Review
Recent insights into humoral and
cellular immune responses against
malaria
James G. Beeson1, Faith H.A. Osier2 and Christian R. Engwerda3
1
The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, Victoria 3050, Australia
Centre for Geographic Medicine Research, Coast, Kenya Medical Research Institute, Kilifi, Kenya
3
The Queensland Institute of Medical Research, The Bancroft Centre, 300 Herston Rd, Royal Brisbane Hospital, QLD 4029, Australia
2
Effective immunity to malaria has been clearly demonstrated among individuals naturally exposed to malaria,
and can be induced by experimental infections in
animals and humans. The large number of malaria antigens has presented a major challenge to identifying
protective responses and their targets, and it is likely
that robust immunity is mediated by responses to
multiple antigens. These include merozoite surface antigens and invasion ligands, variant antigens on the surface of parasitized red blood cells, in addition to
sporozoite and liver-stage antigens. Immunity seems
to require humoral and cellular immune components,
probably in co-operation, although the relative importance of each remains unclear. This review summarizes
recent progress towards understanding the targets and
mechanisms that are important for mediating immunity
to malaria.
Immunity to malaria
The complexity of immune responses to malaria has been
increasingly recognized over recent years, together with an
appreciation that any single antigen-specific response is
unlikely to afford much immunity on its own. This is
reflected in the multiple life-stages in the life cycle of
Plasmodium and the large genome. With around 5000
genes, there are myriad potentially important immune
targets, making the identification of protective responses
highly challenging. Furthermore, immune responses are
not only involved in preventing infection and clearing
parasites but also might instead contribute to the pathogenesis of severe malaria if they are inappropriate in their
nature and extent [1]. Here, we review recent insights into
the nature and targets of immune responses to malaria,
particularly highlighting studies presented at the recent
Molecular Approaches to Malaria meeting*.
After repeated exposure to malaria, individuals eventually develop effective immunity that controls parasitemia and prevents severe and life-threatening
complications (reviewed in Ref. [2]). Similarly, effective
immunity can be induced by repeated experimental infections in animals, and have also been induced by experimental infections in humans [3]. These observations
Corresponding author: Beeson, J.G. (beeson@wehi.edu.au)
Held in Lorne, Australia, February 2008. Abstracts for work cited in this review
can be found in Intl. J. Parasitol (2008) 38, S17–S98..
*
578
continue to provide a strong rationale that an effective
vaccine against malaria is achievable. Effective immunity
seems to require both humoral and cellular immune
responses, probably in co-operation, although the relative
importance of each remains unclear. The acquired
response is thought to target predominantly blood-stage
parasites, but antigens expressed by sporozoites and
malaria-infected hepatocytes also seem to be important.
Recent studies of experimental Plasmodium falciparum
infections in naı̈ve adult volunteers receiving chloroquine
prophylaxis to prevent blood-stage parasitemia revealed
that sterile immunity seemed to be acquired after only a
small number of infections from mosquito inoculations (R.
Sauerwein and colleagues, Radboud University,
Netherlands*).
Humoral immunity
The most direct evidence that antibodies are important
mediators of immunity to malaria comes from passive
transfer studies in which antibodies from malaria-immune
adults were successfully used to treat patients with severe
malaria [4,5]. Studies in mice deficient in Fcg receptors
further support an important role for antibodies [6]. Protective antibodies are thought to target primarily merozoite surface antigens, erythrocyte invasion ligands and
variant surface antigens expressed by P. falciparuminfected erythrocytes (IEs) [7,8].
Merozoite antigens
Longitudinal studies conducted in malaria-endemic areas
aim to correlate measured immune responses with varying
outcomes of malaria, from infection, to mild clinical disease
and severe and fatal malaria. Many studies have evaluated
associations between antibody responses and protection in
longitudinal studies (reviewed in Refs [2,9]). Until
recently, however, these had been restricted to a limited
number of antigens and in most cases have not considered
multi-antigen responses. In an approach that considered
both the magnitude and breadth of the antibody response
to a large panel of merozoite antigens, Osier and colleagues
[10] recently found that a broad antibody response was
strongly associated with protection from clinical malaria
and the strongest associations with protection were found
with combined responses to merozoite surface protein
(MSP) 2 and MSP3. A novel immunoproteomic approach
1471-4922/$ – see front matter ß 2008 Elsevier Ltd. All rights reserved. doi:10.1016/j.pt.2008.08.008 Available online 8 October 2008
Review
Trends in Parasitology
Vol.24 No.12
Table 1. Immune effector mechanisms against Plasmodium
Parasite life stage
Pre-erythrocytic
Sporozoites
Infected hepatocytes
Blood stages
Merozoites
Infected erythrocytes
(asexual and sexual forms)
Immune effector mechanisms
Humoral responses
Cellular responses
Inhibition of hepatocyte invasion by antibodies
Not applicable
CD4+ T-cell help to B cells
Lysis of infected hepatocytes by CD8+ T cells
CD4+ T-cell help for generation of cytolytic CD8+ T cells
Inhibition of erythrocyte invasion
Antibody-dependent cellular inhibition of parasite
replication
Opsonisation of merozoites for phagocytosis by
mononuclear cells
Opsonisation for phagocytosis or complementmediated lysis
Inhibition of vascular adhesion
Inhibition of schizont rupture
Opsonic and non-opsonic phagocytosis of merozoites
CD4+ T-cell help to B cells
using immunoprecipitation of merozoite proteins with
human antibodies and identification of antigens by 2D
gel electrophoresis also highlighted the breadth of the
acquired antibody response and will facilitate the identification of dominant antibody targets (T. Nebl, Walter and
Eliza Hall Institute [WEHI]*). Few studies have considered the combined effects of humoral and cellular
responses. J. Kazura and colleagues (Case Western
Reserve University [CWRU])* reported that antibodies
to MSP-142 were only weakly associated with protection,
whereas the combination of both T-cell interferon-g
responses and immunoglobulin G (IgG) to MSP-142 was
a better predictor of reduced risk of re-infection, thus
supporting the notion that both cell-mediated and humoral
immune responses are required for efficient protection
against malaria.
Antibodies to merozoite antigens are believed to act by
directly inhibiting merozoite invasion of erythrocytes or
opsonising merozoites for phagocytosis [11,12] (Table 1).
Recently, renewed efforts have been made by different
laboratories to optimize functional antibody assays and
understand their acquisition and importance. Two groups
working with different populations in Kenya found that
growth-inhibitory antibodies do not show the expected ageassociated increase as observed with antibodies measured
using standard immunoassays (F. McCallum and colleagues, WEHI and Kenya Medical Research Institute
[KEMRI]; A. Dent and colleagues, CWRU*). Results
indicate that inhibitory antibodies can be acquired at an
early age, but tend to remain stable or decline with increasing age. These antibodies might, therefore, have an important role in the early acquisition of immunity, such as
mediating protection from severe disease. Focused studies
in young children are needed to test this hypothesis. Dent
and colleagues* did find that individuals with the highest
level of inhibitory activity had a modest reduction in risk of
re-infection. Others have previously reported no association between growth inhibition of dialyzed or untreated
serum and risk of symptomatic malaria [13,14]. The IgG
subclass response could also be important for antibody
function. Studies in Papua New Guinea (PNG) children
found that IgG3 to apical membrane antigen 1 (AMA1) was
strongly associated with protection from malaria, whereas
there was only a weak association with IgG1 (D. Stanisic
Opsonic and non-opsonic phagocytosis of infected
erythrocytes
CD4+ T-cell help in the form of pro-inflammatory cytokines
CD4+ T-cell help to B cells
Possible role of T regulatory (Treg) cells
and colleagues, WEHI and PNG-IMR*); and other studies
have also pointed to the importance of IgG3 responses in
protection from malaria [15]. This observation warrants
further investigation because AMA1 vaccine trials indicate
that IgG1 is the dominant IgG subclass induced by immunization [16].
New data are emerging to indicate that the erythrocyte
binding antigen (EBA) and P. falciparum reticulocyte-binding homologue (PfRh) invasion ligand families are important immune targets (J. Beeson and colleagues, WEHI*). P.
falciparum can use different pathways for invasion of erythrocytes during blood-stage infection by varying the expression and/or use of the EBAs and PfRhs [17,18]. Recent
findings indicate that variation in invasion phenotype alters
parasite susceptibility to human inhibitory antibodies and
that this parasite property might exist as a mechanism that
facilitates immune evasion [19]. Comparisons of the inhibitory activity of acquired antibodies against parasites with
different EBA and PfRh expression indicated that the EBAs
and PfRhs are important targets of growth-inhibitory antibodies (K. Persson and colleagues, WEHI*). Few targets of
human invasion-inhibitory antibodies have been identified,
but data indicate AMA1 and MSP1 are also important
targets [20–22]. Of further interest, high levels of antibodies
against the EBAs and PfRh proteins were strongly associated with protection from clinical malaria in longitudinal
studies of children (J. Richards, L. Reiling, and colleagues,
WEHI and PNG-IMR*).
Duffy-binding protein (DBP) has an essential role
during invasion of reticulocytes by Plasmodium vivax,
and is functionally related to the EBAs of P. falciparum
[23]. As for the EBAs, DBP seems to be an important target
of protective immunity. Acquired human antibodies to
DBP were recently shown to inhibit reticulocyte invasion
[24], and antibodies that blocked the binding of DBP to its
receptor (Duffy antigen) were prospectively associated
with protection from infection among children [25]. Antibodies to MSP1 have also been associated with protective
immunity against P. vivax in prospective studies [26].
Interestingly, recent studies in Papua New Guinea
indicate that the acquisition of immunity to P. vivax in
childhood is substantially more rapid than it is to P.
falciparum (I. Muller, PNG-IMR*) [27], which could reflect
biological differences between the parasites.
579
Review
Antigens expressed on the surface of infected
erythrocytes
During intra-erythrocytic development, P. falciparum
expresses highly variant antigens on the erythrocyte surface, known as variant surface antigens (VSAs). These
antigens include P. falciparum erythrocyte membrane
protein 1 (PfEMP1), rifins, STEVOR and others [28].
The importance of each of these antigens is unclear, but
PfEMP1 is thought to be the most important target of
antibodies [29,30]. PfEMP1 is encoded by the var multigene family, and different var genes encode PfEMP1 variants with different antigenic and adhesive properties [31].
Antigenic diversity and variation by P. falciparuminfected erythrocytes, through expression of different
VSAs, enables P. falciparum to cause repeated infections
over time and new infections seem to exploit gaps in the
repertoire of variant-specific antibodies [32]. With increasing exposure a broad repertoire of antibodies is obtained
that eventually provides protection against most variants.
Prospective studies in children provide strong evidence
that VSAs are targets of protective immunity [33,13]. A
wide array of var genes is expressed by parasites in children with malaria and studies are beginning to identify
subsets of var genes associated with severe disease that are
likely to be important immune targets [34–36]. The pattern
of var gene expression is much simpler in placental
malaria; a specific variant of PfEMP1 (var2csa) is
expressed that mediates adhesion of IEs to the placental
lining, and it seems to be an important target of protective
antibodies against malaria in pregnancy [37]. Although
var2csa is less antigenically diverse than other PfEMP1
variants, substantial diversity still poses a challenge for
vaccine development [38]. Antibodies seem to target variant epitopes of var2csa to a substantial extent [39,40];
however, recent studies combining epitope-mapping using
peptide arrays and structural modeling indicate that antibodies in humans and induced in experimental animals by
vaccination also target conserved epitopes (T. Theander
and colleagues, University of Copenhagen, Denmark*) [41].
Other results indicate that placental-binding variants
express common epitopes that have limited global diversity and have a wide geographic distribution (Hommel and
colleagues, WEHI*), and that there is sharing of polymorphic blocks between different variants [42]. These
findings raise hope that a vaccine inducing broad coverage
against different placental-binding variants might be
achievable by targeting conserved and/or common epitopes.
Antibodies to VSAs might act by opsonising IEs for
phagocytosis or complement-mediated lysis and/or by inhibiting vascular adhesion and sequestration. The relative
importance of these potential mechanisms is not well
established in humans, but is essential for understanding
the requirements for protective immunity and potential
vaccine development. Emerging data are highlighting the
likely importance of opsonic phagocytosis in immunity to
malaria in pregnancy [43]. Opsonising antibodies were
associated with higher hemoglobin levels among pregnant
women exposed to malaria and a reduced risk of recrudescent or repeat infections after treatment for malaria in
pregnancy, indicating some protective role (S. Rogerson
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Trends in Parasitology Vol.24 No.12
and colleagues, University of Melbourne, Australia*). Prospective studies are needed to examine these responses
further, especially in comparison to adhesion-inhibitory
activity, and need evaluation in studies of immunity to
childhood malaria.
Cell-mediated immunity
Our understanding of cell-mediated immunity (CMI) in
malaria remains relatively poor, despite the recognition
that CD4+ T-cell help is essential for most Plasmodiumspecific antibody responses [44], and evidence that vaccineinduced P. falciparum-specific CD4+ T-cell responses
might protect against malaria in humans [3]. A large body
of research on interactions between Plasmodium pre-erythrocytic stages and the host has also identified important
roles for memory CD8+ T cells in protection from re-infection, again thought to depend on CD4+ T-cell help [45–
47]. Thus, CMI responses have crucial roles in protective
immunity, but also have the potential to cause tissue
pathology and contribute to the development of severe
malaria [48]. Hence, CMI regulation is important for
determining whether host immune responses can effectively control parasite growth or whether they contribute
to disease.
Linking innate and adaptive immune responses
Understanding the relationship between innate immune
responses and CMI is important because innate immune
responses to pathogens direct the development of subsequent CMI responses [49]. Recent work has focused
particular attention on identifying pattern recognition
receptors, and in particular, Toll-like receptors that
recognize Plasmodium molecules on innate immune cells
[50,51]. The relevance of these findings is supported by
observations in a Plasmodium yoelii model that macrophages and/or monocytes are essential for controlling the
primary wave of blood-stage parasitemia [52]. Recent
studies have extended this area of research to include
the production of the important pro-inflammatory cytokine IFNg by human natural killer (NK) and gd T cells
after exposure to malaria. E. Riley and colleagues
(London School of Hygiene and Tropical Medicine,
UK)* found great diversity in responses between individuals that could be explained, at least in part, by
polymorphisms in NK cell major histocompatibility complex (MHC) receptors. Others found that early IFNg
output in PNG children was dominated by gd T cells,
and (to a much lesser degree) by conventional ab T cells
and NK cells, and that these responses were regulated by
parasite-encoded molecules such as PfEMP-1 and gycosylphosphatidlinositol (S. Schofield, M. D’Ombrain, L.
Robinson, WEHI*). Other studies reported that an early
burst of cytokine production, including IFNg, after 24 h
of non-lethal Plasmodium berghei K173 infection was
associated with survival in C57BL/6 mice (N. Hunt,
University of Sydney, Australia*). However, the absence
of this early response in C57BL/6 mice infected with P.
berghei ANKA correlated with pathogenesis, indicating
that the effective engagement of innate immune
responses was necessary for the generation of an efficient
and non-pathogenic CMI response in malaria.
Review
Antigen presenting cell function
The ability of antigen presenting cells (APC) to capture and
process parasite antigen determines the magnitude and
quality of T-cell responses, and there have been many
reports in the past decade of modulated APC function
during malaria [53]. Recent findings that shed new light
on how APC impact on developing CMI responses in experimental malaria models include the discovery that conventional dendritic cells (cDC) are crucial for priming
pathogenic T cells in experimental cerebral malaria
(ECM) caused by P. berghei ANKA [54]. CD8a+ cDC have
recently been identified as key activators of antigenspecific CD8+ T cells involved in pathogenesis in the same
model [55]. In a lethal malaria model using mice infected
with P. yoelii YM, DC function was impaired [56], and the
pro-inflammatory cytokine tumor necrosis factor (TNF)
seemed to contribute to impaired DC function [57]. These
recent findings were also advanced at the MAM2008 meeting. M. Sponas (National Institute of Medical Research
[NIMR], UK)* described an important role for emerging
CD11c-positive monocytes in the early control of mouse
Plasmodium chabaudi infection. M. Wykes (QIMR)*
reported that more virulent parasite species impair DC
function, and transfer of DCs from mice with non-lethal
infections to mice infected with lethal Plasmodium species
resulted in protection. F. Amante (QIMR)* described a
crucial role for cDC in the generation of pathogenic
CD4+ T-cell responses during ECM caused by P. berghei
ANKA, whereas Rachel Lundie (WEHI)* presented work
that identified CD8+ cDC as the key activators of pathogenic parasite-specific CD8+ T cells that infiltrate the brain
using the same ECM model.
Cytokines and chemokines
The involvement of inflammatory and regulatory cytokines
and chemokines in ECM pathogenesis is well established
[58]. In mice, T cells and TNF family members seem to be
crucial mediators of pathology [59–61], and lymphotoxin ß
receptor (LTßR) was recently reported to have an important role in ECM pathogenesis [62]. This area of research
has been advanced by B. Ryfell (CNRS, Orleans, France)
and L.Randall (QIMR)* who reported crucial roles for the
relatively new TNF family member LIGHT and TNF receptor (TNFR) family members LTßR and TNFRII in the
pathogenesis of ECM caused by P. berghei ANKA. There
has been a substantial amount of recent attention on
chemokines that recruit pathogenic cells to the brain
during ECM, with several studies reporting key roles for
the chemokine (CXC motif) ligand 10 (CXCL10; or IFNgamma-inducible protein 10 [IP-10]), CXCL9 (monokine
induced by IFN-gamma [MIG]) and their receptor CXCR3
[63–66]. C. Nie and colleagues (WEHI)* also reported an
important role for CXCL10 in mediating leukocyte trafficking to the brain in the same model, with evidence that this
chemokine might not only direct the trafficking of pathogenic CD8+ T cells into the brain but could also modulate
developing CMI in other tissue sites. Despite the recognition that host CMI has a key role in the pathogenesis of
ECM in mice, this link in humans is not clear. However,
recent studies have identified a subgroup of children with
fatal malaria that had sequestered leukocytes in the
Trends in Parasitology
Vol.24 No.12
cerebral vasculature; studies on these children could provide important insights into the pathogenesis of severe and
fatal malaria (S. Wassmer, Malawi-Liverpool-Wellcome
Trust Clinical Research program, Malawi and University
of Sydney*).
APC–T-cell interactions
Interactions between T cells and APC are likely to be
essential for the development of immunity to malaria, in
addition to being essential for induction of effective
vaccine-induced immunity. These studies have been aided
by the development of P.chabaudi blood stage antigenspecific T-cell receptor (TCR) transgenic mice [67]. Work
from a mouse P.chabaudi model using parasite MSP1specific TCR, in addition to B-cell receptor transgenic cells,
demonstrated the importance of parasite-specific CD4+ Tcell responses for the generation of long-lived memory B
cell and plasma cell development (J. Langhorne and colleagues, NIMR*). The presence of chronic parasitemia was
found to impair the generation of these responses. An
important recent finding has been that CD8+ T-cell priming in a pre-erythrocytic vaccine model occurs primarily in
lymph nodes draining the site of sporozoite challenge, and
not in the liver or other secondary lymphoid tissue [68]. F.
Zavala and colleagues (Johns Hopkins University, Baltimore, USA)* reported that sporozoite-specific CD8+ T cells
activated in skin-draining lymph nodes migrated to different organs, including the liver, to perform effector functions; once memory CD8+ T cells were generated and these
cells entered the liver, they remained for several months
and were re-activated within hours of a new sporozoite
challenge. These data support recent intravital studies on
the fate of sporozoites after injection into the skin [69],
complimented by studies showing the movement of preerythrocytic parasites after injection into the dermis by an
infected Anopheles mosquito (R. Menard, Pasteur Institute, France*). Sporozites were observed not only in the
liver but, importantly, were also found to be retained in the
dermis for long periods and in the draining lymph nodes
where they were presumably processed and presented by
APC to naı̈ve CD8+ T cells.
Regulatory T cells
The regulation of CMI during malaria infection is thought
to be important for determining whether an efficient antiparasitic CMI response is generated without tissue pathology. T regulatory (Treg) cells have been reported to have
important roles in regulating CMI responses in mouse
models of malaria [70–72]. However, these studies often
utilize anti-CD25 antibodies to deplete Treg cells, and
interpretation of results has been controversial. The use
of these antibodies in the context of malaria infection has
also been questioned [73]. In humans, the production of
transforming growth factor (TGFb) and the presence of
CD4+CD25+FOXP3+ Treg cells were associated with
higher rates of P. falciparum growth in vivo, indicating
that induction of Treg cells could represent a parasitespecific virulence factor [74]. New studies (A. Scholzen, G.
Minigo and colleagues, Monash University, Australia*)
reported malaria-induced changes to Treg cell numbers
and function. P. falciparum-infected erythrocytes were
581
Review
Box 1. Priority research issues
Humoral immune responses
(i) Invasion-inhibitory antibodies:
- Identify the primary targets of invasion-inhibitory antibodies.
- Establish the role of invasion-inhibitory antibodies in protective
immunity.
(ii) Antibodies to surface antigens of infected erythrocytes:
- Establish the importance of the different candidate antigens.
- Understand the importance of opsonic phagocytosis in immunity.
- Define the acquisition and role of adhesion-inhibitory antibodies in
childhood malaria.
(iii) Identify responses involved in protection from severe malaria.
(iv) Identify epitopes of protective antibodies and define their antigenic diversity.
Cellular immune responses
(i) Define cellular immune responses that control of parasite
growth and distinguish them from those that promote disease
pathogenesis.
(ii) Identify tissue-specific antigen presenting cell subsets that
activate effective anti-parasitic immunity.
(iii) Establish the role of T regulatory (Treg) cells in severe and
uncomplicated malaria.
(iv) Identify primary antigenic targets of innate and adaptive cellular
immune responses.
Practical challenges
(i) Greater interaction between human studies and experimental
animal models.
(ii) Expanding the integration of humoral and cellular immunity
into the same studies.
(iii) Strengthening capacity for immunology research in malariaendemic countries.
found to induce Treg cell expansion in vitro among peripheral blood mononuclear cells from healthy donors,
which was accompanied by increased IL-10 and IL-6 production, but not TGFb production, a cytokine thought to
stimulate FoxP3 expression and promote Treg cell development [75]. However, numbers of peripheral blood Treg
cells were lower in malaria-exposed donors, compared to
Australian donors, and were not different between individuals with acute uncomplicated malaria versus asymptomatic malaria. Furthermore, TGFb levels were elevated
in acute malaria compared to exposed asymptomatic individuals. Clearly, the role of Treg cells in determining the
outcome of malaria infections is a topic that will receive
much attention in the coming years, and an area of
research that could shed light on how these responses
might be manipulated in the context of vaccination or
therapy.
Conclusions
Recent findings have highlighted many important
advances being made into dissecting and defining immune
responses to malaria, despite its great complexity. Further
research to define the mechanisms and targets of immunity, including humoral and cellular responses and how
they interact, is crucial for vaccine development and evaluation and to further understand disease pathology (Box 1).
582
Trends in Parasitology Vol.24 No.12
Interactions between humoral and cellular immunologists,
linking studies in humans and experimental animals, and
strengthening the capacity to conduct detailed studies in
malaria-endemic settings will be invaluable for achieving
these goals.
Acknowledgements
The authors wish to thank Arlene Dent and Mirja Hommel for helpful
comments and suggestions on the manuscript.
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