An engineered PET depolymerase to break down and recycle plastic bottles.

Present estimates suggest that of the 359 million tons of plastics produced annually worldwide1, 150-200 million tons accumulate in landfill or in the natural environment2. Poly(ethylene terephthalate) (PET) is the most abundant polyester plastic, with almost 70 million tons manufactured annually worldwide for use in textiles and packaging3. The main recycling process for PET, via thermomechanical means, results in a loss of mechanical properties4. Consequently, de novo synthesis is preferred and PET waste continues to accumulate. With a high ratio of aromatic terephthalate units-which reduce chain mobility-PET is a polyester that is extremely difficult to hydrolyse5. Several PET hydrolase enzymes have been reported, but show limited productivity6,7. Here we describe an improved PET hydrolase that ultimately achieves, over 10 hours, a minimum of 90 per cent PET depolymerization into monomers, with a productivity of 16.7 grams of terephthalate per litre per hour (200 grams per kilogram of PET suspension, with an enzyme concentration of 3 milligrams per gram of PET). This highly efficient, optimized enzyme outperforms all PET hydrolases reported so far, including an enzyme8,9 from the bacterium Ideonella sakaiensis strain 201-F6 (even assisted by a secondary enzyme10) and related improved variants11-14 that have attracted recent interest. We also show that biologically recycled PET exhibiting the same properties as petrochemical PET can be produced from enzymatically depolymerized PET waste, before being processed into bottles, thereby contributing towards the concept of a circular PET economy.

Transcriptome Analysis of Plasmodium falciparum Isolates From Benin Reveals Specific Gene Expression Associated With Cerebral Malaria.

Cerebral malaria (CM) is the severest form of Plasmodium falciparum infection. Children under 5 years old are those most vulnerable to CM, and they consequently have the highest risk of malaria-related death. Parasite-associated factors leading to CM are not yet fully elucidated. We therefore sought to characterize the gene expression profile associated with CM, using RNA sequencing data from 15 CM and 15 uncomplicated malaria isolates from Benin. Cerebral malaria parasites displayed reduced circulation times, possibly related to higher cytoadherence capacity. Consistent with the latter, we detected increased var genes abundance in CM isolates. Differential expression analyses showed that distinct transcriptome profiles are signatures of malaria severity. Genes involved in adhesion, excluding variant surface antigens, were dysregulated, supporting the idea of increased cytoadhesion capacity of CM parasites. Finally, we found dysregulated expression of genes in the entry into host pathway that may reflect greater erythrocyte invasion capacity of CM parasites.

[Determination of prevalence and etiology of anemia during pregnancy in southern Benin, in conjunction with revision of national management policy]. / Prévalence et etiologies de l'anémie chez la femme enceinte au sud Bénin au moment du changement de politique nationale de prise en charge.

BACKGROUND: Anemia during pregnancy is a serious public health problem. Control requires identification of the underlying etiology. The objective of this study carried out in conjunction with revision of the national policy for the protection of pregnant women in Benin was to determine the prevalence and etiology of anemia. METHODS: From October 2006 to April 2007, 300 pregnant women were examined at two maternities in Ouidah, Benin. Sociodemographic and environmental characteristics, dietary data, behavioral practices, and history of malaria infection during pregnancy were collected. Blood and stool samples were tested for the presence of malaria parasites and intestinal worms respectively. Hemoglobin and ferritinemia levels were also determined. RESULTS: The prevalence of anemia (Hb < 11 g/dL) was 65.7% while that of malaria and intestinal worms was 4.3% and 8% respectively. Iron deficiency was not found. A borderline significant correlation was found between helminthiasis and anemia. No correlation was found between anemia and malaria. These findings indicate that kits progressively introduced by the health system during the study period provided relatively effective care. CONCLUSION: This study demonstrates a high prevalence of moderate anemia during pregnancy and suggests that it is mainly due to intestinal helminthiasis. These findings underline the importance of preventive antihelminthic treatment during pregnancy.

Changes in malaria epidemiology in France and worldwide, 2000-2015.

In 2015, 212 million new cases of malaria were reported, causing 429,000 deaths. The World Health Organization (WHO) estimated a 41% decrease in the number of new cases worldwide between 2000 and 2015. The number of deaths from malaria fell by 62% worldwide and by 71% in Africa. In mainland France, malaria is mainly imported by travelers or migrants from endemic areas, in particular sub-Saharan Africa (95%). In France, the number of imported malaria cases, mainly due to Plasmodium falciparum (85%), was estimated at about 82,000 for the period 2000-2015. Over the same period, 6,468 cases of malaria were reported in the French armed forces, of which 2,430 cases (37.6%) were considered as imported because occurring outside of endemic areas. The number of malaria cases also fell between 2000 and 2015 in Mayotte and French Guiana, a malaria transmission zone. Mayotte has entered the elimination of malaria with less than 15 cases per year. In French Guiana, between 300 and 500 cases have been reported annually in recent years. The decline in morbidity and mortality is usually attributed to vector control measures and improved access to effective treatments. However, the Anopheles mosquitoes that transmit the disease have developed resistance against most insecticides. Similarly, malaria parasites have developed resistance against most of the antimalarial drugs used as prevention or treatment, even the latest marketed combinations such as artemisinin-based combination therapies.

PfEMP1 A-Type ICAM-1-Binding Domains Are Not Associated with Cerebral Malaria in Beninese Children.

PfEMP1 is the major antigen involved in Plasmodium falciparum-infected erythrocyte sequestration in cerebrovascular endothelium. While some PfEMP1 domains have been associated with clinical phenotypes of malaria, formal associations between the expression of a specific domain and the adhesion properties of clinical isolates are limited. In this context, 73 cerebral malaria (CM) and 98 uncomplicated malaria (UM) Beninese children were recruited. We attempted to correlate the cytoadherence phenotype of Plasmodium falciparum isolates with the clinical presentation and the expression of specific PfEMP1 domains. Cytoadherence level on Hbec-5i and CHO-ICAM-1 cell lines and var genes expression were measured. We also investigated the prevalence of the ICAM-1-binding amino acid motif and dual receptor-binding domains, described as a potential determinant of cerebral malaria pathophysiology. We finally evaluated IgG levels against PfEMP1 recombinant domains (CIDRα1.4, DBLß3, and CIDRα1.4-DBLß3). CM isolates displayed higher cytoadherence levels on both cell lines, and we found a correlation between CIDRα1.4-DBLß1/3 domain expression and CHO-ICAM-1 cytoadherence level. Endothelial protein C receptor (EPCR)-binding domains were overexpressed in CM isolates compared to UM whereas no difference was found in ICAM-1-binding DBLß1/3 domain expression. Surprisingly, both CM and UM isolates expressed ICAM-1-binding motif and dual receptor-binding domains. There was no difference in IgG response against DBLß3 between CM and UM isolates expressing ICAM-1-binding DBLß1/3 domain. It raises questions about the role of this motif in CM pathophysiology, and further studies are needed, especially on the role of DBLß1/3 without the ICAM-1-binding motif.IMPORTANCE Cerebral malaria pathophysiology remains unknown despite extensive research. PfEMP1 proteins have been identified as the main Plasmodium antigen involved in cerebrovascular endothelium sequestration, but it is unclear which var gene domain is involved in Plasmodium cytoadhesion. EPCR binding is a major determinant of cerebral malaria whereas the ICAM-1-binding role is still questioned. Our study confirmed the EPCR-binding role in CM pathophysiology with a major overexpression of EPCR-binding domains in CM isolates. In contrast, ICAM-1-binding involvement appears less obvious with A-type ICAM-1-binding and dual receptor-binding domain expression in both CM and UM isolates. We did not find any variations in ICAM-1-binding motif sequences in CM compared to UM isolates. UM and CM patients infected with isolates expressing the ICAM-1-binding motif displayed similar IgG levels against DBLß3 recombinant protein. Our study raises interrogations about the role of these domains in CM physiopathology and questions their use in vaccine strategies against cerebral malaria.

Placental malaria, maternal HIV infection and infant morbidity.

Co-infection with malaria and HIV in pregnant women is particularly common in sub-Saharan Africa and has serious consequences for both mother and newborn child. Numerous studies have been published on the effects in pregnancy of HIV on malaria infection and on the effects of malaria on HIV infection. The increased prevalence and intensity of parasitaemia (placental and peripheral infection and parasite density) in HIV-infected women is well established. Similarly, malaria infection seems to be associated with higher viral loads. However, there is still uncertainty as to the influence of malaria on the clinical course of HIV infection, mother-to-child transmission of HIV, and the consequences of co-infection on post-neonatal infant morbidity and mortality. These questions require further investigation. In terms of prevention, intermittent preventive treatment with two doses of sulfadoxine-pyrimethamine (SP) has been found less effective in preventing malaria in HIV-infected than uninfected women, and a higher dosage (such as monthly SP) has been recommended. Regarding malaria, there is also a lack of clear recommendations for women taking daily cotrimoxazole prophylaxis, and anti-malarial-anti-retroviral interactions are not well understood. Multi-centre clinical trials should be undertaken to investigate effective, coherent and well-tolerated strategies to prevent malaria in HIV-infected women. Safe alternatives to SP should be identified and evaluated rapidly. Finally, a central pharmaco-vigilance network should be instituted to report adverse effects.

[Multiple imputation of missing at random data: General points and presentation of a Monte-Carlo method]. / L'imputation multiple des données manquantes aléatoirement : concepts généraux et présentation d'une méthode Monte-Carlo.

BACKGROUND: Statistical analysis of a data set with missing data is a frequent problem to deal with in epidemiology. Methods are available to manage incomplete observations, avoiding biased estimates and improving their precision, compared to more traditional methods, such as the analysis of the sub-sample of complete observations. METHODS: One of these approaches is multiple imputation, which consists in imputing successively several values for each missing data item. Several completed data sets having the same distribution characteristics as the observed data (variability and correlations) are thus generated. Standard analyses are done separately on each completed dataset then combined to obtain a global result. In this paper, we discuss the various assumptions made on the origin of missing data (at random or not), and we present in a pragmatic way the process of multiple imputation. A recent method, Multiple Imputation by Chained Equations (MICE), based on a Monte-Carlo Markov Chain algorithm under missing at random data (MAR) hypothesis, is described. An illustrative example of the MICE method is detailed for the analysis of the relation between a dichotomous variable and two covariates presenting MAR data with no particular structure, through multivariate logistic regression. RESULTS: Compared with the original dataset without missing data, the results show a substantial improvement of the regression coefficient estimates with the MICE method, relatively to those obtained on the dataset with complete observations. CONCLUSION: This method does not require any direct assumption on joint distribution of the variables and it is presently implemented in standard statistical software (Splus, Stata). It can be used for multiple imputation of missing data of several variables with no particular structure.

Risk factors and consequences of congenital Chagas disease in Yacuiba, south Bolivia.

OBJECTIVE: To determine the risk factors of congenital Chagas disease and the consequences of the disease in newborns. METHODS: Study of 2712 pregnant women and 2742 newborns in Yacuiba, south Bolivia. Chagas infection was determined serologically in mothers and parasitologically in newborns. Consequences of congenital Chagas disease were assessed clinically. RESULTS: The prevalence of Chagas disease in pregnant women was 42.2%. Congenital transmission was estimated at 6% of infected mothers leading to an incidence rate of 2.6% among newborns. Main risk factors of congenital transmission were mothers' seropositivity and maternal Trypanosoma cruzi parasitaemia. Parity was higher in infected than in non-infected mothers, but it was not associated with the risk of congenital transmission. The rate of congenital infection was significantly higher in newborns from multiple pregnancies than in singletons. However, we did not observe statistically significant consequences of Chagas disease in newborns from single pregnancies or among twins. CONCLUSIONS: The main risk factors for congenital transmission were infection and parasitaemia of mothers. Consequences of the disease seemed mild in newborns from single pregnancies and perhaps more important in multiple births.

[Clinical research on malaria: what for the future?]. / Quel avenir pour la recherche clinique sur le paludisme?

Malaria still remains one of the main public health problems in the world. In spite of early and numerous clinical trials, the situation seems to have been worsening in the last ten years. Malaria clinical research involves several levels: Several meta-analyses have been performed on this topic (in particular, the Cochrane Database Library has published studies on malaria prevention during pregnancy, management of clinical malaria attacks, vaccine trials or impregnated bed net trials). All these studies show the uneven quality of trials (only 10% to 50% can be kept in the analysis for methodological reasons), which seldom lead to similar conclusions. Besides, as resistances of both parasites and vectors to drugs or insecticides are regularly increasing, trials have to be repeated and new molecules have to be found and evaluated. Finally, practical application of such interventions may be difficult, due to the heterogeneity of epidemiological situations and the poverty of target populations. Various initiatives aiming to develop malaria clinical research have recently been launched. Donators are public or international (Global Fund, Roll Back Malaria Initiative, NIH, EDCTP programme), as well as private (Bill & Melinda Gates Foundation). These substantial funds should enhance the research of new antimalarial drugs and large-scale, adequately designed trials. However, to make sure these trials really benefit to populations exposed to the disease, ethical principles should be co-elaborated with developing countries, within collaborative networks between laboratories from industrialized and developing countries.

Compared prevalence of infections by HIV-1 and HIV-2 during a 2-year period in suburban and rural areas of Ivory Coast.

The testing for human immune deficiency virus type 2 (HIV-2) antibodies of 794 sera collected in July-August 1985 in the four regions of Korhogo, Bondoukou, Man, and Bouaké in Ivory Coast and the collection and testing for HIV-1 and HIV-2 antibodies of 1,126 sera collected in July-August 1987 in the same regions and age groups showed a remarkable stability in the prevalence of infection by these two retroviruses (0.7 and 0.4% in 1985 vs. 0.9 and 0.2% in 1987, respectively, for HIV-1 and HIV-2) in rural areas. In contrast, the increase in prevalence of both HIV-1 (from 1 to 1.9%) and HIV-2 (from 0.8 to 1.3%) from 1985 to 1987 in the urban population was accompanied by a sharp increase during these 2 years of the number of acquired immune deficiency syndromes in regional hospitals.

PIP: The testing for human immune deficiency virus type 2 (HIV-2) antibodies of 794 sera collected in July-August 1985 in the 4 regions of Korhogo, Bondoukou, Man, and Bouake in Ivory Coast and the collection and testing for HIV-1 and HIV-2 antibodies of 1126 sera collected in July-August 1987 in the same regions and age groups showed a remarkable stability in the prevalence of infection by these 2 retroviruses (0.7 and 0.4% in 1985 vs 0.9 and 0.2% in 1987, respectively for HIV-1 and HIV-2) in rural areas. In contrast, the increase in prevalence of both HIV-1 (from 1-1.9%) and HIV-2 (from 0.8-1.3%) from 1985-87 in the urban population was accompanied by a sharp increase during these 2 years in the number of AIDS cases in regional hospitals. (author's modified).

Mother-to-child transmission of human immunodeficiency virus type 1 and type 2 and dual infection: a cohort study in Banfora, Burkina Faso.

A prospective cohort study on the mother-to-child transmission of human immunodeficiency virus type 1 (HIV1), type 2 (HIV2) and dual positivity (HIV1 + HIV2) was carried out in Banfora, West Burkina Faso. The study samples consist of 117 newborns of HIV-seropositive women matched to 234 newborns of HIV-seronegative women. Among cases, 91 were born of HIV1-seropositive mothers, 15 were born of HIV2-seropositive mothers and 11 were born of HIV1 and HIV2 dual-seropositive mothers and were included in an 18-month follow-up. Calculation of the mother-to-child transmission rate was according to the recommendations of the European Economic Community working group. The HIV1 mother-to-child transmission rate was estimated to be 27.8% (95% confidence interval (CI) 24.5 to 32.4) with one method and 25.5% (95% CI 13.5 to 37.5) with a second method. For HIV2, this rate was estimated to be 29.5% (95% CI 26.0 to 39.8) and was not statistically different from the HIV1 mother-to-child transmission rate. No case of transmission was observed in children born of dual seropositive mothers. Survival rate at month 18 was significantly lower for children born of HIV1 mothers: 83.7% (95% CI 78.2 to 92.2). Survival rates were similar between children born of HIV2-seropositive (86.7), dual HIV1 + 2-positive (100) and seronegative mothers (92.0%). Findings suggest a higher mother-to-child transmission rate of HIV2 in children born in Burkina Faso than in Europe and a low clinical expression of HIV2 in children.

Risk factors for preterm delivery in Burkina Faso (west Africa).

The environmental and socioeconomic risk factors for preterm delivery were assessed in a West African urban population (Bobo-Dioulasso, Burkina Faso). The study population were 102 cases of preterm delivery matched with 102 controls obtained from 4124 sequential deliveries which occurred between May and October 1989 in the three maternity centres in the city. The univariate analysis identified the risk factors as age (< 20 years), primiparity, marital status (single), low frequency of antenatal visits, death of a previous child and level of education of the mother. The following risk factors identified by multivariate analysis (logistic regression) are consistent with those identified in previous studies: youth of the mother, primiparity (P = 0.01) and death of a previous child (P < 0.05). On the other hand, in this study, the level of education of the parent was identified as an independent risk factor (P < 0.001). This finding could be used to determine a target population for prevention programmes.

PIP: Between May and October 1989 in Burkina Faso, a pediatrician daily visited the clinic at the maternity hospital, the Farakan maternity clinic, and the Guimbi maternity clinic (the only 3 maternity clinics) in Bobo-Dioulasso to confirm the diagnosis of preterm delivery (gestational age 28-37 weeks) and to collect data on 102 deliveries and on 102 full-term deliveries occurring at the same time. The physician and epidemiologists conducted perhaps the first case control study of preterm delivery risk factors in West Africa. The incidence of preterm deliveries was 2.6%. The univariate analysis identified the following to be risk factors of prematurity: being 20 years old (odds ratio [OR] = 6.9 for 15-19 year olds vs. older women; p .01), primiparity (OR = 2.88; p = .03), being single (OR = 3.44; p .01), having less than 3 prenatal care visits (OR = 7.9; p .001), death of a previous child (OR = 3.1; p .01), and malaria prophylaxis (OR = 1.7; p = .05). Absence of schooling of parents appeared to be a protective factor (OR = .47; p .001). The multivariate analysis uncovered 3 significant risk factors of prematurity: young mother and primiparity (OR = 4.4; p = .01), less than 3 prenatal visits (OR = 9.3; p .001), and death of a previous child (OR = 2.2; p .05). Lack of schooling continued to have a protective effect when researchers adjusted for other variables (OR = .37; p .001). As a possible explanation for education being a risk factor of prematurity in Burkina Faso, the researchers suggested that educated parents are more likely to use motorized transport on bumpy roads for 6-7 hours at a time which caused intrauterine vibrations, resulting in preterm delivery. In developed countries, education reduces the risk of preterm delivery.

Longitudinal study of Plasmodium falciparum infection and immune responses in infants with or without the sickle cell trait.

BACKGROUND: Individuals may be homozygous (SS) or heterozygous (AS) sickle cell gene carriers or have normal adult haemoglobin (AA). Haemoglobin S could have a protective role against malaria but evidence is sparse and the operating mechanisms are poorly known. METHODS: We followed two cohorts of children. The first was enrolled at birth (156 newborn babies) and the second at 24-36 months old (84 children). Both cohorts were followed for 30 months; monthly for parasitological data and half yearly for immunological data. RESULTS: In the first cohort, 22%, and in the second 13% of children were AS. Whatever their age parasite prevalence rates were similar in AA and AS individuals. Mean parasite densities increased less rapidly with age in AS than in AA children, and were significantly lower in AS than in AA children >48 months old. The AA children tended to be more often admitted to hospital than AS children (22% versus 11%, NS). Both anti-Plasmodium falciparum and anti-Pfl55/RESA antibody rates increased more rapidly in AA than in AS children. Conversely, the prevalence rate of cellular responders to the Pfl55/RESA antigen was similar in AA and AS children during the first 2 years of life, then it was higher in AS than in AA children. CONCLUSIONS: Sickle cell trait related antimalarial protection varies with age. The role of the modifications of the specific immune response to P. falciparum in explaining the protection of AS children against malaria is discussed.

Risk factors of malaria infection during pregnancy in Burkina Faso: suggestion of a genetic influence.

A cohort of 570 untreated pregnant women from Burkina Faso was studied to assess the influence of epidemiologic factors on malaria infection, which was quantified as the mean of serial, season-adjusted parasitemia measurements (mean parasite density [MPD]) carried out during the last five months of gestation. A significant effect of the area of maternal residence on the MPD was found (P < 0.003) and was probably due to geographic differences in mosquito transmission conditions. The strong relationship observed between parity and malaria infection (P < 0.0001), with MPD levels decreasing as the number of gestations increased, confirms that primigravidae are a high-risk group whose protection should be a priority. After adjustment for two relevant epidemiologic factors (i.e., area of residence and parity), the residual MPD values fitted a mixture of two distributions. This result supports the view that a major gene is involved in the determination of malaria infection intensities and is consistent with the results of a recent familial study in Cameroon.

Longitudinal survey of Loa loa filariasis in southern Cameroon: long-term stability and factors influencing individual microfilarial status.

A longitudinal, one-year survey of Loa loa infection was carried out in an endemic area of southern Cameroon. Parasitologic samplings (calibrated thick blood smears) were performed every two months to study the evolution of loiasis infection at both the population and the individual level. The mean number of measurements by subject was 3.8 (range 1-6). At the population level, prevalence of infection and microfilarial load were found to be very stable over time. This observation is consistent with the existence of an important reserve of parasitic material available for vectors and the maintenance of high levels of transmission. At the individual level, both the microfilarial status (microfilaremic/nonmicrofilaremic) and the level of parasitemia showed a remarkable stability over time. Age was the relevant factor that influenced the individual microfilarial status in the whole population. When only microfilaremic individuals were taken into account, age did not influence the level of microfilaremia, suggesting that loiasis could be considered as a noncumulative disease. The stability of individual microfilarial status and the pattern of infection variations observed with age support the view that genetic factors might be involved in host defense mechanisms against loiasis infection.

Effect of chloroquine chemoprophylaxis during pregnancy on birth weight: results of a randomized trial.

To determine the effect of chloroquine chemoprophylaxis during pregnancy on birth weights, a randomized trial was carried out in 1987 and 1988 in Banfora, Burkina Faso (West Africa). Seven hundred forty-five randomly selected women treated with chloroquine sulfate were compared to with 719 controls who received no treatment. In spite of an unquestionable effect of chloroquine in preventing placental infection (4.1% infected placentas in the treated group versus 19.0% in the controls), the mean difference in birth weights between the two groups (6 g) was not significant. The difference in the proportion of low birth weight (LBW) newborn babies in two groups (16.3% versus 16.4%) was also not significant. However, there was a strong relationship between placental infection and birth weight (the mean birth weight difference between infected and uninfected placentas was 113 g, and the proportion of LBW babies was 26.0% in infected placentas versus 14.8% in uninfected placentas). The small difference in birth weights observed between the two groups may be due to the fact that the prevalence rate of placental infection is low and that prophylaxis is effective only on a portion of the subjects in the treated group. It may also indicate that malaria is only one of several risk factors responsible for LBW. The relatively small increase in birth weight, the expected poor acceptance of mass prophylaxis, and the spreading of chloroquine-resistant Plasmodium strains should be considered before extending malaria chemoprophylaxis to all pregnant women. It might be worth considering to limit prophylaxis to primigravidae.

Increase of birth weight following chloroquine chemoprophylaxis during the first pregnancy: results of a randomized trial in Cameroon.

A randomized trial was carried out from 1991 to 1993 among women attending an antenatal clinic in Ebolowa, Cameroon where malaria is hyperendemic and transmission occurs at a high level all year round. All pregnant women attending the clinic for their first prenatal visit between October 1991 and November 1992 were alternately assigned to chloroquine (CQ) or control (CT) groups. Chloroquine was given under observation at a weekly oral dose of 300 mg. At delivery, smears from maternal, cord, and placental blood were made and stained with Giemsa for parasites. An in vivo chloroquine sensitivity investigation was carried out on women attending the postnatal consultation to evaluate the level of chloroquine resistance in the target population. The efficacy of chloroquine was moderate in placental infection (39.2% infected in the CQ group versus 57.8% in the CT group: P = 0.05), probably because of a resistance to chloroquine estimated to be 10.9%. In the CQ group, the mean birth weight was significantly higher (P = 0.02) and the proportion of low birth weight newborns was lower (10.5% versus 27.7%; P = 0.02). A strong correlation between placental infection and birth weight was observed: the mean birth weight difference between infected and noninfected placentae was 359 g (P < 0.0001) and the proportion of low birth weight new born babies was 35.6% versus 5.9% (P = 0.0001). In Cameroon, in spite of a moderate resistance to chloroquine, this drug proved to be highly effective in increasing birth weight when administered to primigravidae. We therefore think such a prophylaxis should be recommended only to primigravidae in high transmission areas.

Genetic control of blood infection levels in human malaria: evidence for a complex genetic model.

There is now accumulating evidence for the involvement of genetic factors in the control of immune response against malaria. These arguments come from numerous animal models, from population studies showing associations of red blood cell genetic defects as well as HLA antigens with severe malaria, and from familial studies including a recent segregation analysis, which led to detection of a major gene effect predisposing to high infection levels. The heterogeneity and complexity of this genetic control is one of the main findings of these previous studies, and probably a major cause of the difficulty in developing an effective malaria vaccine. A segregation analysis of blood infection levels is performed here in 44 pedigrees living in the tropical rain forest of southern Cameroon and exposed to high vectorial transmission intensity. The results confirm the existence of complex genetic factors controlling blood infection levels in human malaria but are not consistent with the parent-offspring transmission of a single Mendelian gene. This study also shows the dramatic effect of age on infection levels and its interaction with a putative major gene suggesting that genetic related differences are much more important in children than in adults. Further genetic studies focused on children may help to identify the nature of the genetic factors involved in the expression of human malaria, by means of linkage analyses using both familial information and genetic markers.

Malaria and pregnancy in Cameroonian primigravidae: humoral and cellular immune responses to Plasmodium falciparum blood-stage antigens.

To investigate the mechanisms underlying the increased susceptibility to malaria in pregnant women, we determined the level of malaria-specific immunity in primigravidae. Humoral and cellular in vitro responses to unpurified (a crude schizont extract and a gametocyte preparation) and purified (affinity-purified Pf155/ring-infected erythrocyte surface antigen [RESA]) Plasmodium falciparum proteins, an immunodominant 45/47-kilodalton antigen from Mycobacterium bovis, and leucoagglutinin were compared between 52 primigravidae and 52 nonpregnant women from a semirural area of Cameroon. In vitro cellular responses were investigated in terms of lymphocyte proliferation, as well as production of interleukin-2 (IL-2), interferon-gamma (IFN-gamma), and IL-4. Cells from primigravidae exhibited a reduced proliferative response to schizont and gametocyte antigens, as well as to the M. bovis antigen. Conversely, the IL-2 response to Pf155/RESA was reduced. Interleukin-4 and IFN-gamma production did not appear to be affected in primigravidae. Antibody levels were also similar between pregnant and nonpregnant women. Our results underline the importance of examining several parameters of T cell activation with different types of antigens for a correct evaluation of the ability of lymphocytes to respond to malaria.