Hindawi Publishing Corporation
Journal of Parasitology Research
Volume 2012, Article ID 413052, 12 pages
Macrophage Migration InhibitoryFactor inProtozoan Infections
Marcelo T. Bozza, Yuri C. Martins, Let´ ıciaA.M. Carneiro,and ClaudiaN.Paiva
Laborat´ orio de Inflamac ¸˜ ao e Imunidade, Departamento de Imunologia, Instituto de Microbiologia,
Universidade Federal do Rio de Janeiro, 21941-902, Rio de Janeiro, RJ, Brazil
Correspondence should be addressed to Marcelo T. Bozza, email@example.com
Received 2 September 2011; Revised 1 November 2011; Accepted 7 November 2011
Academic Editor: Marcela F. Lopes
Copyright © 2012 Marcelo T. Bozza et al. This is an open access article distributed under the Creative Commons Attribution
License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly
Macrophage migration inhibitory factor (MIF) is a cytokine that plays a central role in immune and inflammatory responses. In
the present paper, we discussed the participation of MIF in the immune response to protozoan parasite infections. As a general
The immune/inflammatory response triggered during infec-
tion has an essential role in eliminating the infectious agent
and in promoting tissue repair . The very existence
of multicellular organisms in an environment replete of
infectious agents is made possible by an effective immune
system, indicating that the ability to control infections has
been throughout evolution an important selective pressure
to mold the immune system. However, it is not unusual that
the tissue damage observed during infectious processes is
caused by the immune/inflammatory response itself. Innate
immune receptors recognize conserved microbial molecules
from all classes of microorganisms [1, 2]. The activation
of these receptors elicits selective intracellular signaling cas-
cades that result in the production of cytokines, chemokines,
lipid mediators, and reactive oxygen/nitrogen species. Both
the intensity and the quality of the inflammatory responses
are determined by the detection of combinations of micro-
bial molecules and molecules from host origin such as
cytokines, ATP, and ROS [3, 4]. This activation of the
immune system is considered essential for pathogen killing
but, on the other hand, is also critically involved in tissue
damage and sepsis [1–4]. Thus, the pathology of infectious
diseases can result either from a direct effect of the infectious
agents or from the immune/inflammatory response, both of
which can cause metabolic changes, cellular malfunctioning,
and cell death. In fact, the pathology of most infectious
diseases is the intricate result of these two forces.
Macrophage migration inhibitory factor (MIF) activity
was described in the sixties and it is considered one of the
first cytokines to be described [5, 6]. The MIF gene was
cloned in 1989 using a functional assay based on its ability to
inhibit the random migration of macrophages . A major
breakthrough in the characterization of MIF was achieved
by a remarkable study that identified proteins secreted by
the pituitary gland upon stimulation by LPS . Among
these proteins was MIF, and the authors went on to show
that blockade of MIF protected mice from LPS-induced
lethality, indicating its prominent proinflammatory role in
endotoxemia. These studies led to renewed scientific interest
a complex scenario of its biology has emerged and it is now
clear that MIF is an important inflammatory mediator that
participates in both innate and adaptive immune responses
Preformed MIF protein is found in many cell types and
is released in response to different stimuli, such as infections
and cytokine stimulation . Physiological increases in
MIF, and, once released, MIF can counterregulate the anti-
inflammatory effects of steroids on cytokine production
[10, 11]. The pro-inflammatory activities of MIF include
tumor necrosis factor (TNF), interleukin-1 (IL-1), and nitric
oxide (NO) by macrophages, the production of arachidonic
2Journal of Parasitology Research
effects of steroids
Figure 1: The effects of MIF on macrophage activation. Release of preformed MIF induced by different types of stimuli, such as infections,
cytokines, and variations on glucocorticoid levels, has paracrine and exocrine effects: triggering of the CD44/CD74 receptor complex and
the CXCR2 and CXCR4 chemokine receptors results in the production of tumor-necrosis-factor-α (TNF-α), interleukin-1 (IL-1), and nitric
oxide (NO,) as well as of arachidonic acid and eicosanoids through the induction of phospholipase A2and cyclooxygenase, and in increased
expression of TLRs and adhesion molecules in macrophages. The exocrine effects of MIF include induction of chemotaxis and promoting
the survival of leukocytes.
A2 and cyclooxygenase via a protein kinase A and ERK-
dependent pathway, the increased expression of TLRs and
adhesion molecules, antagonistic effects on glucocorticoids
activity, and its role as a chemoattractant and in promoting
the survival of leukocytes (Figure 1) [12–19]. These effects
of MIF are, at least in part, mediated by activation of the
CD74-CD44 receptor complex, as well as of the CXCR2
and CXCR4 chemokine receptors (Figure 1) [18–21]. MIF
also increases macrophage survival through inhibition of
p53 activity, thus reducing activation-induced apoptosis
. Interestingly, the inhibitory effect of MIF on p53 is
dependent on COX-2 and autocrine production of PGE2by
macrophages . This increased survival of macrophages
promoted by MIF might affect the immune response to
Studies using antibody neutralization, antagonists, or
gene deletion demonstrated that MIF plays a critical role in
the pathogenesis of several inflammatory disorders, such as
sepsis, glomerulonephritis, arthritis, colitis, encephalomyeli-
tis, atherosclerosis, and asthma [8, 9, 14, 18, 23–27]. Indeed,
MIF has been shown to influence the pathogenesis of
infectious diseases, participating in the protective immune
response or playing a critical role in its immunopathogenesis
[8, 9, 14, 19, 28–35]. Similarly, polymorphisms of the human
MIF gene have been associated with increased susceptibility
to or severity of a number of inflammatory diseases . In
the present paper we discuss the role of MIF in the host-
parasite interaction upon infection caused by protozoan
parasites (Table 1).
2.The Role of Host MIF in
the Pathogenesis of Malaria
modium. Presently, it is accepted that five species can cause
disease in humans: Plasmodium malariae, Plasmodium vivax,
Plasmodium falciparum, Plasmodium ovale, and Plasmodium
knowlesi . Together, these species are responsible for
around 225 million cases of malaria and nearly one million
deaths per year . Although all five species can cause
severe diseases , P. falciparum infections are the most
prevalent in the world and are the most likely to complicate,
which makes this species responsible for over 90% of the
deaths . Severe malarial anemia (SMA) and cerebral
malaria (CM) are the most common and life-threatening
complications caused by P. falciparum infections .
3.Host MIF IsDetrimental in
Experimental murine models of malaria infection have
provided an invaluable resource for studying the role of
inflammatory and immune responses in the pathology of
malaria . Infections caused by the four rodent parasite
species (P. chabaudi, P. yoelii, P. berghei, and P. vinckei)
vary in virulence and pathology depending on the strains of
Plasmodium and laboratory mouse used . For example,
BALB/c mice develop a lethal infection with rapidly increas-
ing parasitemia and anemia that peak approximately on day
Journal of Parasitology Research3
Table 1: Role of MIF in the control of parasite burden and in the pathogenesis of protozoan infections.
system of MIF
Effects of MIF on
Control of parasite
TNF and NO
lesion sizes and
effects of IFN-γ on
reduces their NO
does not alter Th1
lesion sizes, a
RH and avirulent
IL-1β, IL-12, TNF,
NO, and IFN-γ
lesions, a finding
MMP9 in ileum,
contributes to its
damage, and is
involved in a
with liver impact
parasite burden in
ileum, while it
IL-12, IFNγ, IL-23,
and TGF-β and
maturation of DC
parasite burden in
brain and livers
IL-1β, IL-12, and
classical heart and
lesions, a finding
vitro alone and
TNF and IFNγ
severe anemia and
Plasmodium chabaudi AS
4Journal of Parasitology Research
Table 1: Continued.
system of MIF
Effects of MIF on
Control of parasite
Plasmodium chabaudi adami
MIF promotes Th2
polarization (in its
absence, cells react
MIF is associated
with a number of
plasma and MIF
leukocytes in vitro
with severity of
in endemic zone;
in endemic zone;
MIF promoter and
8 of infection when inoculated with P. chabaudi chabaudi
AS . For this reason, this parasite-mouse combination
is considered an experimental model of SMA. On the other
hand, the same strain of mouse develops a nonlethal self-
resolving infection with peak parasitemia also on day 8
of infection followed by cell-mediated parasite killing and
total parasite clearance on day 15 when inoculated with P.
chabaudi adami DK . This second model is considered
suitable to study the interactions between macrophages
and T cells involved in parasite elimination. Alternatively,
C57Bl/6 mice develop a neurologic syndrome similar to
human CM and characterized by ataxia, convulsions, and
coma upon infection with P. berghei ANKA or P. yoelii
17XL [54–56]. Interestingly, P. yoelii 17XL, but not P. berghei
ANKA, also induces CM when inoculated in BALB/c mice
However, none of the rodent Plasmodium strains are
of infection and complications observed in some mouse-
parasite combinations including SMA and CM differ from
the human spectrum of disease . For instance, peak
anemia in the P. c. chabaudi AS-BALB/c model correlates
with a peak parasitemia of around 20%, which makes the
destruction of infected erythrocytes a major contributor
to the physiopathogenesis of anemia in this model [52,
57]. Although it also occurs in acute hyperparasitemic
infections, the development of SMA in humans occurs
mainly in chronic infections with low parasitemias (<5%)
and appears to be more related to other mechanisms
such as the destruction of uninfected erythrocytes and
the suppression of the erythropoietic response . The
majority of mouse models of CM are characterized by the
brain microvasculature as occurs in human CM .
Studies using mouse models of malaria indicate that MIF
plays a detrimental role during the infection [43, 44, 53].
Mif−/−mice in the BALB/c background or animals treated
with anti-MIF neutralizing monoclonal antibodies are more
resistant to Plasmodium chabaudi adami infection than wild-
type controls presenting a significant reduction in peak
and cumulative parasitemia . Accordingly, the infection
of BALB/c mice with P. chabaudi chabaudi AS, a mouse
model of SMA, revealed that elevated concentrations of MIF
in the plasma are associated with severity of anemia and
suppression of erythropoiesis [43, 53]. In addition, Mif−/−
mice infected with P. c. chabaudi develop a parasitemia curve
similar to that of wild-type controls but present less severe
anemia, less inhibition of erythroid colony formation, and a
higher survival .
It is not clear why blockade of MIF reduces parasitemia
during P. c. adami but not P. c. chabaudi infection. As
the development of immunity and/or anemia in mouse
Journal of Parasitology Research5
and human malaria result from a complex process that
involves multiple factors [57, 59], these findings indicate
that MIF could act modulating different mechanisms during
Plasmodium infection. For example, MIF attenuates the
enhancing IL-4 . Nevertheless, experimental evidence
has suggested no role for IFN-γ and TNF as inhibitors
of erythropoiesis in mice  and serum concentrations
of these cytokines are the same during the critical period
of anemia in Mif−/−and wild-type mice infected by P. c.
chabaudi , indicating that the role of MIF in this mouse
model of SMA is independent of the contribution of TNF or
Production of MIF in mouse SMA seems to be triggered
by hemozoin, which is an insoluble heme polymer pro-
duced by parasite catabolism of host hemoglobin [43, 53].
Hemozoin contributes to the suppression of erythropoiesis
in several ways, including the induction of MIF [61–63].
infected erythrocytes and synthetic hemozoin in a dose
response manner [43, 53]. MIF inhibits erythroid colony
formation and differentiation in mouse and human bone
marrow cell cultures containing erythropoietin by modu-
lating MAP kinase activation [10, 43]. Taken together these
data indicate that MIF plays a role in the physiopathology of
mouse SMA by decreasing red blood cell production during
Nevertheless, the role of MIF in semi-immune mouse
followed by antimalarial treatment in C57Bl/6 mice) that
present low levels of parasitemia during anemic episodes and
are believed to be more closely related to the human pathol-
ogy [64, 65] was not investigated yet. It is also still unclear
what is the relationship, if any, between MIF production
during Plasmodium infection in mice and other mechanisms
known to be involved in mouse SMA such as lysis of
infected erythrocytes due to schizogony and destruction of
noninfected erythrocytes , by phagocytosis , and
4.Host MIF Seems to Be Protectivein
Studies conducted in Africa have reported lower concentra-
tions of MIF in P. falciparum-infected children when com-
pared to asymptomatic ones [46, 67, 68]. These studies have
shown an inverse correlation between MIF concentrations
and parasite burden  and suggested a protective role
for MIF during noncomplicated malaria  and human
SMA . Furthermore, the data above is corroborated
by an experimental work with healthy European volun-
teers showing that MIF concentrations are decreased in
response to early P. falciparum infection but are increased
in response to antimalarial treatment . Several other
reports in children [43, 69] and adults [70, 71] infected
with P. falciparum showed conflicting results adding to the
controversy on the role of MIF on malaria pathogenesis.
The reasons behind these discrepancies are not obvious
but one should consider that factors such as the previous
degree of immunity of the studied population, which can
change the pattern of response to the infection , and the
presence of Plasmodium-derived MIF homologues  were
analyzing the different studies.
concentrations and hemozoin accumulation was showed in
children affected by severe anemia indicating that, different
from mouse models, hemozoin may decrease MIF produc-
may lie in a feedback loop involving long-lasting hemo-
zoin activation of macrophages in these children. In fact,
PBMC from malaria-na¨ ıve patients can react to hemozoin
by either increasing or decreasing MIF production ,
depending on whether they have a generally well-preserved
MIF production. Additionally, MIF polymorphisms also
give rise to variable magnitudes of response to hemozoin
 and could also help to explain the variability found
in these studies regarding MIF production in response
to hemozoin. Accordingly, there is an association between
certain MIF haplotypes of the −173G/C and −794CATT5-8
polymorphisms and susceptibility to SMA [43, 47].
Few studies in humans indicate that MIF is involved
in the pathogenesis of cerebral malaria [72–74]. Necropsy
studies show a decrease in endothelial cell expression of MIF
in brain vessels of cerebral malaria patients when compared
to endothelial cells from axillary and chest vessels [72, 73].
A clinical study in India showed that high concentrations
of MIF in the plasma are associated with death in cerebral
malaria patients . Finally, women with placental malaria
infection presented significantly higher levels of MIF in the
placental intervillous blood when compared to uninfected
pregnant women also indicating a role for this cytokine in
malaria infection during pregnancy [69, 75].
5.The Role of PlasmodiumMIFin
the Pathogenesis of Malaria
MIF homologues have been identified in all species of
Plasmodium examined to date—P. falciparum [76–78], P.
vivax , P. berghei [54, 79], and P. yoelii [55, 56]. The
data from the studies cited above indicate that Plasmodium
MIF (pMIF) is structurally similar to mammalian MIF with
around 30% amino acid sequence identity and possesses
some, but probably not all, activities normally attributed
to the latter. pMIF expression increases with blood-stage
parasite maturation: minimal in ring stage and peaking
in the trophozoite and schizont stages [54, 55, 76]. There
is no evidence showing that pMIF is actively or passively
secreted to the blood stream by the parasite, but it is released
extracellularly upon schizont rupture, when it becomes
available to interact with the host immune cells [54, 55].
Indeed, pMIF has been detected in culture supernatant and
plasma of Plasmodium-infected mice and humans [55, 56,
residues in the molecular region known to be involved
6Journal of Parasitology Research
in the catalytic sites, it seems that the tautomerase and
oxidoreductase activities are highly depressed in pMIF when
compared to mammalian MIF. Alternatively, pMIF might
have a different substrate specificity and the physiological
substrate has yet to be identified [54–56].
In terms of functional studies, in vitro assays and animal
models have shown that pMIF shares some biological
properties with mammalian MIF. Indeed, both pMIF and
mammalian MIF reduce AP-1 expression, interact with
human CD74, induce macrophage chemotaxis, and inhibit
erythropoiesis and macrophage apoptosis [54–56, 79, 80].
On the other hand, pMIF does not stimulate the release
of IL-8, TNF, or IL-12 from mice and human monocytes
or enhance the response of these cells to LPS [55, 78], a
key function of mammalian MIF. Finally, a study showed
that pMIF and mouse MIF act synergistically to activate the
but act antagonistically at higher concentrations , indi-
cating that pMIF and mammalian MIF can interact in a
The role of pMIF during malaria infection is also not
completely understood. Although counterintuitive, studies
in mouse models indicate that pMIF attenuates Plasmodium
virulence by modulating host immune responses [54–56].
C57Bl/6 and BALB/c mice showed a reduction in disease
severity when infected with transgenic strains of P. yoelii
17X and P yoelii 17XL that constitutively overexpress P. yoelii
MIF (PyMIF)  or when treated with recombinant PyMIF
. This was phenotypically manifested by a decrease
in peak and cumulative parasitemia in mice infected with
the nonlethal strain P. yoelii 17X and prolonged course of
infected with the lethal strain P yoelii 17XL [55, 56]. On the
other hand, the development of cerebral complications in
C57BL/6 mice and hyperparasitemia and severe anemia in
BALB/c mice did not differ upon infection with P. berghei
wild-type or P. berghei MIF knockout parasites . Once
again, studies in humans failed to recapitulate observations
from mouse models as pMIF amounts in uncomplicated
malaria patients are positively correlated with parasitemia,
disease severity, and plasma concentrations of TNF, IL-10,
and MCP-1 . Thus, future studies are required to define
the role of host and Plasmodium MIF in the pathogenesis of
6.CriticalRole of MIF in
Toxoplasma gondii Infection
Toxoplasma gondii is an intracellular parasite of the phylum
Apicomplexa that is highly adapted to infect different
cell types and tissues. T. gondii enters its host via the
gastrointestinal tract and the innate immune response in the
intestine is triggered by the recognition of parasite molecules
by enterocytes, macrophages, and dendritic cells (DCs)
. The establishment of an antigen-specific Th1 response
is essential to protective immunity but also potentially
detrimental as excessive intestinal inflammation and tissue
necrosis can lead to bacterial translocation and death .
The proinflammatory cytokines IL-12, TNF, IFN-γ, and IL-
1β promote resistance against T. gondii in part due to the
responsible for parasite elimination.
A model of systemic infection with T. gondii through the
intraperitoneal route demonstrated an increased susceptibil-
ity of Mif−/−mice when compared to wild-type mice .
Mif−/−mice presented higher parasite burden in brains and
peritoneal macrophages and reduced plasma concentrations
of IL-12, TNF, IFN-γ, IL-1β, and nitrite during infection
. These findings were expected considering that MIF is
an enhancer of IL-12 and TNF production by macrophages.
A recent study using a model of oral T. gondii infection
in the BALB/c background also demonstrated an increased
and DC activation on Mif−/−mice compared to wild-type
mice . DCs obtained from spleens and mesenteric lymph
nodes from Mif−/−mice orally infected with T. gondii had
impaired maturation, with decreased expression of CD80,
CD86, CD40, and MHC class II . Thus, the protective
role of MIF in T. gondii infection is apparently related to the
production of proinflammatory cytokines, the activation of
DC, and the better control of parasite burden.
BALB/c mice are naturally resistant to oral infection with
T. gondii, while those of C57BL/6 are highly susceptible
displaying intestinal inflammation especially in the ileum
[82–84]. This increased lethality of C57BL/6 is related to
the extensive intestinal inflammation, tissue necrosis, and a
sepsis-like syndrome. Using the peroral route of infection in
C57BL/6 mice, it was shown that Mif−/−mice have reduced
intestinal and systemic inflammation and survive longer
compared to wild-type mice, despite an increase in intestinal
IL-12, IFN-γ, and IL-23 and an increased expression of IL-
22 in ileal mucosa. Signs of systemic inflammation including
the increased concentrations of inflammatory cytokines in
the plasma and liver damage were less pronounced in Mif−/−
mice compared to wild-type mice . Although MIF has
been regarded as essential in host protection during T. gondii
infection, these findings demonstrated a pathogenic role of
MIF in natural T. gondii infection in susceptible hosts. This
dichotomy seems to depend on the route of infection and
the genetic background of the host. Thus, MIF is necessary
to control parasite burden in resistant and susceptible hosts,
but it increases intestinal tissue damage causing death in
susceptible hosts while it is essential for survival in resistant
A major consequence of human T. gondii-infection is the
severe congenital malformations when the primary infection
occurs in the first trimester of pregnancy. A series of studies
demonstrated a putative role of MIF on placental biology
upon infection with T. gondii. Infection or stimulation of
chorionic explants with molecules of T. gondii, IFN-γ, and
IL-12 evoked the secretion of MIF [85, 86]. MIF and its
receptor, CD74, are present in the syncytiotrophoblast layer
and mesenchyme . MIF induces ICAM-1 expression
increasing the interaction of villous explants with monocytes
. These results suggest that MIF, by influencing the
recruitment of T. gondii infected monocytes, could facilitate
Journal of Parasitology Research7
the dissemination of the infection into the deep placental
tissues or increase the tissue damage due to inflammation.
The same group recently demonstrated, however, that MIF is
important for control of placental T. gondii infection in first
trimester of pregnancy .
7.MIF IsProtectiveinLeishmania Infection
Leishmaniasis, caused by the protozoan parasites from the
genus Leishmania, comprises a large spectrum of clinical
manifestations including benign ulcer, destructive muco-
cutaneous lesions, disseminated cutaneous lesions, and
systemic visceral forms . In the mammalian host,
mainly macrophages. Parasite killing requires macrophage
activation with ensuing NO and ROS production .
Infection with Leishmania major causes skin lesions, which
in general parallel the parasite load. A highly polarized Th1
response is effective against L. major, activating macrophages
to produce NO and resulting in resolving skin lesions. Addi-
tion of MIF to macrophage cell cultures results in increased
L. major elimination . Though the MIF concentration
required to reduce L. major burden in macrophages is high
(1μg/mL, 100 times that of other cytokines with leishmani-
cidal effects, such as IFN-γ), this concentration is within
the range reached in inflammatory conditions. The MIF-
and NO by infected macrophages, and can be reversed by the
addition of IL-10, TGF-β or IL-13, indicating that it depends
on an M1 activation status . The expression of MIF
increases during L. major footpad inoculation in popliteal
lymph node, but the kinetics of its expression compared to
that of MIF secretion by T cells upon antigenpresentation
suggests that lymph node MIF comes from another cellular
source . Consistent with the observed role of MIF as
an enhancer of macrophage leishmanicidal function, oral
administration of Salmonella typhimurium transfected with
MIF reduces the size of skin lesions , while Mif−/−mice
are highly susceptible to L. major, developing severe skin
lesions late after infection . MIF does not affect Th
polarization in L. major infection, as indicated by the similar
IFN-γ and IL-4 production among T cells from Mif−/−
and wild-type mice. However, IFN-γ-activated macrophages
from Mif−/−mice infected in vitro with L. major have
slightly decreased parasite clearance , indicating that
either they are somewhat insensitive to IFN-γ or MIF
production is partially required as an intermediary step to
IFN-γ-induced leishmanicidal activity. The contribution of
against cutaneous leishmaniasis was demonstrated using a
model of vaccination with the L. pifanoi antigen P-4 .
BALB-c mice immunized with P-4 expressed around 10-
fold higher amounts of MIF, TNF, and IFN-γ mRNAs than
the adjuvant controls. Moreover, blockage of MIF with anti-
of macrophages cultured with CD4+lymphocytes obtained
from P-4-immunized mice.
Patients with visceral leishmaniasis due to infection with
L. donovani presented CD4+lymphocytes expressing low
amounts of CD2, IFN-γ, and MIF . Antileishmanial
treatment caused immunological recovery with increased
expression of CD2 and production of MIF. On the other
hand, a recent study demonstrated that patients with visceral
leishmaniasis caused by L. chagasi have increased plasma
concentrations of MIF . The MIF concentrations were
higher in patients with the active form compared to patients
LPS in the plasma of patients with active disease and the LPS
concentrations positively correlated with MIF.
8.Identification of LeishmanialMIF and
Its Role inInfection
The complete genome sequencing of L. major revealed two
genes with significant sequence similarities to human MIF
(22% identity) . Cloning and expression of one of these
leishmanial orthologues of MIF allowed detailed functional
and structural characterizations [93, 94]. The X-ray crystal
structure of Lm1740MIF/LmjMIF1 demonstrated an overall
global topology similar to that of human MIF, but the
catalytic site has substantial differences that correlate with
the low tautomerase activity of Lm1740MIF/LmjMIF1 and
the lack of inhibitory effect of ISO-1, a MIF antagonist that
binds to the catalytic site [93, 94]. Similar to the other MIF
structures, the L. major orthologue proteins adopt trimeric
ring architecture. Lm1740MIF binds to CD74, the MIF
receptor, indicating a putative role of L. major MIF affecting
host immunity . In fact, LM1740 induces a signaling
cascade on monocytes dependent on CD74 and similar
to the one triggered by mammalian MIF. This includes
the ability of L. major MIF orthologues to induce ERK1/2
phosphorylation, to cause the reduction of Ser15-p53 in the
cytoplasm, and to protect macrophages from NO-induced
apoptosis . Since the macrophage is the main cell type
hosting Leishmania, the ability of L. major MIF to increase
the survival of macrophages might represent an important
selective advantage that guarantees more efficient amastigote
Trypanosoma cruzi Infection
Trypanosoma cruzi is an intracellular protozoan that can
infect many cell types, including macrophages. The effec-
tive response to T. cruzi comprises innate activation of
macrophages to induce NO production and, ultimately, the
establishment of antigen-specific Th1 CD4 and CTL CD8
responses . Mice genetically deficient in Mif also are
more susceptible to Trypanosoma cruzi infection . This
and also decreased IL-12 and IFN-γ production by spleno-
cytes stimulated with T. cruzi antigens early in the acute
phase, indicating that in contrast to the trypanosomatid,
L. major, MIF participates in Th1 polarization in T. cruzi
infection. This deficient Th1 polarization is reflected by
decreased titers of anti-T. cruzi IgG2a (but not IgG1). Also,
8Journal of Parasitology Research
Mif−/−mice have decreased plasma concentrations of TNF,
IL-1β, and IL-18, suggesting that decreased production of
proinflammatory cytokines underlies their susceptibility to
T. cruzi infection. The deficient Th1 polarization, specific
IgG and pro-inflammatory cytokine secretion are all highly
compatible with susceptibility to T. cruzi infection, but there
is currently no functional data to support this hypothesis. In
fact, IFN-γ-activated macrophages have a prominent role in
T. cruzi clearance through NO production, a function that
can be enhanced by TNF production. As MIF controls TNF
production by macrophages in a number of cases and, along
with TNF, enhances production of NO by macrophages and
the elimination of trypanosomatid L. major , it seems
likely that MIF enhances macrophage trypanocidal activity.
Interestingly, increased expression of MIF was observed
in myocardium and skeletal muscles from acutely T. cruzi
infected BALB/c mice and positively correlated with parasite
burden and myopathic alterations .
A prior intracellular infection can sensitize the organism
to septic shock by priming monocytes to overreact in the
presence of very low amounts of TLR ligands, as happens
in influenza , VSV , LCMV infection , among
others. T. cruzi-infected mice are highly susceptible to sys-
temic inflammation, which can be caused by infection itself
in mice lineages that develop severe inflammatory response
or by administration of TNF, anti-CD3 , SEB , or
LPS . The lethal synergism between T. cruzi infection
and LPS inoculation likely results from redundant lethal
pathways induced by TNF and MIF: although both Mif−/−
and Tnfr1−/−infected mice succumb to LPS administration,
treatment with anti-MIF rescues Tnfr1-deficient mice from
lethal shock . However, at present there are no studies
demonstrating a contribution of MIF to human mortality in
Almost no information is available on MIF biology
in Chagasic patients. The only study that addressed this
issue demonstrated that the MIF-173G/C polymorphism
confers susceptibility to Chagas disease in two cohorts from
Colombia and Peru . Future studies are essential to
characterize the participation of MIF in the physiopathology
and immunity to T. cruzi infection.
In this paper we described the involvement of MIF in sev-
eral models of protozoan infections, considering common
themes and certain peculiarities specific to each parasite. In
general, MIF seems to participate in the control of parasite
burden but, in many cases, with the cost of promoting
tissue damage due to increased inflammation. The essential
role of MIF in the pathogenesis of infectious diseases and,
target still require extensive clinical studies. Thus, for the
years to come, several aspects of the biology of MIF and
its participation in the response to infectious diseases,
including parasitic diseases, need to be addressed opening
up new highways of research and, possibly, novel therapeutic
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