Download mechanisms used by some parasitic protozoa to evade the immune

Published by A.P.E.
Research and Reviews in Parasitology, 59 (3-4): 71-83 (1999)
© 1'999 Asociaci6n de Parasit61ogos Espafioles (A.P.E.)
Printed in Barcelona, Spain
MECHANISMS USED BY SOME PARASITIC PROTOZOA
TO EVADE THE IMMUNE RESPONSE
S. ZAMBRANO-VILLAI, D.M. ROSALES-BORJAS2 & L. ORTIZ-ORTIZ3
iCenlro Universitario de Ciencias Exactas e lngenierias, Universidad de Guadalajara,
Guadalajara, Jalisco, Mexico
2Hospital Universitario Dr. Miguel Orad, Guanare, Edo. Portuguesa, Venezuela
3Departamento de Inmunologia, Instituto de Investigaciones Biomedicas, UNAM,
Apartado PostaL 700228, Ciudad Universitaria, 04510 Mexico D.F., Mexico
Received
10 January
1998; accepted 28 July 1999
REFERENCE:
ZAMBRANO-VILLA
(S.), ROSALES-BORJAS
(D.M.) & ORTIZ-ORTIZ
(L.),
the immune response. Research and Reviews ill Parasitology, 59 (3-4): 71-83.
1999.-
Mechanisms used by some parasitic protozoato evade
SUMMARY:
The present review describes mechanismsto evade the host immune response used by some protozoa that are pathogenicto man. Relatively complex mechanismsare discussed, beyond the encystment shown by some parasites.These allow protozoato penetrateand multiplywithin
the cell, vary their surface antigens, eliminate their protein coat to evade the effect of complement and/or antibody,and modulatethe host immune
response acting at effector level and causing immunosuppressionthrough induction of suppressor cells which include macrophagesand T lymphocytes. In some cases, immunosuppressionis related to intrinsic properties of parasite products; in others, protozoa use antigenic mimicry involved in the autoimmunitywhich frequently appears in associationwith parasitic diseases. However, among the most interestingmechanismsof evasion is the one by which parasites preferentially induce a particular subset of T helper cells which secrete cytokines, thus modulating the host
immune response.
KEYWORDS:Immune response,Protozoa, immunosuppression,cytokines, T helper cells, CD4, CD8.
INTRODUCTION
The host-parasite
relationship
maintains an equilibrium as long as there is harmony between the two components. It ends when one of them senses danger of survival or damage, and that is when the host tries to
eliminate the parasite, and the parasite struggles to survive, attempting to escape the host's defense mechanisms. This contest will result in either elimination of the
parasite or infection of the host, leading to various possible pathologies and sometimes to the host's death.
The host's defense mechanisms
include everything
from the primary barriers to the most elaborate devices,
which involve a large variety of cells and molecules capable of specific recognition and elimination of many invasive agents. These cells and molecules are organized
and act together dynamically (SHER & SCOTT, 1993).
In spite of the high amount of antigens presented by
the parasite to the host, and the host's vast immune and
inflammatory response, parasites manage to survive within the host for lengthy periods. This may be due to genetic factors (WAKELIN & BLACKWELL, 1993) or to alternative causes such as the host's incapacity to respond
effectively, due to an immune response diminished by
environmental or physiological factors (GoDFREY-FAUSSETT et al., 1993).
Protozoa are responsible for several human diseases,
among them malaria, sleeping sickness, Chagas disease,
amebiasis, giardiasis, toxoplasmosis
and leishmaniasis.
The host immune response and its effectiveness largely
depend on the type of parasite and its site. Some parasites present extracellular stages where the humoral immune response is effective, while others present intrace-
llular stages where they are protected from this response,
even though the infected cell may be attacked by mechanisms of cell-mediated
immunity
(SHER & SCOTT,
1993). In spite of this, parasites manage to survive by
various mechanisms, some of which have been compiled
in the present review.
MALARIA
Malaria affects more than 250 million people, and causes death in 1%. The infection is caused by Plasmodium
vivax, P. malariae, P. ovale and P. falciparum. The first
three cause the classic symptoms of malaria, i.e., fever
and malaise with intermittent paroxysms. On the other
hand, P.falciparum is known for its virulence and prevalence (RrLEY, HVIID & THEANDER, 1994). In this parasitemia, Plasmodium has shown to be resistant to drugs,
besides the resistance to DDT exhibited by the vector,
the Anopheles mosquito. The infection involves a complex life-cycle with intra- and extracellular stages. In endemic regions the immune response to the parasite is
poor, particularly in children, who become more susceptible and exhibit a more severe pathology. Adults present
a lower infection prevalence and less severe symptoms,
suggesting protection (CHRISTOPHERS, 1924). The poor
immune response may be due to changes presented by
the parasite's surface as it passes through its various stages, from sporozoite to merozoite and gametocyte, and to
the intracellular phase inside the liver or erythrocyte. We
have to consider that the most susceptible stage of the parasite is the sporozoite and that its duration is very short,
not even an hour, before it infects the liver cells. This is a
72
very short period for the immune system to mount a response to eliminate the parasite, and even if this should
occur, the protozoan is capable of evading the effect of
an antibody by eliminating its protein cover, the circumsporozoite, a 45kDa antigen (KUBY, 1997).
Each phase of the cellular cycle is associated with the
expression of stage- and species-specific proteins, many
of which are inserted into the parasite membrane surface
and seem to be the target of the naturally acquired immune response (DAY & MARSH, 1991). Stage-specific
proteins tend to be highly polymorphic and antigenically
variable (MCCUTCHANet al., 1988). In contrast, some
internal antigens are less variable and seem to be at least
partially conserved among Plasmodium species. Some
of these are liberated by infected erythrocytes in large
quantities during the rupture of the schizont and seem to
be involved in triggering the cascade of cytokines which
produce most of the symptomatology and pathology of
the infection (KWIATKOWSKI, 1991; TAVERNE et al.,
1990). Evidence suggests that acute malaria infection induces a temporary reduction of the immune response.
An association with increased susceptibility to infections
has been observed during this phase. It is not known if
these effects are due to the parasitemia or to the generalized physiopathological effects of the disease (RrLEY,
HVIm & THEANDER,1994).
During acute infection with P. jalciparum, circulating
T-Iymphocytes are reduced in number (WYLER, 1976;
GREENWOOD,ODULOJU& STRATTON,1977; MERINOet
al., 1986) accompanied by a decrease in the lymphoproIiferative response and in the cytokines of peripheral
blood mononuclear cells (PBMC) when stimulated by
malarial antigens (HO et al., 1986; THEANDER et al.,
1986; RILEY et al., 1988). It has been suggested that the
loss of response of the PBMC in patients with malaria
may be due to the activation of CD8+ suppressor cells
(LELCHUK, SPROTT & PLAYFAIR, 1981; THEANDERet
al., 1986), although the role of antigen specific suppressor cells during acute malaria is controversial (WHITTLE
et al., 1990; Ho et al., 1986).
The decrease in PBMC response to malarial antigens
during acute infection may also be due to generalized
physiologic effects of the febrile disease. Thus, the depression observed in vitro of the proliferative response
to malaria soluble exoantigens can be partially reverted
by the addition of indomethacin to cell cultures, indicating that prostaglandins secreted by activated macrophages may be responsible for the effect (RILEY et al.,
1989b). Furthermore, acute phase proteins, which are liberated in serum during infection, can bind to the surface
of lymphoid cells. This may inhibit lymphocyte proliferation (CHERESH,HAYNES& DTSTASTO,1984), and thus
may also be responsible of the suppression observed in
vitro against malarial and other antigens (THEANDERet
al., 1987; RILEYet al., 1988).
It has also been reported that some malarial antigens
can induce suppression directly. Thus, a low molecularweight glycoprotein from P. berghei, which in vivo sup-
S.
ZAMBRANO-VILLA,
D.M.
ROSALES-BORJAS
& L.
ORTIZ-ORTIZ
presses the primary humoral immune response to thymus-dependent
antigens (SROUR, SEGRE & SEGRE,
1988) and a schizont extract from P. jalciparum which
in vitro suppresses the Iymphoproliferative response of a
malarial and other soluble antigens (RILEY et al., 1989a)
have been isolated. The mechanisms responsible for suppression are not well known, although it has been suggested that hemozoin accumulation derived from the parasite in macrophages may inhibit their accessory
function (MORAKOTE& JUSTUS, 1988).
AFRICAN TRYPANOSOMIASIS
Another disease in which the parasite uses interesting
mechanisms to evade the immune response of the host is
the sleeping sickness produced in humans by two subspecies of African trypanosomes, Trypanosoma brucei
gambiense and T. brucei rhodesiense, and in cattle by T.
brucei brucei, T. vivax, T. evansi and T. congolense.
These trypanosomes live in the blood of the host and
show no intracellular stages, which makes them a target
for antibody-mediated destruction. The protozoan remains in circulation where it divides each 4 to 6 hours.
The infection presents various stages, during the initial
or systemic stage the parasite divides in the blood and
progresses to a neurologic stage in which it infects the
central nervous system, producing megaloencephalitis
with eventual loss of conscience (VICKERMAN, 1985).
During the initial stage, the parasite grows indefinitely in
waves, as a result of the humoral immune response
which eliminates, with the first wave, most parasites by
opsonization in liver macrophages, more than by complement-mediated lysis (URQUHART& HOLMES, 1987).
However, those which survive due to a modification of
their glycoproteic coat, a phenomenon known as antigenic variation (GRAY & LUCKINS, 1976), start a new
surge which is once more suppressed by the formation of
antibodies against the new antigens present on the surface of the parasite. However, a small number of parasites survive and change their superficial coat again, starting a new surge, and so on. This glycoproteic coat,
called variant surface glycoprotein (VSG) (VICKERMAN,
1978), is generated by rather infrequent genetic processes in which the organism carries a large repertoire of
VSG genes, each one coding for a VSG with different
primary sequence, particularly at the N termini, and sequence similarities near the C termini (MATTHYSSENSet
al., 1981; RICE-FIGHT, CHEN & DONELSON, 1981). An
interesting aspect is that the parasite only expresses a
single VSG gene at anyone time. The activation of the
VSG gene results in its duplication and transposition to
an active site of transcriptional expression on the telomeric end of specific chromosomes. The activation of
the new gene displaces the previous gene from the telomeric site of expression. Even though several VSG genes can potentially express themselves, this is limited by
unknown control mechanisms which allow only one site
73
Immune evasion mechanisms by protozoa
of expression at a time (BORST & CROSS, 1982; LAURENTet al., 1983; MYLER et al., 1984; VAN DER PLOEG,
1987). In consequence, this repeated antigenic change of
VSG in the trypanosome allows it to evade the humoral
immune response, resulting in successive surges of parasitemia. This phenomenon makes it difficult to develop a
vaccine against the disease.
Since the pathogenesis is linked to the incapacity of
the untreated patient to eliminate the parasite, attempts
have been made to determine how the parasite interacts
with the immune system and alters the cytokine balance
and that of other mediators, thus allowing the pathology
to develop. During development of the parasitemia several populations of Band T lymphocytes are altered (URQUHARTet al., 1973; PEARSONet al., 1978; SACKS &
ASKONAS, 1980; GASBARREet aI., 1981). During infection, Band
T lymphocytes proliferate and respond
against a series of antigens unrelated to the parasite
(HUDSONet al., 1976; ASKONASet al., 1979), but surprisingly, the capacity to induce T cell-dependent cell responses decreases, with progressive alteration of the helper, suppressor
and cytotoxic
T-cell
functions
(GOODWINet aI., 1972; PEARSONet al., 1979; CHAROENVIT, CAMPBELL& TOKUDA, 1981), until the disease
continues with the sole function of the T -independent B
cells, which generally increase (HOUBA, BROWN &
ALLISON, 1969; MURRAY et al., 1974; ASKONASet al.,
1979). In consequence, the parasite induces paradoxical
changes characterized by polyclonal expansion associated to immunosuppression
(lAYAWARDENA& W AKSMAN, 1977; DIFFLEY, 1983). The T cell-dependent immune response against the persistent trypanosoma
antigens is depressed, although the T -independent B cell
response to the VSG surface epitopes (REINITZ& MANSFIELD,1990; SILEGHEMet al., 1994) can very likely control subsequent parasitemias.
It has also been observed that the parasite activates the
macrophages, initiating a series of events which result in
immunosuppression.
The macrophage thus activated
causes a change in the pattern of cytokines produced by
activated T cells, regulating an increase in interferon(IFN) "I and a decrease of expression of the IL-2 receptor, which causes an impaired proliferative responsiveness (SILEGHEMet al., 1994). These results indicate that
the parasite molecules which trigger the cascade are not
suppressor factors but factors which activate the macrophage. These alterations may be partially responsible for
the altered immune response and other aspects of pathogenesis.
AMERICAN TRYPANOSOMIASIS
Chagas disease is produced by another
Trypanosoma cruzi. This parasite affects
million people in the American continent,
causes has no cure and it is a main factor
death. The disease is transmitted to man
trypanosoma,
more than 20
the disease it
of premature
via the insect
vector's feces. The parasite has a life-cycle with intraand extracellular phases. In the blood stream it is found
as flagellated trypomastigotes and intracellularly as
amastigotes. The amastigote divides by binary fission
forming parasite nests or pseudocysts, particularly in
cardiac muscle fibres. The disease is frequently lethal in
children and infants, but in adults the initial infection often turns into a chronic disease, sometimes after a long
interval, causing an illness characterized by megacardia
with megacolon, megaesophagus and degeneration of
the central and peripheral nervous system. A mystery in
this disease are the pathologic alterations which vary
from subclinical to lethal in a period which can be short
or long. Another characteristic is that the infection is generally associated with suppression of the immune response (BRENER, 1980).
In a study performed on mice infected with trypomastigotes which were immunized 5 days later with donkey
erythrocytes, the response to the red blood cells, both by
IgM and by IgG, was significantly reduced (CLINTONet
aI., 1975). A similar effect was observed with other T-dependent and T-independent antigens (RAMOS et al.,
1978). The observed immunosuppression became more
evident later on as the parasitemia advanced in blood and
tissues. Surprisingly, phagocytic activity of the immunosuppressed animals was increased, which suggested that
suppression at least was not due to a blocking of the mononuclear phagocytic system, as has been observed in
leishmaniasis (CLINTONet aI., 1969) and in African trypanosomiasis (GOODWINet al., 1972). On the other hand,
a similar phenomenon was noticed in experimental infections with another protozoan, Plasmodium vinckei (Cox,
BTLBEY& NICOL, 1964), in which increased activity of
the mononuclear phagocytic system is associated with
important immunosuppression
(SALAMAN, WEDDERBURN& BRUCE-CHWATI, 1969; BARKER, 1971; GREENWOOD,PLAYFAIR& TORRIGIANT,1971). With respect to
the management of antigen by peritoneal cells of animals
infected by T. cruzi, they did not differ in their capacity to
bind antigen nor in the immunogenicity of the antigen associated with cells, compared to observations in normal
animal cells (RAMOS et al., 1978). In support of this, it
was found that animals infected with T. cruzi developed
nonspecific resistance to challenge with an unrelated intracellular microorganism Listeria monocytogenes, associated with an increased mononuclear phagocytic activity. This antibacterial response of animals infected with
T. cruzi has been reported in infections by other protozoa
(MAUEL & BEHIN, 1974). As with other microorganisms,
T. cruzi and other protozoa induce polyclonal B lymphocyte activation, which is characterized by the spontaneous appearance of antibodies, predominantly of the
IgM class, against antigens not related with the parasite
(ORTIZ-ORTIZet al., 1980). Polyclonal activation may be
responsible for the immunoglobulin alterations reported
for Chagas disease (SCHMUNISet aI., 1978). However, it
is not known whether this phenomenon participates in the
human infection with this protozoan.
74
The nonspecific stimulation of antibody-forming cells
to soluble proteins such as human globulin and to syngeneic erythrocytes is particularly interesting, considering
the potential for autoimmune diseases after parasitic infection. If B cells specific for autoantigens are stimulated either by infectious organisms or by the host's inflammatory response to the parasite, the resulting
autoantibodies may potentially induce autoimmune disease (ORTIZ-ORTIZet al., 1980).
The antigenic similarity of the parasite with the host
(molecular mimicry) may be a further mechanism used
by the parasite to evade the immune response of the host
and also be responsible for autoimmunity in Chagas disease. Autoantibodies have been reported against cardiac
tissue (endocardium, vascular and interstitial tissue),
Schwann cells, laminin, striated muscle and neurons. By
crossed absorption studies, it has been demonstrated that
these autoantibodies define epitopes shared by the host
and the parasite. The autoimmune basis for the chronic
pathology has been experimentally demonstrated by
adoptive transfer studies (non-adherent spleen cells) in
mice, demonstrating that the host and the parasite share
antigens, which may be the reason for T cell-mediated
autoimmunity (HALL, 1994).
Immunosuppression observed during experimental infection by T. cruzi has been confirmed by various authors, who have contributed to its better understanding.
Thus, RAMOSet al. (1978) found that the lymphoproliferative response induced with Con A in spleen cells of
BALB/c mice was suppressed by T cells obtained from
mice infected with T. cruzi. The spleen cells from infected mice also showed alterations in IL-2 production
when stimulated with Con A which was not restored by
addition of IL-l, and addition of exogenous IL-2 did not
correct lymphoproliferative
suppression (HAREL-BELLANet al., 1983, 1985). However, addition of exogenous IL-2 in a murine model of experimental infection
did restore suppression of the response to sheep erythrocytes determined in the spleen by the production of antibody-forming cells (TARLETON& KUHN, 1984). Suppressor cells have been characterized as spleen-adherent
Tny-ILyt-z
(TARLETON,1988a, b). The suppressor effect has been reverted by incubation in culture medium,
suggesting that it could have been caused directly by the
parasite on the lymphocytes (KIERSZENBAUNet al.,
1989).
In a recent study of patients with chronic chagastic
miocarditis, an association has been reported between
the increase in T CD8+ cells and the presence of T. crusi
antigen, while the number of T CD4+ cells did not vary
significantly, which indicates that the T CD8+ cells are
responsible for immune activation in this disease. The
correlation between T. cruri antigens and T CD8+ cell increase strongly suggests a direct influence of the parasite
on the development of miocarditis (HIGUCHI et al.,
1997).
Besides, T. cruzi extend their permanence in the vertebrate blood stream through the expression of surface
S. ZAMBRANO- VILLA, D.M. ROSALES-BORJAS & L. ORTlZ-ORTlZ
molecules with anti-complementary properties (T-DAF,
gp58/68 and gp160) which confer them resistance to seric complement-dependent
lysis (FISHER et al., 1988;
JOINERet al., 1988; NORRIS, HART & SO, 1989), surface
molecule turnover through the endocytic pathway, of
great use to the parasite for eliminating membranebound antibodies (TEXEIRA& SANTANA,1989), and the
liberation of immune membrane complexes by means of
phospholipase which degrades anchoring glycoproteins
(ALMElDA et al., 1994). Recently, it has been reported
that the IgM bound to the membrane on the trypomastigote surface limits the binding of IgG to the parasite and
alters the elimination of the parasite induced by IgG in
strains Y and CL, thus favoring its transmission to the
hematophagous vector host (GARCIAet al., 1997).
AMEBIASIS
The intestinal protozoan Entamoeba hystolytica is the
causal agent of amebiasis, a disease of world-wide distribution. Endemicity and mortality rates are very high in
Africa, South America, India and Mexico (W ALSH,
1986). In Mexico, where seroprevalence was found to be
8,41 % in representative samples from the 32 examined
entities (CABALLERO-SALCEDO
et al., 1994), the disease
is endemic with areas of high predominance not related
to climatic conditions. Exposure to infectious contact
with amebas occurs at all ages, with high frequency at
school age. Poor sanitary conditions, low educational level and bad hygienic habits contribute to the spread of
the disease. The human host is infected by parasite cysts
which then turn into trophozoites and colonize the lumen
of the colon, where they multiply and live as commensals. However, when trophozoites lyse the colon epithelial cells and penetrate the intestinal mucosa, they can
cause massive and fatal destruction of the host tissues.
The most relevant characteristic of this parasite is its extensive cytolytic capacity, which can be considered as its
main pathogenic function. It has been reported that after
cell-cell contact, the ameba liberates a protein into the
intercellular space which inserts itself into the membrane, forming an ion channel similar to that observed in
cytotoxic lymphocytes (TSCHOPP & NABHOLZ, 1990).
This event is initiated by intimate contact between the
parasite and the target cell which is established mainly
through a lectin-like molecule (PETRI et al., 1987). In a
few minutes, important changes can be noticed in the
target cell, such as swelling and surface alterations
which finally cause the membrane to lose its functions
and the cell to die. The pore-producing factor is known
as amebapore. Isoforms have been reported which constitute a family with a similar sequence to that of a polypeptide found in NK and cytotoxic T cells. Other candidates have been reported as mediators of cytolysis
(RAVDIN, 1989), whose biological and functional significance is currently under study. Amebic granules contain a battery 01 aggressive components such as hydroly-
Immune evasion mechanisms by protozoa
tic enzymes, among them an A2 acidic phospholipase
with a phospholipase hydrolyzing activity on artificial
membranes which is augmented in the presence of amebapore (LEIPPE, 1997). Additionally, potent cysteine
proteases have been found whose secretion may contribute to the damage of host cells and tissues. In fact, it
has been observed that before intestinal invasion, these
cysteine proteases degrade the extracellular matrix and
host mucoproteins, dislodge the epithelial cells and degrade the basal epithelial membrane; besides, they can
interfere with the immune response by degrading IgA
and IgG. They also activate the alternative complement
pathway and elude the inflammatory response by inactivating C3a and C5a (QUE & REED, 1997).
When the ameba is exposed to seric complement alone
or in the presence of specific antibodies, it is destroyed
by the activation of the alternative and of the classic antibody-dependent pathways. The activation exerted by the
ameba on the alternative complement pathway has been
known for a few years (ORTIZ-ORTIZet al., 1978). However, the sensibility of the ameba to this activation is still
being discussed. Thus, while some authors prove its sensibility (HAMELMANNet al., 1993), others disprove it
(REED, SARGEAUNT& BRAUD, 1983; REED et al., 1986).
Recently, in a study performed on 21 patients from
which E. histolytica was isolated and its presence characterized by the techniques of polymerase chain reaction
and hexokinase isoenzyme typing, it was found that 90%
of trophozoites were lysed by the alternative complement
pathway after 30 min in the presence of human serum,
regardless of whether it came from symptomatic or
asymptomatic subjects (W ALDERICH,WEBER & KNOBLOCH, 1997). However, the ameba somehow escapes
the lytic complement effect when it invades the host's
tissues (CALDERON& Tov AR, 1986; MOGYOROS,CALEF
& GITLER, 1986; HAMELMANNet al., 1993). It has not
been discarded that the ameba may acquire resistance to
this humoral factor in vivo and that it is sensitive to the
effects of the alternative pathway only during the phase
within the intestine; when the ameba colonizes the intestinal epithelium it does not need to be protected from the
complement effects. On the other hand, when it invades
the host and is exposed to the complement effects it needs to be protected and that is when it adapts to the presence of the seric factor (W ALDERICH,WEBER & KNOBLOCH, 1997). It has been proposed that the main
mechanism of resistance of E. histolytica to lysis by
complement may be through the acquisition of regulating
molecules (GUTIERREZ-KoBEH, CABRERA & PEREZMONTFORT,1997), as the human erythrocyte restriction
factor is incorporated to the membranes of sheep erythrocytes, protecting them from reactive lysis by C5b-9
(ZALMAN,WOOD & MULLER-EBERHARD,1987).
On the other hand, the antibody also activates the complement when it combines with the ameba and in doing
so, it destroys the trophozoite. Here, once more, the
ameba evades the effect of the antibody through a mechanism which allows it to polarize the antibodies depo-
75
sited on the surface towards the uroid region where they
are spontaneously eliminated by the ameba as supramolecular aggregates or caps, membrane compounds, without causing the parasite any harm. It is possible that the
polarization of surface antigens interferes, avoiding the
lytic effect mediated by the complement (CALDERON&
AVILA,1986).
Tissue invasion by the ameba has been associated
with suppression of the cell-mediated response, which
can facilitate its extra-intestinal survival and the production of the hepatic abscess. Most studies suggest that
cell-mediated immunity is the most viable deposit of acquired protective immunity (ORTIZ-ORTIZ, 1994). The
arguments that support this are: the cellular anergy
which accompanies the initial invasion by E. histolytica
(ORTIZ-ORTIZet al., 1975); the elevated incidence of invasive amebiasis in animals or humans who have received treatments which suppress T cells or splenectomy
(GHADTRIAN& MEEROVTTCH,1981a, b; TRTSSL,1982);
the protective effect of T cell stimulants (GHADTRIAN,
MEEROVITCH& HARTMANN,1980); the appearance and
persistence of delayed-type hypersensitivity (DTH) to
amebic antigens after recovery from amebic liver abscess (KRETSCHMERet al., 1972; ORTIZ-ORTIZ et al.,
1973a, b); the adoptive transfer of immunity by sensitized T lymphocytes and the amebolytic effect of cytotoxic T lymphocytes stimulated with antigen and activated
macrophages (ORTIZ-ORTIZ, 1994).
The parasite seems to exert different modulatory effects on macrophages and T cells, which surely allow its
survival within the host. In a model of intestinal amebiasis in mice it has been found that infection induces a cyclic depression of DNA synthesis when spleen cells are
stimulated with T or B lymphocyte mitogens or with antigen. In the supernatant of these cells stimulated with
concanavalin A (Con A), a similar response is observed
in the production of interleukin (IL)-2. This effect is eluded when spleen cells are treated with phorbol myristate
acetate and ionomycin, indicating a defect at the level of
the transduction signal. These cell alterations may facilitate the invasion of the host by the protozoan (GHOSH,
CASTELLANOS-BARBA
& ORTIZ-ORTIZ,1995).
In support of the role of cellular immunity in amebiasis it has been reported that human macrophages stimulated in vitro with IFN-)' present an amebicidal effect
which is dependent on contact. IFN-)' with lipopolysaccharide (LPS), tumor necrosis factor (TNF)-a and colony stimulating factor 1, present potent amebicidal activity which seems to involve oxidative and non-oxidative
mechanisms (CAMPBELL& CHADEE, 1997). The requirement for macrophage activation suggests that the response of a Th l-type T -cell secreting IFN-)', IL-2 and
TNF-I3, would be necessary for effective immunity
against amebae.
The cytotoxic capacity of macrophages is reduced during the acute phase of hepatic amebiasis. In a study performed with an experimental model of hepatic abscesses
in the hamster, we found that the capacity of the mono-
76
nuclear phagocytic system of animals infected with amebae to eliminate an intracellular microorganism, specifically Candida albicans, was significantly altered. Evidently, this alteration very likely favors the survival of
trophozoites in the liver (CAPIN, GONZALEZ-MENDOZA
& ORTIZ-ORTIZ, 1980). It has been suggested that suppression of macrophage activity during amebiasis is
mainly a local event mediated by direct exposure to the
ameba and its products (DENIS & CHADEE, 1988). These
events can influence the presentation of the antigen by
the macrophage to T cells, thus diminishing cell-mediated immunity and cytokine secretion, some of which are
necessary to activate the macrophage. In this sense, it
has been reported that treatment of mouse macrophages
with amebic antigens reduces in vitro the expression of
la molecules induced by IFN-')' (DENIS & CHADEE,
1988; WANG & CHADEE, 1995). This effect has been
partially considered to be due to prostaglandin E2
(PGE2), since it is blocked by cyclooxygenase inhibitors
(indomethacin) which revert the amebic suppressor effect of la in the macrophage. In this sense, it has been reported that PGE2 may be produced by the ameba (BELLEY & CHAOEE, 1995) and may also elevate cAMP
levels, triggering the phosphokinase A (PKA) pathway
which inhibits the expression of la molecules of the macrophage surface (FIGUEREIDO,1990). Furthermore, the
ameba also elevates the levels of cAMP in human macrophages through a monocyte locomotion inhibitory
factor (RIco et al., 1995).
The role of cytokines produced during amebic infection has been studied and TNF-a plays a relevant role. If
increased it promotes macrophage amebecidal activity,
while reduced levels may favor the development of amebic granulomas. Amebic stimulation of macrophage
PGE2 production participates in suppressing TNF-a production (CAMPBELL& CHAOEE, 1997).
Spleen cells from mice inoculated with a surface protein of 220 kDa have been found not to proliferate in vitro when stimulated by this protein, although they do induce IL-4 and IL-lO secretion (TALAMAS-RoHANAet
al., 1995). Moreover, during the initial phases of experimental hepatic abscesses in gerbils, IL-4 is produced
(CAMPBELL& CHADEE, 1997). These cytokines may
suppress macrophage function, while the 220 kDa protein suppresses T-cell mitogenesis. Likewise, in addition
to the production of Th2 cytokines, amebic infection is
associated with suppression of IFN-')', a cytokine produced by Th I, which activates macrophages (SALATA et
al., 1990).
All these factors may participate in suppressing cellmediated immunity during the amebic hepatic abscess.
PGE2 production during invasive amebiasis may regulate T cells since it inhibits their proliferation (BELLEY&
CHADEE,1995) and the production of the Th 1 cytokines,
IL-2 and IFN-')' (BETZ & FOX, 1991). It may be said that
during amebic invasion, the parasite manipulates the
functions of T cells and macrophages with the purpose
of increasing the survival of the parasite within the liver
S. ZAMBRANO-VILLA, D.M. ROSALES-BORJAS & L. ORTIZ-ORTIZ
granuloma. Furthermore, amebas are capable of downregulating the expression of la molecules in the macrophage, possibly inhibiting their antigen-presenting cell
activity and the activation of T cells.
GIARDIASIS
Giardia lamblia is one of the most common enteropathogenic protozoa. Infection with this parasite may cause
acute or chronic diarrhea, characterized by intestinal malabsorption, and in children with chronic disease it may
be associated to retardation in growth and development.
However, the clinical spectrum may be very diverse,
from the asymptomatic carrier to persistent diarrhea with
malabsorption (WOLFE, 1984). In spite of extensive investigation in animal models and during human infection, little is known about the immunologic factors
which determine the elimination of the acute disease and
the development of protective immunity.
The Giardia trophozoite colonizes the proximal small
intestine and is responsible for diarrhea and malabsorption, while the cyst is the form of transmission since it is
capable of leaving the host and surviving in an adequate
environment (FARTHING,1994). Patients with the symptomatic disease present anti-Giardia antibodies of the
classes IgM, IgG and IgA. Since trophozoites do not appear to invade tissues, the mucous surfaces remain stimulated by Giardia antigens during the entire life-span
of the parasite. In this case, immunity to Giardia is closely associated to the type of immune response generated by the mucous-associated lymphoid tissue (FAUBERT, 1996). In this respect, evidence to date suggests
that slgA in the intestinal lumen is likely to be involved
in parasite clearance (FARTHING,1989). A protective effect of anti-trophozoite antibodies might result from inhibition of trophozoite attachment to intestinal epithelial
cells (INGE, EOSON & FARTHING, 1988), as occurs in
amebiasis (CARREROet al., 1994) or from opsonization
of trophozoites for phagocytosis (KAPLAN& ALTMANSHOFER,1985). However, clearance of murine infection is
also T-cell dependent (PETRO et al., 1992). Epidemiological evidence suggests that the presence of slgA antibodies may contribute to the protection against giardiasis
in infants fed with maternal milk (ANDREWS & HEwLETT,1981).
Invasion of the intestinal epithelium by the parasite is
a rare event although diverse mechanisms are found in
the mucosa to prevent it, for example, cytotoxic intraepithelial Iymphocytes, antibody mediated cytotoxicity
(ADCC) and the complement system (DEGUCHI et al.,
1987). The role of cellular immunity seems to be relevant in the infections caused by this flagellated protozoan. Experimentally, nude mice (nu/nu) present a prolonged
infection
which can be eradicated
by
reconstitution with normal syngeneic Iymphocytes (ROBERTS-THOMSON& MITCHELL, 1978). CD4 cells seem
to be important for the elimination of the parasite during
77
Immune evasion mechanisms by protozoa
infection, since they may be involved in the switch of
IgM to the production of IgA in B cells.
Not much is known about the ability of Giardia to
evade the host's resistance mechanisms. However, attention has been directed to a group of cysteine-rich surface
proteins which exhibit antigenic variation in Giardia
isolates. The phenomenon of antigenic variation has
been well established and it occurs both in vitro and in
vivo (ADAM et al., 1988; NASH et al., 1988, 1990;
GOTTSTEINet al., 1990). The frequency of surface antigen modifications has been determined, and depending
on the particular Giardia isolate, they occur in one out of
every 6 to 13 generations. The biological significance of
this antigenic variation remains unknown, although it
was originally thought that it could constitute a mechanism of evasion of immunologic effectors of the host, as
happens with saliva trypanosomes. Not more than one
cyclic modification has been demonstrated for surface
antigens in the human infection and in other animals.
However, it has recently been shown that Giardia isolates possess unique anti genic variants which differ in susceptibility to digestive proteases of the host, trypsin and
a-chymotrypsin; thus, certain surface antigens seem to
protect the parasite from enzymatic attack (NASH, MERRITT& CONRAD, 1991).
TOXOPLASMOSIS
Toxoplasmosis is caused by Toxoplasma gondii, an
obligatory intracellular parasite of world-wide distribution which causes infection in most mammals. In man,
seroprevalence is very high although the disease is rare
(GARCIA& BRUCKNER,1993). After infection, the parasite remains inactive indefinitely in the central nervous
system and other host tissues. The human infection is
usually mild or asymptomatic, although in immunologically compromised patients the disease can be lethal
(LEVY, BREDESEN & ROSENBLUM, 1985). The tachyzoite is very prolific; it infects almost all nucleated cells
and generates the formation of parasitophorous vacuoles
which do not fuse with intracellular organelles, thus preventing their destruction (MAUEL, 1996). The tachyzoite
divides by binary fusion, forming an intracellular pseudocyst which distorts the host cell and finally destroys it.
The tachyzoites liberated in this process invade adjacent
cells. One important characteristic of this protozoan is
that it induces a potent immune response in the host
which is absolutely necessary for the host's survival and,
therefore, for parasite survival, as it limits its multiplication and dissemination. The rise in host immunity is associated to the parasite's transformation to a latent state,
thus escaping elimination by forming inactive cystic
structures (DARCY & SANTORO,1994).
The host controls the parasite mainly through IFN-l'
from T and NK cells. Infection is characterized by a response with a characteristic pattern of cytokines from Th
type 1 cells (Thl), i.e., cytokines which produce a strong
cellular immunity (elevated IFN-l'/ decreased IL-4)
(SHER & COFFMAN,1992).
T. gondii seems to possess a superantigen which stimulates non-immune T cells to produce IFN-l'. It is likely
that IL-12 and the superantigen induce a highly polarized
response to Thl cells, characteristic of the T. gondii infection (DENKERS, 1996a). The superantigen is different
from the peptidic antigens of T cells in that it binds to the
external part of the class 11, lA and lE molecules of the
MHC. Moreover, the interaction occurs regardless of the
haplotype and with no requirement of intracellular processing. The combination of the superantigen and the
class 11 molecules of the MHC interacts with the T cell
receptor which expresses the variable 13 chain (VI3).
Thus, numerous families of CD4+ and CD8+ T cells
which express the appropriate VI3 chain are activated,
instead of the clonotypic response which the conventional antigen activates (HERMAN,1991).
During the early stages of infection, elevated levels of
IFN-l' are required to control tachyzoite proliferation
and the T. gondii superantigen may contribute to the production of IFN-l' by massive activation of T Vb5+ cells.
Interestingly, in vitro studies indicate that the Vb5+ cell
which expands is predominantly CD8+, a producer of
IFN-l' (ROMAGNANI,1997).
During chronic infection, tachyzoite replication is minimal and the requirement for IFN-l' decreases. The host
may use down-regulatory mechanisms to evade the important immunogenicity of this parasite. The induction
of V135 non-responsiveness may be an example of that
mechanism (DENKERS,1996b).
LEISHMANIASIS
Approximately 12 million people are infected and 350
million at risk of being infected with leishmaniasis. Disease variations of this illness have been described (MoDABBER,1987). Leishmania is a protozoan which lives
exclusively in mononuclear phagocytes. However, it
lacks a specialized mechanism to penetrate cells and it
therefore depends on the phagocytic potential of the host
cell to be infected (MAUEL, 1996). When the host macrophage internalizes the Leishmania, the phagosome
which arises rapidly fuses with the lysosomes forming a
phagolysosome which contains cathepsins and dipeptidyl
peptidases I and 11(PRINA et al., 1990). The Leishmania
amastigotes seem to be adapted to life inside the acid medium of the phagolysosome, since they are metabolically
more active in acid than in neutral pH. It is not known
how this protozoan resists the degrading action of this
and other enzymes. The phagolysosome appears to be the
final site in which the parasite survives and multiplies.
Two surface molecules of Leishmania have been implicated in the inhibition of the macrophage degrading processes: a gp63 surface protease (BORDIER,1987) and a lipophosphoglycan
(LPG) (TuRCO & DESCOTEAUX,
1992). Nevertheless, the mechanisms used by these mo-
78
lecules remain largely unknown. Apparently, LPG protects the parasite from the lytic effect mediated by complement (PUENTESet al., 1990). Besides, during the initial stages of macrophage infection LPG promotes the
intracellular survival of promastigotes. This molecule is
liberated by promastigotes and is known as excreted factor, which possibly protects them against initial intralysosomal degradation (HANDMAN& GREENBLATT,1977).
LPG also contributes to the infection potential of these
protozoa by direct scavenging of oxygen intermediates or
by an indirect effect on the respiratory burst through modulation of host cell signaling pathways. LPG belongs to
a class of bacterial glycolipids which are quite effective
at capturing hydroxyl radicals and superoxide anions,
possibly due to their structure, formed by repeating oxidizable phosphorylated disaccharide units (MAUEL, 1996).
L. donovani promastigotes, which do not contain
much catalase, seem to be less resistant to damage mediated by oxidants, and to intracellular death, than amastigotes, which have a much larger amount of catalase
and superoxide dismutase. Furthermore, Leishmania
contains an antioxidant composed of two molecules of
glutathione conjugated with spermidine, which have a
similar function to glutathione in other cells (FAIRLAMB
et al., 1985).
Survival of Leishmania seems to depend on its capacity to avoid the respiratory burst of the host. Macrophage protein kinase C (PKC) activity is altered by intracellular Leishmania. The respiratory burst depression in
human monocytes infected with L. donovani is accompanied by a decrease in protein phosphorylation, which
correlates with a weak translocation of PKC to the membrane (OLIVIER,BROWNSEY& REINER, 1992). This suggests that Leishmania interferes with the transduction
signal in macrophages, particularly
with PKC-dependent pathways, where LPG (DESCOTEAUX& TURCO,
1993) and gp63 (SORENSEN,HEY & KHARAZMI, 1994)
have been implicated.
It is also necessary to mention that other mechanisms,
beside these molecules, also contribute to parasite protection. In this sense, the parasite may promote its survival by preventing host cell death, which is accomplished
by inhibiting apoptosis, possibly by stimulation of the
granulocyte-macrophage colony stimulating factor (GMCSF), and production of TNF-a (MOORE & MATLASHEWSKI,1994).
Other interesting effects which favor survival of this
protozoan are: a notorius suppression of the expression of
class I and 11 molecules of the MHC, through macrophage
stimulation by IFN-')' (RElNER, NG & Mc MASTER,
1987); a release of PGE2 (RElNER & MALELMUD,1985)
and transforming growth factor 13 (BARRALet al., 1993)
which inhibit the immune response; downregulation of
TNF-a receptor expression in LPG-treated macrophages
(DESCOTEAUXet al., 1991) by inhibiting macrophage activation by TNF-a (CORRADIN,BUCHMULLER-RoUILLER
& MAUEL, 1991); and inhibition of neutrophil and monocyte chemotaxis (FRANKENBURGet al., 1990).
S. ZAMBRANO-V1LLA, D.M. ROSALES-BORJAS & L. ORTlZ-ORTlZ
The role of Thlffh2 cells has been reported to be protective against infection with L. major. The capacity of
specific T CD4+ cells to transfer the resistance or exacerbation of the disease to immunodeficient or sublethally
irradiated naive hosts correlates with the production of
cytokines derived from Thl or Th2 cells (SCOTT et al.,
1988; HOLADAYet al., 1991). At the beginning of Leishmania infection in resistant (C57BL/6) or susceptible
mice (BALB/c) a strong mixed response is observed in
the CD4+ cell population, which consists in IL-2, IL-4
and IL-13, with a maximum on day 4. However, the resistant strain rapidly down regulates IL-4 transcription,
while BALB/c mice continue to express IL-4 levels consistent with Th2. It has been observed that IL-4 gene
knockout BALB/c mice, despite lacking IL-4, remain
susceptible to infection with L. major. On the other
hand, observations in resistant mice revealed that infected macrophages produce IL-12 and NK cells produce
IFN-')', and both are responsible for the protective Thl
response in this type of mice (ROMAGNANI,1997). The
susceptible strain, however, could change its phenotype
after administration of anti -IL-4 or IL-12 during the first
weeks of infection (COFFMANet al., 1991; CHATELEIN,
V ARKILA& COFFMAN, 1992; SYPEK et al., 1993). It is
currently known that the only factors involved in the
process of subset differentiation of CD4+ T cells in vivo
are IL-4 and IFN-')'. However, this evidence derives
from the study of some models of infectious diseases
and it is not known how general the roles of these two
cytokines are (COFFMANet al., 1991). Many questions
still need to be answered with regard to the participation
of the Thl and Th2 subunits in leishmaniasis. However,
results obtained at present and their application to treatment of the disease in humans are promising.
CONCLUSIONS
The protozoa here reviewed possess mechanisms which
allow them to evade the effect of the host immune response in various ways. Some protozoa do so by changes
or mutations of surface proteins, others by mechanisms
which somehow allow them to survive the effect of intracellular enzymes of the phagocytic cell, or else, of the noxious effect of the antibody or complement by a mechanism of «denuding» in which membrane and antibody are
oriented towards one extreme of the cell and subsequently
eliminated. Others possess the ability to inactivate or acquire resistance to the effects of complement. However,
most seem to have an effect on the regulation of T lymphocytes and its cytokines, since an inappropriate response
at this level may be of vital importance to the survival of
the host, and therefore, of the parasite.
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