, triggering the phosphokinase A
pathway, which, in turn, inhibits the expression of Ia
molecules on the macrophage surface and the release
by T cells of Th1 cytokines such as IL-2 and IFN-γ but
not of Th2 cytokines [43]. Similarly, macrophages
derived from ALA patients constitutively release low
levels of TNF-α, whereas peritoneal and spleen
macrophages, and Kupffer cells from infected animals
do not [44].
Interestingly, it has also been shown that spleen
cells from mice inoculated with a surface protein of
220 kDa did not proliferate in vitro, although they
were induced to secrete Th2 cytokines such as IL-4
and IL-10 (Ref. [45]). It might be said that, during
E. histolytica invasion, the parasite controls the IR by
modulating the function and set of cytokines released
by macrophages and T cells with the purpose of
increasing its survival within the liver granuloma.
Leishmaniasis
Human leishmaniasis occurs in cutaneous,
mucocutaneous and visceral forms, although these
are not absolute categories. Leishmania lives
exclusively in mononuclear phagocytes but lacks any
specialized mechanism to penetrate cells and
therefore depends on the phagocytic potential of the
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host cell to be infected. Two surface molecules of
Leishmania have been implicated in the attachment
and uptake of promastigotes by the host cells, in
addition to the inhibition of the macrophage
proteolytic processes: the gp63 surface protease and a
lipophosphoglycan (LPG). Interestingly, the roles of
these molecules in immune evasion appear to
complement each other. During the initial stages of
macrophage infection with Leishmania donovani,
LPG promotes intracellular survival of promastigotes
by inhibiting the fusion of the parasite-containing
phagosome with the lysosomes [46]. If the
phagolysosome does form, gp63 assumes a protective
function by inhibiting degradative phagolysosomal
enzymes [47]. Once the parasites become amastigotes
inside the macrophage, they adapt to the life inside
the acid medium of the phagolysosome because the
amastigotes are metabolically more active in an acid
than a neutral environment. Unlike amastigotes,
which have large amounts of catalase and superoxide
dismutase, the survival of promastigotes (which have
less of these enzymes) depends on their capacity to
avoid the respiratory burst. Here again, LPG and
gp63 contribute by blocking the oxidative burst
through abnormal activation of protein kinase C and
reduction of its translocation to the membrane [48].
Moreover, LPG is also involved in the direct
scavenging of oxygen intermediates thanks to its
structure, which contains repetitive oxidizable
phosphorylated disaccharide units.
The parasite also promotes its survival inside
the macrophage by preventing apoptosis,
antigen presentation by MHC molecules and
responsiveness to cytokines. The stimulation of
granulocyte–macrophage colony-stimulating factor
and TNF-α has been suggested as possibly
responsible for the inhibition of apoptosis [49]. As for
antigen presentation, in macrophages stimulated by
IFN-γ, Leishmania components including
glycosylinositolphospholipids inhibit the expression
of the MHC class-I and -II molecules, and peptide
loading to the few MHC molecules produced [50].
Similarly, gp63 from Leishmania major and
L. donovani cleave CD4 molecules on T cells,
interfering with the stabilization of the interaction
between antigen-presenting cells and T helper cells
[51]. In addition, amastigotes internalize and degrade
class II MHC molecules [52] and downregulate the
expression of macrophage co-stimulatory molecules,
such as the heat-stable antigen and B7-1 [53]. Similar
to E. histolytica, Leishmania induces the release of
PGE2 [54] and TGF β [55], blocking macrophage
functionality. Through LPG, they also control the
response of infected macrophages by downregulating
the expression of the TNF-α receptor [56] and
inhibiting the chemotaxis of neutrophils and
monocytes [57].
The mechanisms developed by this parasite to
evade complement could be among the most
sophisticated of any parasite. Unlike procyclic
 Review TRENDS in Parasitology Vol.18 No.6 June 2002 277

promastigotes, metacyclic promastigotes can resist the same results (Table 1). Strategies depend on the
the complement by spontaneously shedding the momentary requirements of the parasite (which in
membrane attack complex (C5b–C9), probably owing turn depend on the factors such as life-cycle stage), on
to the elongation of the LPG molecule on their surface the location of the parasite inside the host (blood,
[58]. The gp63 also protects the parasite through the mucosa, inside a cell) and on the immunological
proteolytic conversion of C3b to C3bi on the parasite status of the microenvironment. In general, the most
surface [59]. Finally, Leishmania protein kinases common evasion mechanisms are those that avoid
can phosphorylate some complement components, confronting parasites with cellular immunity
including C3, C5 and C9, blocking both pathways (macrophages and T cells, especially the Th1
of activation [60]. response) and the antibody-dependent lytic effect of
Cell-mediated immunity based on a Th1 response complement. In an exhibition of sophisticated action,
has been reported to protect against infection with protozoan parasites secrete molecules that either
L. major, whereas susceptibility seems to be related modulate the immune response by controlling the set
to a Th2 response. In this context, it has been found of cytokines produced or directly cause anergy of
that the L. major metacyclic promastigotes do not immune cells by blocking receptors or inhibiting
induce IL-12 production but actively suppress the production of cytokines and their receptors.
transcription of its gene [61]. Because IL-12 is a major The importance of cellular immunity in the control of
physiological promoter of IFN-γ production and protozoa is evident from their effect on T cells and on
Leishmania is highly susceptible to killing by IFN-γ- the function of macrophages, the pillars of this
activated macrophages, this ability to suppress IL-12 kind of immunity. However, despite the fact that
production would be expected to provide a clear parasites manage the host response for survival,
survival advantage to the parasite. Many questions they do it in a sophisticated way that allows the
Acknowledgements still need to be answered about the participation of infected host to live and, in many cases, to struggle
We thank Th1 and Th2 subsets in leishmaniasis. However, the with other infections. Indeed, doing this is an
Isabel Pérez Montford for
her assistance in
data available at present and their application to essential rule for a successful parasite. Critically
translating this the treatment of the disease in humans are promising. evaluating the mechanisms for evading the immune
manuscript. Our work was system and how were they acquired in parallel with
supported by a grant from
Conclusion the evolution of the human immune system will
Consejo Nacional de
Ciencia y Tecnología, Most protozoan parasites share various mechanisms provide insights into the fundamental aspects of the
5078-M9406 (L.O.O.). used to evade the immune response with practically host–parasite relationship.
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Century (Özcel, M.A. and Alkan, M.Z., eds), acute falciparum malaria. Clin. Exp. Immunol. 19 Reinitz, D.M. and Mansfield, J.M. (1990) T-cell-
pp. 1–13, CAB International 73, 17–22 independent and T-cell-dependent B-cell
2 Ramasamy, R. (1998) Molecular basis for evasion 11 Riley, E.M. et al. (1989) Suppression of in vitro responses to exposed variant surface glycoprotein
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