malaria , caused by protozoan parasites of the genus plasmodium , is one of the leading causes of illness and death worldwide .
its effects are exacerbated by its ability to modulate immune responses , which not only impairs the patient 's ability to fight the malarial infection , but can leave them vulnerable to some secondary infections and reduce the immune response to certain vaccines .
although this partial immunosuppression has been recognized for many years , the underlying mechanisms are not well understood , and the results of studies in both humans and animals have sometimes been contradictory . in recent years , attention has focused on interference of parasites with the myeloid cells of the immune system , in particular the antigen - presenting dendritic cells that are essential for the initiation of almost all adaptive immune responses .
one consequence of malarial infection is the production of the so - called ' malaria pigment ' from the breakdown of hemoglobin by the parasite in infected red blood cells .
malaria pigment is a polymerized form of heme also known as hemozoin and has long been suspected to affect the function of myeloid cells . in this issue of journal of biology , millington and colleagues  
show how ingestion of malaria pigment by dendritic cells alters their function over the course of the infection , with consequences for the adaptive immune response to different asexual blood stages of the parasite .
immature phagocytic dendritic cells reside in most tissues and constantly sample their environment by phagocytosis and pinocytosis , surveying for invading pathogens . when pathogens enter a tissue or the blood stream , they are usually first recognized by pattern recognition receptors ( prrs ) on the surface of dendritic cells , which recognize molecules common to different classes of pathogen .
binding of pathogens or their products to the prrs triggers the migration of the dendritic cell into lymphoid tissues and its maturation into a powerful antigen - presenting cell .
activated dendritic cells migrate to a draining lymph node or to the spleen , where they initiate an adaptive immune response by presenting pathogen antigens to t lymphocytes ( t cells ) .
as they mature , their phagocytic activity decreases , but they increase expression of the cell - surface major histocompatibility complex ( mhc ) molecules that bind processed pathogen - derived peptides and display them on the dendritic - cell surface . at the same time the maturing dendritic cell starts to increase the expression of cell - surface proteins known as co - stimulatory molecules , which together with mhc - peptide complexes enable dendritic cells to activate any t cells that bind to the antigens displayed on its surface .
as in many other infectious diseases , dendritic - cell function in plasmodium infections has been studied extensively in vivo and in vitro , but results have been contradictory , depending on the plasmodium species , the inoculation dose and the type of dendritic cells   under investigation .
mice , in which most work has been done , are susceptible to infection with the species plasmodium chabaudi chabaudi , p. yoeli , and p. berghei .
a number of studies have shown that dendritic cells can mature in response to plasmodium infection and induce a powerful t - cell response . in one example , the culture of immature bone - marrow - derived dendritic cells with mouse red blood cells infected with p. chabaudi chabaudi resulted in limited maturation of the dendritic cells , which could be enhanced by external maturational stimuli such as bacterial lipopolysaccharide ( lps ) , tumor necrosis factor- ( tnf- ) or cd40 ligand .
in a different study covering the first four days of a p. chabaudi chabaudi infection , a subset of splenic dendritic cells found in the marginal zone of the spleen and characterized by the cell - surface marker protein cd11c were observed to migrate from the marginal zone into the t - cell rich periarteriolar sheath , the area in which immune t - cell responses are initiated .
these dendritic cells showed enhanced expression of mhc class ii molecules and co - stimulatory molecules typical of mature dendritic cells . in yet another study , splenic cd11cdendritic cells isolated at the peak of a p. yoeli infection were able to activate antigen - specific t cells and induce secretion by the t cells of the cytokines interleukin 2 ( il-2 ) , interferon- ( ifn- ) and tnf- , a cytokine profile characteristic of the th1 class of differentiated effector t cells .
in contrast , other studies have reported that dendritic cells failed to mature when co - cultured with red blood cells infected with p.
chabaudi chabaudi or p. yoeli , even though the dendritic cells were subsequently capable of inducing t - cell responses in vivo when transferred into uninfected mice .
in one study , at the peak of blood - stage infection ( the stage at which the parasite infects red blood cells ) the response of cd8 cytotoxic t cells ( the killer subset of t lymphocytes ) to liver - stage parasites was inhibited in vivo , most probably as a result of cytokines secreted by dendritic cells .
more recently , wilson and colleagues   showed that inoculation of mice with p. berghei induced a systemic activation of splenic dendritic cells similar to that observed after administration of dna containing unmethylated cpg , which is a ligand for a type of prr known as toll - like receptor 9 ( tlr-9 ) .
as with activation by cpg , however , if another antigen was administered on day 3 or 4 of a p. berghei infection , the dendritic cells proved unable to cross - present this exogenous anitgen and activate cd8 t cells . at this stage of infection ,
the defect in antigen presentation appeared to be due to reduced dendritic - cell phagocytic activity .
these studies used a wide variety of in vitro cell culture systems , functional read outs , plasmodium species and mouse strains .
a general trend emerges , however , suggesting that there is a dual response of dendritic cells to plasmodium blood - stage infection , with an early phase of activation , in conditions of low parasitemia , and a late phase of functional inhibition , in conditions of high parasitemia .
the study by millington and colleagues   now not only reconciles the disparate results on dendritic - cell function in rodent malaria , but also provides novel insights into the consequences of dendritic - cell modulation in vivo .
their careful studies demonstrated an unambiguous biphasic response of dendritic cells to p. chabaudi chabaudi blood - stage infection in mice in vivo .
they began their investigations with a simple question : at which stage during the course of a blood - stage infection does suppression of immune responses occur ? to answer this question they immunized mice with the protein antigen ovalbumin ( ova ) and bacterial lps ( which provides a nonspecific stimulus for an immune response ) at different time points during a p. chabaudi chabaudi infection and monitored the antibody response to ova . only during the late stages of the infection ,
when most parasites had been cleared , did the mice show greatly reduced ova - specific igg responses .
.   then demonstrated , through a series of carefully controlled experiments , that hemozoin acts directly on the dendritic cells and inhibits their maturation in response to maturational stimuli such as lps or the cell - surface protein cd40 ligand ( cd40l ) .
likewise , cd11c dendritic cells isolated from the spleens of infected mice were activated early but not late during infection , and at the later stage were refractory to subsequent stimulation with lps .
inhibition of dendritic - cell maturation during the late stages of infection had consequences for the initiation of adaptive immune responses : antigen - specific t cells were activated by dendritic cells but failed to proliferate and secrete cytokines . of particular importance , these t cells did not migrate into b - cell follicles in the spleen to provide the required help to b cells , and so there was also a failure to mount a specific antibody response ( figure 1 ) .
hemozoin is released together with other cell debris when the mature blood - stage forms of the parasite cause red blood cells to rupture , and it is rapidly taken up by monocytes ( immature precursors of macrophages and dendritic cells ) and dendritic cells .
hemozoin reacts with membrane phospholipids , generating hydroxy - polyunsaturated fatty acids that cause membrane peroxidation .
hydroxy - polyunsaturated fatty acids inhibit monocyte functions such as phagocytosis , activation by inflammatory cytokines , and generation of the oxidative burst .
it has been shown to bind to tlr-9 on the myeloid and plasmacytoid subsets of dendritic cells in rodents , although this observation was not confirmed in another study . however , activation of dendritic cells via tlr-9 early during infection , but paralysis of dendritic cells via ingested hemozoin during the late stage of infection would agree with the results of millington et al . .
thus , hemozoin is directly associated with the alteration of cellular responses observed during acute malaria in mice and humans . in humans ,
modulation of dendritic - cell function might be caused by adhesion of infected erythrocytes to the adhesive cell - surface protein cd36 expressed on dendritic cells .
adhesion of p. falciparum - infected erythrocytes to cd36 is mediated by the p. falciparum erythrocyte membrane protein 1 ( pfemp-1 ) .
does the work of millington et al .   rule out a role for cd36 in the modulation of dendritic - cell function ?
pfemp-1 is not produced by the plasmodium species that infect mice , and although rodent plasmodium species can adhere to cd36 to a certain extent , the ligand ( or ligands ) mediating cd36 adhesion in rodents are not known , and expression of adhesion ligand occurs much later , during the asexual blood - stage phase . in addition , the expression pattern of cd36 on human and mouse dendritic cells is fundamentally different : only cd8 dendritic cells in the periarteriolar lymphatic sheath express cd36 .
nevertheless , work by arese and colleagues   has shown that monocyte function , differentiation to dendritic cells , and dendritic - cell maturation were impaired in vitro after ingestion of hemozoin by human monocytes . unlike pfemp-1 , hemozoin is present in both human and rodent plasmodium species , yet both mechanisms can contribute to the modulation of dendritic - cell function in humans .
the seminal in vivo studies presented here in journal of biology by millington et al .  
convincingly show that hemozoin impairs dendritic - cell function in vivo in a rodent model of malaria , and that it significantly contributes to immune suppression during acute blood - stage malaria .
the deleterious effects of dendritic - cell paralysis on humans infected with p. falciparum in endemic malaria areas is easy to envisage .
if immune suppression is induced , adaptive immune responses to variant antigens expressed during later stages of an infection or to super - infecting parasites may not be induced efficiently .
( a ) early on during infection , engagement of tlr-9 by hemozoin and interaction with infected red blood cells may result in dendritic - cell maturation .
activated t cells proliferate and migrate into primary b - cell follicles where they provide help for antibody production by b cells .
( b ) with increasing parasitemia , more and more myeloid dendritic cells in the spleen are paralyzed through ingestion of increasing amounts of hemozoin , with negative effects on downstream t - cell and b - cell responses .
 the capacity of malarial infection to suppress the patient 's immune responses both to the parasite and to other antigens has long puzzled researchers . a prime suspect , the parasite - produced pigment hemozoin , has now been clearly shown to mediate immunosuppression by inhibiting dendritic cell activity . 
None
To activate or not to activate?
Nailing the suspect
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