Chronic infection during placental malaria is associated with up-regulation of cycloxygenase-2
© Sarr et al; licensee BioMed Central Ltd. 2010
Received: 7 October 2009
Accepted: 9 February 2010
Published: 9 February 2010
Placental malaria (PM) is associated with poor foetal development, but the pathophysiological processes involved are poorly understood. Cyclooxygenase (COX) and lipoxygenase (LOX) which convert fatty acids to prostaglandins and leukotrienes, play important roles in pregnancy and foetal development. COX-2, currently targeted by specific drugs, plays a dual role as it associates with both pre-eclampsia pathology and recovery during infection. The role of COX during PM was questioned by quantifying at delivery COX-1, COX-2, 15-LOX, and IL-10 expression in two groups of malaria infected and uninfected placenta.
Placental biopsies were collected at delivery for mRNA isolation and quantification, using real time PCR.
COX-2 and IL-10 mRNAs increased mainly during chronic infections (nine- and five-times, respectively), whereas COX-1 transcripts remained constant. COX-2 over-expression was associated with a higher birth weight of the baby, but with a lower rate of haemoglobin of the mother. It was associated with a macrophage infiltration of the placenta and with a low haemozoin infiltration. In the opposite way, placental infection was associated with lower expression of 15-LOX mRNA. A high degree of haemozoin deposition correlates with low birth weight and decreased expression of COX-2.
These data provide evidence that COX-2 and IL-10 are highly induced during chronic infection of the placenta, but were not associated with preterm delivery or low birth weight. The data support the involvement of COX-2 in the recovery phase of the placental infection.
In Africa, most of the malaria mortality and morbidity is borne by children and pregnant women with an estimate 200,000 infant deaths each year as a result of malaria infection in pregnancy . During placental malaria (PM) parasites accumulate in the placenta with an increased risk of low birth weight (LBW) . This accumulation can be related to low blood flow through the placenta and to specific adhesion of infected red blood cells (IRBCs) on syncytiotrophoblast. This adhesion is mediated by chondroitin sulphate A and specific var antigens. Monocytes also accumulate in the intervillous space of the placenta  mostly attracted by release of MIF [4, 5]. Pro-inflammatory cytokine release also associates with this accumulation of parasites, pigment, and monocytes in the tissue [6, 7].
Decreased blood flow in the placenta is the major factor triggering LBW, which had previously been linked to a modulation of placental cytokine expression . In this context, prostaglandins (PGs) are important modulators of vascular perfusion and fever . Conversion of arachidonic acid to PGs is catalyzed by two isoforms of cyclooxygenase (COX-1 and COX-2) . COX-2-generated PGs are important in inflammation and host defence and is up-regulated prior to the onset of labour [10, 11]. Whereas COX-1-generated PGs is implicated in homeostasis and survival of the foetus, and mainly secreted in decidual lining of the uterus [12, 13] without modulation during gestation or labour. The role of COX-1 and -2 during placental pathology was suspected some time ago when bacterial lipopolysaccharide mediated foetal death was related to an over-production of COX-2 . In the same line COX-2 over expression was reported during pre-eclampsia , but not after this episode  and was associated with apoptosis in smooth chorion trophoblast cells of human foetal membrane tissues . This enhancement seems to be triggered by leukocyte microparticles [15, 18]. However, Khan et al published conflicting results describing a reduction of COX-2 and of the amount of NHE-1 in pre-eclamptic placentas with an unaltered level of COX-1 .
During placental malaria, modulation of these PGs pathway could play a role in preterm delivery and low birth weight as observed during pre-eclampsia. A foetal COX-2 gene polymorphism was associated with placental malperfusion during placental malaria . In the general, circulation PGE2 and blood mononuclear cell COX-2 expression were also reported to be inversely related with disease severity in children with malaria [21, 22].
Two other arachidonic acid pathways, the epoxide and the lipoxygenase (LOX) pathway , are involved in pathology during pregnancy . LOX leads to synthesis of leukotrienes and lipoxins with immune and anti-inflammatory activity. Three enzymes control this pathway: 5-LOX produced by neutrophils, 12-LOX produced by platelets, and 15-LOX located in macrophages and endothelia. 15-LOX is highly inducible and produces hydroxyeicosatetraenoic (HETE) compounds . Interestingly, 15-HETE is a powerful inhibitor of pro-inflammatory eicosanoids, whereas 5-HETE and 12-HETE are chemotactic factors for neutrophils and they also stimulate vasodilation through PG synthesis .
Eicosanoids are thus powerful regulators of placenta perfusion and overall of the pregnancy outcome. New analgesic and anti-inflammatory drugs, inhibitors of COX activity, are often used in malaria endemic areas to reduce fever, pain, and inflammation . They can interfere with PGs regulations and modulate the outcome of the pregnancy even if antenatal administration of celecoxib (a COX-2 inhibitor) seems to improve placental perfusion in the pregnant rabbit . All these data pave the way of new studies to understand the pathophysiology of placental malaria, and this study was designed to address the role of these enzymes during PM in low malaria transmission area. The purpose of this study was to evaluate the levels of COX-1, COX-2, and 15-LOX mRNA genes in human placenta infected by P. falciparum compared to uninfected placenta. Although delivery is only an instant in the whole pregnancy, it is however a good snapshot of the placenta statement. Studies conducted at delivery also give information on the late stage of the mother-baby interaction.
Collection of placentas was done at delivery, at the maternity ward the Centre de Santé Roi Baudoin, Guediawaye, Dakar Sénégal. Details regarding enrolment and standard laboratory procedures have been reported elsewhere . It involved women, more than 16 years, with an uncomplicated delivery of live newborns. For all women giving informed consent, an immuno-chromatography test (ICT, PfHRP2 MaKromed) was carried out on placental blood. A standard questionnaire was used to record information including: mother's age, gravidity, gestational age (determined by the date of the last menstrual period and morphometric measurement of the uterus during antenatal clinic visits) and history of malaria attacks. Babies and placentas were weighed immediately after birth. Gender and Apgar scores were recorded. LBW was defined as < 2,500 g, and prematurity as gestational age < 37 weeks. Women with haemoglobin (Hb) less than 11 g/dl were considered anaemic.
The HIV infection status of the participants was not established at the time of the study however, HIV sero-prevalence in Senegalese population was low (0.8% of parturients in Dakar) . All ICT-positive women received chloroquine after delivery. Anaemic women received iron and folic acid supplements.
After collection, whole placentas were refrigerated until assessment (less than two hours after delivery). For each placenta, four biopsies were sampled , rinsed in phosphate buffer saline (PBS), rapidly frozen in liquid nitrogen and stored at -80°C until RNA extraction. An additional four biopsies were sampled for histology and immunohistochemistry studies.
Histology and immunohistochemistry
Immediately after collection, samples for histology and immunohistochemistry were fixed in 4% buffered paraformaldehyde and processed as previously described . 5 μm cryosections were stained either with haematoxylin-eosin (H&E) or with May-Grünewald-Giemsa (MGG). Quantification of parasites was done in placenta for 100 fields (magnification 1000×) of MGG stained sections and in blood by examination of Giemsa-stained thick smears. Haemozoin (HZ) was identified on sections as brown granular material with high refringence on polarization microscope, which differentiates then from formalin crystals. Contain in HZ was qualitatively assessed on sections as: no HZ, low HZ (1-2 crystals/field at ×1000) or high HZ (> 2/field).
Acute infections (AI) were defined by the presence of parasites on sections without malaria pigment, chronic infections (CI) by presence of parasites and pigment, and past infections (PI) by the presence of pigment alone. PfHRP2+ placentas with no evidence of parasites or pigment were classified as "no-parasite" (NP). For the control group all PfHRP2 rapid diagnosis test, parasites and pigment detection were negative in placenta and in the venous blood.
For immunochemistry, after blocking endogenous peroxidases and non-specific binding, tissue sections were incubated for 1 h at room temperature with primary antibodies or control isotypes and revealed using LSAB detection kit (DakoCytomation). Antibodies used were CD68 (PG-M1), and HLA-DR (TAL.1B5) from DakoCytomation mouse antibodies against. The number of cells in the intervillous space was counted over 100 fields (magnitude ×400).
Nucleotides sequences of the primers and probes used for real time PCR. PPIA: Peptidyl Propyl Isomerase A.
(a: Probe, b: Primer F, c: primer R)
Amplicon size (bp)
a) Fam-CTG GCC TCA GCA CTC TGG AAT GAC AA-Tamra
b) ATG ATG GGC CTG CTG TGG A
c) CCA ACA CTC ACC ATG CCA AAC
a) Fam-TGC CCA GCA CTT CAC GCA TCA GTT-Tamra
b) GCT CAA ACA TGA TGT TTG CAT TC
c) GCT GGC CCT CGC TTA TGA
a) Fam-TCC ACC AGG CTT CTC TCC AGA TGT CC-Tamra
b) GGA GAC AGT GAT GGC GAC ACT
c) TCT GCC CAG CTG CCA AGT
a)Fam-AGC TCA AAG GAG ACG CGG CCC A-Tamra
b) GTC AAC CCC ACC GTG TTC TT
c) CTG CTG TCT TTG GGA CCT TGT
a)Fam-CAG GCA ACC TGC CTA ACA TGC TTC-Tamra
b) TGA GAA CAG CTG CAC CCA CTT
c) ATC TCC GAG ATG CCT TCA GC
Differences between groups were compared using Mann-Whitney U test (MW) for two groups or with Kruskal-Wallis test (KW) and Median test for more than two. Correlations were calculated using a Spearman R test (SP). Alpha risk was set at 0.05.
Chronic infection is associated with lower birth weight
Clinical and laboratory data of enrolled women according to the class of infection.
No. of women
Primigravidae n (%)
Secundigravidae n (%)
Multigravidae n (%)
24.6 ± 1.6
25.6 ± 1.13
25.2 ± 2.3
26.6 ± 0.6
26.0 ± 1.96
24.8 ± 2.3
Pregnancy duration, weeks
40.8 ± 1.2
40.5 ± 2.6
41.1 ± 1.1
40.9 ± 0.9
41.1 ± 1.1
41.3 ± 1.3
Birth weight (g)
3,153 ± 93
2,723 ± 93*
2,995 ± 137
2,623 ± 131*
2,862 ± 167
2,411 ± 251*
11.9 ± 0.3
9.4 ± 2.5*
10.2 ± 1.2
8.5 ± 0.4*
8.4 ± 1.1*
10.2 ± 0.9
Past and chronic infections are associated with a higher level of COX-2 and IL-10 mRNA
Because IL-10 has been shown to exert direct regulatory effects on prostaglandin production, we also measured IL-10 mRNA in our placental samples. The levels of IL-10 transcripts were higher in PfHRP2+-placentas than in controls (MW p = 0.004, Figure 1A) and correlated with COX-2 expression (n = 54, SP p = 0.006 R = 0.36; and p = 0.008 R = 0.36). However none of these markers correlated with the parasitaemia. In the opposite way 15-LOX was lower in PfHRP2+-placentas than in controls (MW p = 0.0002) (Figure 1A), but correlates with parasitaemia in the placenta (SP R = 0.416, p = 0.0076) and with COX-2 mRNA expression (SP p = 0.018, R = 0.37).
The levels of COX-2 mRNA but not of COX-1, 15-LOX, and IL-10, trend to decrease when parity increased (Figure 1B), but there was no significant difference for any of these genes according to duration of the pregnancy or with the presence of fever at delivery.
Elevated level of COX-2 is associated with anaemia in the mother but not with low birth weight
COX-2 expression increase with macrophage recruitment and with decrease of pigment deposit
High level of pigment in the placenta was associated with significantly lower birth weight (KW p = 0.013, n = 44, Figure 3A, left panel), and with lower haemoglobin level in the mother (KW p = 0.018, Figure 3A, middle panel). However lower pigment density associated with a higher level of COX-2 and IL-10 transcripts (Figure 3d), without significant change for COX-1 (MW, p < 0.001 for both).
As detected by immunohistochemistry (Figure 3c), macrophages (CD68+) and activated HLADR+ presenting cells increased in PfHRP2+-placenta (p < 0.001 for both, DNS), mainly during late infection (CI or PI versus Ctrl: MW p < 0.001). Primiparous and secondiparous women exhibited higher levels of CD68+ cells when compared to multiparous (p < 0.05) while CI had significantly higher levels of CD68+ cells compared to PfHRP2- or control (p = 0.002). The density of macrophages (CD68) increased in the placenta when the amount of pigment was low (median test p < 0.0001). The count of macrophage was significantly correlated with COX-2 (SP p = 0.014, R = 0.331), IL-10 (SP p = 0.014, R = 0.332) and 15-LOX mRNA (SP p = 0.0003, R = 0.539). In the placental tissue sections COX-1 protein was detected by immunolabelling in trophoblasts, mononuclear interstitial cells and, most often, in foetal endothelial cells. COX-2 and 15-LOX were mainly detected in macrophages, endothelial cells and trophoblasts. During past and chronic infection, COX-2 was highly expressed in trophoblasts (Sarr, personal communication).
This study is part of a project conducted on the pathophysiology of PM in West African urban areas. Despite the low transmission rate of malaria, a high prevalence of PM was observed in this area , but its pathogenesis is still poorly understood.
As previously described  COX-1 expression remained low in all the samples of our study, in comparison with COX-2. COX-2 expression clearly increased after long-term malaria active infection (CI) of the placenta. Consistent with previous reports , chronic infection was associated with a macrophage infiltration of the placenta, which correlated with COX-2 over-expression. In placenta COX-2 was mainly detected in macrophages, vascular lymphocytes and fibroblasts , which can explain this correlation. These data indicate that low amount of pigment was associated with the highest levels of COX-2 and IL-10 transcripts, whereas, high amount of HZ was associated with a lower COX-2 expression. In the same line, women with high amount of HZ had babies with lower birth weights and lower level of haemoglobin. This is in line with data showing inhibition of intervillous blood mononuclear cells (IVBMCs) charged in HZ and in particular suppression of PGE2, TNF, and IL-10 secretion [33, 34]. This phagocytosis of haemozoin was reported i) to enhance matrix metalloproteinase-9 activity and TNF production in human monocytes [35, 36], and ii) to reduce immune response by an activation of a Toll-like receptor 9 mediates mechanism . Overall a low charge in HZ could be a signal to attract macrophages and stimulates cells whereas a high charge could inhibit them.
All these data are consistent with an inflammatory process [3, 38]. However, COX-2 (unrelated to the term of the pregnancy) was positively correlated with the birth weight, which supports a protective role of this process for the foetus development. Macrophages can also participate in this protective role, as well as prostacyclins secreted by chorion endothelium, which are known to induce relaxing of foetal vasculature . High level of COX-2 was also previously associated with recovery from anaemia . Along the same lines, IL-10 mRNA was significantly higher in infected placentas compared to uninfected ones, as previously described [40, 41]. High level of IL-10 could be deleterious, as IL-10 is known to inhibit COX-2 expression in preterm human placenta  and secretion of inflammatory cytokines by monocytes . It was also associated with high parasitaemia, severe anaemia and a low level of COX-2 in PBMC [8, 22].
However this could not be relevant during PM as i) COX-2 seems mainly expressed by placenta and not by PBMC and as ii) the effect of IL10 on COX-2 and PGE2 seems to be different in preterm and in term placentas . In the same line, IFN-gamma and oestrogen receptor-beta modulates COX-2 expression in human placental villous endothelial cells [44, 45] and need to be measured.
Interestingly, 15-LOX expression correlated with the presence of parasites in the intervillous space, which is consistent with study stating that 15-HETE and 15-HPETE stimulated red blood cell adhesion to endothelium . However 15-LOX mRNA expression remained lower in infected samples compared to uninfected or control samples, which can exclude its role in the sequestration of parasites in the placenta.
In summary, this study showed that COX-2 and IL-10 are highly expressed in active PM. COX-2 correlates with macrophage infiltration and is related to a better outcome of the pregnancy with higher birth weight. All these data support the increase of COX-2 as a witness of placental defence against infection and draw attention on uncontrolled use of anti-COX2 during placental malaria.
low birth weight
rapid diagnosis test
peripheral blood mononuclear cell
No parasite and pigment (PfHRP2+)
Plasmodium falciparum histidine rich protein.
We thank the medical staff of Centre de Sante Roi Baudoin, Guediawaye, for their help during this study, and the women who agreed to participate. This study was supported by the Louis D. Foundation (Académie des Sciences, Paris, France), the RESMAL-chip programme (UE) and FSP-RAI programme (Ministère français des Affaires étrangères). D Sarr was supported by a grant from FSP-RAI and E Frealle by a grant from the "Fondation de la Jeunesse Internationale"
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