First malaria infections in a cohort of infants in Benin: biological, environmental and genetic determinants. Description of the study site, population methods and preliminary results

Objectives: Malaria infection of the placenta during pregnancy was found to be associated with infant susceptibility to malaria. Other factors such as the intensity of malaria transmission and the nutritional status of the child might also play a role, which has not been adequately taken into account in previous studies. The aim of this study was to assess precisely the parts played by environmental, nutritional and biological determinants in first malaria infections, with a special interest in the role of placental infection. The objective of this paper is not to present final results but to outline the rationale of the study, to describe the methods used and to report baseline data. Design: A cohort of infants followed with a parasitological (symptomatic and asymptomatic parasitaemia) and nutritional follow-up from birth to 18 months. Ecological, entomological and behavioural data were collected along the duration of the study. Setting: A rural area in Benin with two seasonal peaks in malaria transmission. Participants: 656 infants of women willing to participate in the study, giving birth in one of the three maternity clinics and living in one of the nine villages of the study area. Primary Outcome Measures: The time and frequency of first malaria parasitaemias in infants, according to Plasmodium falciparum infection of the placenta. Results: 11% of mothers had a malaria-infected placenta at delivery. Mosquito catches made every 6 weeks in the area showed an average annual P falciparum entomological inoculation rate of 15.5, with important time and space variations depending on villages. Similarly, the distribution of rainfalls, maximal during the two rainy seasons, was heterogeneous over the area. Conclusions: Considering the multidisciplinary approach of all factors potentially influencing the malaria status of newborn babies, this study should bring evidence on the implication of placental malaria in the occurrence of first malaria infections in infants

Leishmaniavirus-dependent metastatic leishmaniasis is prevented by blocking IL-17A

Cutaneous leishmaniasis has various outcomes, ranging from self-healing reddened papules to extensive open ulcerations that metastasise to secondary sites and are often resistant to standard therapies. In the case of L. guyanensis (L.g), about 5-10% of all infections result in metastatic complications. We recently showed that a cytoplasmic virus within L.g parasites (LRV1) is able to act as a potent innate immunogen, worsening disease outcome in a murine model. In this study, we investigated the immunophenotype of human patients infected by L.g and found a significant association between the inflammatory cytokine IL-17A, the presence of LRV1 and disease chronicity. Further, IL-17A was inversely correlated to the protective cytokine IFN-γ. These findings were experimentally corroborated in our murine model, where IL-17A produced in LRV1+ L.g infection contributed to parasite virulence and dissemination in the absence of IFN-γ. Additionally, IL-17A inhibition in mice using digoxin or SR1001, showed therapeutic promise in limiting parasite virulence. Thus, this murine model of LRV1-dependent infectious metastasis validated markers of disease chronicity in humans and elucidated the immunologic mechanism for the dissemination of Leishmania parasites to secondary sites. Moreover, it confirms the prognostic value of LRV1 and IL-17A detection to prevent metastatic leishmaniasis in human patients

Leishmania guyanensis suppressed inducible nitric oxide synthase provoked by its viral endosymbiont

Inducible nitric oxide synthase (iNOS) is essential to the production of nitric oxide (NO), an efficient effector molecule against intracellular human pathogens such a

Infections in Infants during the First 12 Months of Life: Role of Placental Malaria and Environmental Factors

Background: The association between placental malaria (PM) and first peripheral parasitaemias in early infancy was assessed in Tori Bossito, a rural area of Benin with a careful attention on transmission factors at an individual level. Methodology: Statistical analysis was performed on 550 infants followed weekly from birth to 12 months. Malaria transmission was assessed by anopheles human landing catches every 6 weeks in 36 sampling houses and season defined by rainfall. Each child was located by GPS and assigned to the closest anopheles sampling house. Data were analysed by survival Cox models, stratified on the possession of insecticide-treated mosquito nets (ITNs) at enrolment. Principal Findings: Among infants sleeping in a house with an ITN, PM was found to be highly associated to first malaria infections, after adjusting on season, number of anopheles, antenatal care (ANC) visits and maternal severe anaemia. Infants born from a malaria infected placenta had a 2.13 fold increased risk to present a first malaria infection than those born from a non infected placenta ([1.24-3.67], p<0.01) when sleeping in a house with an ITN. The risk to present a first malaria infection was increased by 3.2 to 6.5, according to the level of anopheles exposure (moderate or high levels, compared to the absence of anopheles). Conclusions: First malaria infections in early childhood can be attributed simultaneously to both PM and high levels of exposure to infected anopheles. Protective measures as Intermittent Preventive Treatment during pregnancy (IPTp) and ITNs, targeted on both mothers and infants should be reinforced, as well as the research on new drugs and insecticides. In parallel, investigations on placental malaria have to be strengthened to better understand the mechanisms involved, and thus to protect adequately the infants high risk group

Cohort profile: effect of malaria in early pregnancy on fetal growth in Benin (RECIPAL preconceptional cohort).

PURPOSE: REtard de Croissance Intra-uterin et PALudisme (RECIPAL) is an original preconceptional cohort designed to assess the consequences of malaria during the first trimester of pregnancy, which is a poorly investigated period in Africa and during which malaria may be detrimental to the fetus. PARTICIPANTS: For this purpose, a total of 1214 women of reproductive age living in Sô-Ava and Akassato districts (south Benin) were followed up monthly from June 2014 to December 2016 until 411 of them became pregnant. A large range of health determinants was collected both before and during pregnancy from the first weeks of gestation to delivery. Five Doppler ultrasound scans were performed for early dating of the pregnancy and longitudinal fetal growth assessment. FINDINGS TO DATE: Pregnant women were identified at a mean of 6.9 weeks of gestation (wg). Preliminary results confirmed the high prevalence of malaria in the first trimester of pregnancy, with more than 25.4% of women presenting at least one microscopic malarial infection during this period. Most infections occurred before six wg. The prevalence of low birth weight, small birth weight for gestational age (according to INTERGROWTH-21st charts) and preterm birth was 9.3%, 18.3% and 12.6%, respectively. FUTURE PLANS: REtard de Croissance Intra-uterin et PALudisme (RECIPAL) represents at this time a unique resource that will provide information on multiple infectious (including malaria), biological, nutritional and environmental determinants in relation to health outcomes in women of reproductive age, pregnant women and their newborns. It will contribute to better define future recommendations for the prevention of malaria in early pregnancy and maternal malnutrition in Africa. It confirms that it is possible to constitute a preconceptional pregnancy cohort in Africa and provides valuable information for researchers starting cohorts in the future

Exacerbated leishmaniasis caused by a viral endosymbiont can be prevented by immunization with Its viral capsid

Recent studies have shown that a cytoplasmic virus called Leishmaniavirus (LRV) is present in some Leishmania species and acts as a potent innate immunogen, aggravating lesional inflammation and development in mice. In humans, the presence of LRV in Leishmania guyanensis and in L. braziliensis was significantly correlated with poor treatment response and symptomatic relapse. So far, no clinical effort has used LRV for prophylactic purposes. In this context, we designed an original vaccine strategy that targeted LRV nested in Leishmania parasites to prevent virus-related complications. To this end, C57BL/6 mice were immunized with a recombinant LRV1 Leishmania guyanensis viral capsid polypeptide formulated with a T helper 1-polarizing adjuvant. LRV1-vaccinated mice had significant reduction in lesion size and parasite load when subsequently challenged with LRV1+ Leishmania guyanensis parasites. The protection conferred by this immunization could be reproduced in naïve mice via T-cell transfer from vaccinated mice but not by serum transfer. The induction of LRV1 specific T cells secreting IFN-γ was confirmed in vaccinated mice and provided strong evidence that LRV1-specific protection arose via a cell mediated immune response against the LRV1 capsid. Our studies suggest that immunization with LRV1 capsid could be of a preventive benefit in mitigating the elevated pathology associated with LRV1 bearing Leishmania infections and possibly avoiding symptomatic relapses after an initial treatment. This novel anti-endosymbiotic vaccine strategy could be exploited to control other infectious diseases, as similar viral infections are largely prevalent across pathogenic pathogens and could consequently open new vaccine opportunities

TP-2Rho Is a Sensitive Solvatochromic Red-Shifted Probe for Monitoring the Interactions between CDK4 and Cyclin D

International audienc

Pre-conception serum ferritin concentrations are associated with metal concentrations in blood during pregnancy: A cohort study in Benin

BACKGROUND: Iron deficiency is a common nutritional deficiency that impacts maternal health and fetal development and is also associated with increased uptake of toxic metals. Women in sub-Saharan Africa are highly exposed to both iron deficiency and metals in the environment. As research on the developmental origins of health and disease increasingly shows impacts of pre-conception maternal health on pregnancy and fetal health, these environmental exposures are of concern. OBJECTIVES: This study investigated the association between iron status pre-pregnancy and blood metal concentrations in the first trimester of pregnancy with potential implications for iron supplementation. METHODS: Pre-conception and first trimester blood samples taken from 262 Beninese women were tested for serum ferritin, inflammation markers, manganese (Mn), cadmium (Cd), lead (Pb), copper, zinc, selenium, mercury and arsenic. Associations between serum ferritin adjusted for inflammation and metal concentrations were analyzed using multivariate linear regression. RESULTS: Women with iron deficiency before conception (13%) were more likely to remain iron deficient in the first trimester (4%) (adjusted OR = 41.2, 95%CI 6.2; 275.0) even within the context of routine iron supplementation during pregnancy. Lower pre-pregnancy serum ferritin concentrations were significantly related to higher concentrations of Mn, Cd and Pb in the first trimester. Every 1% increase in serum ferritin concentration was associated with a 0.13% decrease in Mn (adjusted β = -0.13, 95%CI -0.18; -0.07), a 0.22% decrease in Cd (adjusted β = -0.22, 95%CI -0.28; -0.15) and a 0.06% decrease in Pb concentration (adjusted β = -0.06, 95%CI -0.12; -0.006). DISCUSSION: These results suggest that increasing iron stores prior to pregnancy may prevent excessive uptake of toxic concentrations of the metals Mn, Cd and Pb and argue in favour of testing the effects of iron supplementation prior to pregnancy on metal concentrations.Impact du paludisme précoce au cours de la grossesse sur la croissance fœtale au Béni

IL-17A production is associated with LRV1 presence and disease chronicity in human cutaneous leishmaniasis.

<p>78 cutaneous leishmaniasis patients infected with <i>L</i>.<i>g</i> parasites were separated into two groups based on their LRV1 status (n = 30 LRV1+, n = 48 LRV1-). Two further clinical groups could be distinguished based on the duration of the patients’ symptomatic infection: 64 acute patients (lesion history of 0–5 months) and 14 chronic patients (lesion history of 5–12 months). <b>(A)</b> Distribution of symptomatic cohorts among LRV1+ and LRV1- infection. <b>(B)</b> IL-17A transcripts were measured in all biopsies by qRT-PCR. Values were calculated using the ∆∆CT method and normalized to the average of LRV1-<i>L</i>.<i>g</i> infection in the acute cohort. <b>(C)</b> IFN-γ transcripts were measured in biopsies of acute patients by qRT-PCR and normalized as before. <b>(D)</b> Previous qRT-PCR results were expressed for each individual as an IL-17A/IFN-γ ratio. <b>(E)</b> Lymphocytes were extracted from blood samples of acute patients (LRV+ n = 5, LRV- n = 4) and separated into CD4+ and CD4- groups by MACS. Cells were re-stimulated <i>ex vivo</i> with <i>L</i>.<i>g</i> parasites prior to IL-17A quantification by ELISA in supernatants. Data are mean +/- SEM using at least 2 technical replicates per condition. Significance tested by an unpaired, parametric <i>t</i>-test and indicated as *: P<0.05, **P<0.005, ***P<0.0001.</p

IL-17A mediates LRV1-dependent metastasis.

<p><b>(A-C)</b> Mice deficient in IFN-γ^-/- or IFN-γ^-/- IL-17A^-/- (DKO) were infected in footpads with either <b>(A)</b> LRV1+ or <b>(B)</b> LRV1- <i>L</i>.<i>g</i> promastigotes. Footpad swelling was measured weekly. <b>(C)</b> The number of secondary lesions was counted in all groups at 7 weeks post infection. <b>(D-H)</b> IFN-γ^-/- mice were infected in their footpads with LRV1+/- <i>L</i>.<i>g</i> parasites. At the onset of visible lesions (2.5 weeks post infection) IFN-γ^-/- mice were treated i.p with either one of the IL-17A inhibitors every 2 days, namely Digoxin (Dig) or SR1001 (SR). <b>(D)</b> The change in footpad swelling was measured weekly. <b>(E)</b> At 7 weeks post infection, the number of secondary lesions was counted in all groups of treated mice. <b>(F)</b> At week 4 post infection, popliteal lymph node cells from mice presented in <b>(D)</b>, were restimulated for 72h <i>in vitro</i> with UV inactivated <i>L</i>.<i>g</i> parasites. IL-17A production in culture supernatants was measured by ELISA. After 7 weeks, lymphocytes from <b>(G)</b> popliteal and <b>(H)</b> iliac lymph nodes were also restimulated <i>in vitro</i> in order to quantify IL-17A production by ELISA. Graphs are representative of a minimum of 2 independent experiments, using at least 5 mice per condition and represented as mean ± SEM. Significance is tested by one-way Anova (disease score) or an unpaired, parametric <i>t</i>-test (bar graphs) and indicated as *: P<0.05, **P<0.005, ***P<0.0001.</p