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      Chemokine levels and parasite- and allergen-specific antibody responses in children and adults with severe or uncomplicated Plasmodium falciparum malaria

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          Chemokine a nd antibody response profiles were investigated in children and adults with severe or uncomplicated Plasmodium falciparum malaria; the aim was to reveal which profiles are associated with severe disease, as often seen in nonimmune children, or with mild and uncomplicated disease, as seen in semi-immune adults. Blood samples were obtained from children under 5 years of age as well as adults with falciparum malaria. Classification of malaria was performed according to parasite densities and hemoglobin concentrations. Plasma levels of chemokines (IL-8, IP-10, MCP-4, TARC, PARC, MIP-1δ, eotaxins) were quantified, and antibody responses (IgE, IgG1, and IgG4) to P. falciparum, Entamoeba histolytica-specific antigen, and mite allergen extracts were determined. In children with severe malaria proinflammatory, IL-8, IP10, MIP-1δ, and LARC were at highly elevated levels, suggesting an association with severe disease. In contrast, the Th2-type chemokines TARC, PARC, and eotaxin-2 attained in children the same levels as in adults suggesting the evolution of immune regulatory components. In children with severe malaria, an elevated IgG1 and IgE reactivity to mite allergens and intestinal protozoan parasites was observed. In conclusion, exacerbated proinflammatory chemokines together with IgE responses to mite allergens or E. histolytica-specific antigen extract were observed in children with severe falciparum malaria.

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          Immunoglobulin G subclass-specific responses against Plasmodium falciparum merozoite antigens are associated with control of parasitemia and protection from symptomatic illness.

          Substantial evidence indicates that antibodies to Plasmodium falciparum merozoite antigens play a role in protection from malaria, although the precise targets and mechanisms mediating immunity remain unclear. Different malaria antigens induce distinct immunoglobulin G (IgG) subclass responses, but the importance of different responses in protective immunity from malaria is not known and the factors determining subclass responses in vivo are poorly understood. We examined IgG and IgG subclass responses to the merozoite antigens MSP1-19 (the 19-kDa C-terminal region of merozoite surface protein 1), MSP2 (merozoite surface protein 2), and AMA-1 (apical membrane antigen 1), including different polymorphic variants of these antigens, in a longitudinal cohort of children in Papua New Guinea. IgG1 and IgG3 were the predominant subclasses of antibodies to each antigen, and all antibody responses increased in association with age and exposure without evidence of increasing polarization toward one subclass. The profiles of IgG subclasses differed somewhat for different alleles of MSP2 but not for different variants of AMA-1. Individuals did not appear to have a propensity to make a specific subclass response irrespective of the antigen. Instead, data suggest that subclass responses to each antigen are generated independently among individuals and that antigen properties, rather than host factors, are the major determinants of IgG subclass responses. High levels of AMA-1-specific IgG3 and MSP1-19-specific IgG1 were strongly predictive of a reduced risk of symptomatic malaria and high-density P. falciparum infections. However, no antibody response was significantly associated with protection from parasitization per se. Our findings have major implications for understanding human immunity and for malaria vaccine development and evaluation.
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            Long-Term Clinical Protection from Falciparum Malaria Is Strongly Associated with IgG3 Antibodies to Merozoite Surface Protein 3

            Introduction A malaria vaccine is urgently needed [1,2]; however, the rational development of such a vaccine has suffered from a lack of knowledge of the relevance of experimental models [3]. This has resulted in a highly unsatisfactory situation in which each hypothesis derived from such models is investigated in lengthy and costly clinical trials. The lack of a reliable surrogate marker of protection in humans is thus a recognized limitation to the identification and development of efficacious vaccines [4]. The role of antibodies in clinical protection against malaria erythrocytic stages has long been recognized by in vivo transfer of antibodies from protected African adults to nonprotected individuals infected with P. falciparum [5,6]. However, several decades later it remains unclear which of the many antibody specificities contained in such sera may play a critical role, and hence which of the corresponding antigen(s) may represent potential vaccine candidate(s). Identification of such antigens requires the characterization of antibody species in relation to the precisely defined medical status of individuals exposed under field conditions, and in a longitudinal manner, since malaria attacks are spread over time. The corresponding epidemiological conditions were therefore established in an area of Senegal so as to fulfil two main features: (i) to include active case detection, i.e., by daily medical visits to each individual over several years and by providing access to medical care 24 h a day, (ii) making use of improved diagnostic criteria in order to distinguish malaria from other fevers, namely the pyrogenic threshold of parasite density as defined in this particular area [7], the validity of which was confirmed independently [8,9]. Employing these criteria represents a substantial improvement in the assessment of bona fide clinical malaria episodes since, as shown below, both refractory and susceptible individuals can be accurately identified using these criteria in all age groups. Most immunoclinical studies have dealt with a single antigen in a given location, precluding any comparative assessment of the relevance of each antigen. The aim of the present study was to correlate clinical protection in an endemic population with the immune response to five leading malarial vaccine candidates that are currently underway in, or about to enter, numerous clinical trials (see list of trials at http://www.who.int/vaccine_research/documents/en/malaria_table.pdf) [1]. Four of these molecules are the targets of antibodies that inhibit red blood cell invasion, namely merozoite surface protein 1 (MSP1) [10], MSP2 [11], apical membrane antigen 1 (AMA1) [12,13], and ring-infected erythrocyte surface antigen (RESA) [14], whereas MSP3 is targeted by cytophilic antibodies inhibiting intra-erythrocytic parasite growth in a monocyte-dependent manner [15]. Methods Study Area and Collection of Clinical Data The village of Dielmo (13°45′N, 16°25′W) is localized in one of the rare areas of Senegal, West Africa where malaria is holoendemic (experiencing perennially a high level of transmission by mosquitoes, due to the presence of a permanent stream), with an average of 5.16 infective bites per week during the first 2 y of the survey [16]. The 247 inhabitants of Dielmo village were enrolled in a prospective study using to our knowledge one of the most stringent protocols of clinical follow-up ever applied in the field and consisting of daily surveillance by medical staff (present 24 h/d, 7 d/wk) in order to identify and to analyse all episodes of morbidity [16]. The field set-up was designed and tested over 1 y before the actual study was conducted (e.g., questionnaires used for daily surveillance were written in three languages, and the reliability of responses were systematically addressed). Each villager was visited daily at home and had the ability to consult at any time one of the two medical doctors permanently on-site. In the event of a report or complaint of fever, headache, or vomiting, a medical examination and three thick blood films were made. One of the thick blood smears was Giemsa-stained and examined immediately on-site for the purpose of deciding on treatment. The other two slides were dehaemoglobinized, stained, and examined in our central laboratory in Dakar, using more rigorous and standardized conditions with quality control assessment [16]. The results of the latter slides were used for the present study. The criteria leading to a given episode of morbidity being attributed to malaria have been studied in detail and defined previously [7]: a malaria attack was defined as an episode of fever (temperature >38.5 °C) associated with a parasite density exceeding an age-dependent pyrogenic threshold described for this village (the parasite density threshold for each age group was determined to be 24,500 parasites/μl at ages 21 y age groups, respectively), though the majority had acquired protection. However, in adults, symptoms were of short duration and resolved spontaneously, i.e., without requiring treatment in most cases [7,16,36]. Figure 1 Means and Standard Deviations of Anti-MSP3-b IgG1, IgG2, IgG3, IgG4, and IgM Antibody Responses per Age Group Concentrations of antibodies are estimated as described in the Methods section. For each age group the mean number of malaria attacks recorded during the first year of follow-up is indicated by the shaded area. The numbers of individuals in each age group were: 5 (0–1 y), 14 (2–3 y), 17 (4–5 y), 14 (6–7 y), 12 (8–9 y), 13 (10–11 y), 11 (12–14 y), 18 (15–18 y), 13 19–21 y), 100 (>21 y), respectively. The existence of such rapidly acquired protection in very young children and, conversely, the occurrence of brief malaria attacks in adults, have seldom been reported previously, possibly due to the use of less-stringent surveillance setups. The pattern of clinical incidence in Dielmo remains similar to that described in other high-endemicity African areas [37] with a far greater number of attacks in younger individuals, e.g., 3.45 clinical attacks per year in children aged 1–5 y versus 0.1 attack per year in adults. Nevertheless, the daily surveillance of highly exposed villagers made it possible to distinguish in every age group individuals with or without malaria attacks who can therefore be referred to below as “nonprotected” and “protected,” respectively, for the duration of the 2 y follow-up period. The monthly surveys of entomological inoculations, conducted during the clinical follow-up period, showed a very high level of transmission, with an estimate of 260 infective mosquito bites per person per year, i.e., 520 parasite inoculations over the 2 y survey, with little house to house variation, leading us to exclude the hypothesis that villagers without malaria attacks were not exposed. This clinical situation was in most instances stable since only 13% of participants changed clinical status from the first to the second year of follow-up. The cases recorded are therefore well suited to the identification of immune correlates of protection and, furthermore, for the first time this analysis can be performed in an age-independent manner. Cytophilic Anti-MSP3 Antibodies Correlate with Clinical Immunity The overall prevalence of IgG and IgM antibodies against the MSP3-b epitope in the 217 individuals studied was high (97.2% and 93.1%, respectively), whereas the prevalence of IgA was low (19.3%). MSP3-specific IgE antibodies could not be detected (unpublished data). Among the IgGs, the two cytophilic classes, IgG1 and IgG3, were the most abundant (Figure 1) and they both increased as a function of age, whereas the increase was modest for IgG2 and IgM antibodies, and low for IgG4 antibodies in all age groups. Responses to other malaria antigens, including MSP1, MSP2-FC27, MSP2-3D7, RESA, and AMA-1, were also found to increase with age in this study (unpublished data) as has been observed in previous studies [38–42]. Therefore, due to this age-dependent increase, all antibodies measured showed an overall inverse relationship with the prevalence of clinical attacks (Figure 1, shaded area), a phenomenon reported in most previous studies in African settings and sometimes taken as indicating that protection is afforded by those antibodies [33,38,43–45]. The prevalence of responses to pre-erythrocytic antigens, such as CS, LSA1, and LSA3, also showed an age-dependent increase and confirmed the high degree of exposure to infected mosquitoes (see Figure S1). Antibodies against the pre-erythrocytic antigens were not included in the present statistical analysis. We first sought by stepwise regression analysis if it was possible to select a subset of antibody responses that would tend to predict the number of malaria attacks when controlling for age. We then examined the predictive value in terms of clinical protection of a positive antibody response for each IgG isotype, to each of the five molecules studied, for both each year separately and combined. A highly consistent association was observed between protection and anti-MSP3 IgG3 antibodies for each of the years studied, as well as for the two years combined, and this indication persisted even when controlling for age (age-adjusted odds ratio [OR] and 95% CI = 7.19 [2.70–22.85], p 20, p median) were considered high responders (closed circles). Individuals with antibody responses below the median (
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              IL-27 promotes IL-10 production by effector Th1 CD4+ T cells: a critical mechanism for protection from severe immunopathology during malaria infection.

              Infection with the malaria parasite, Plasmodium, is characterized by excessive inflammation. The establishment of a precise balance between the pro- and anti-inflammatory responses is critical to guarantee control of the parasite and survival of the host. IL-10, a key regulatory cytokine produced by many cells of the immune system, has been shown to protect mice against pathology during acute Plasmodium0 chabaudi chabaudi AS model of malaria. However, the critical cellular source of IL-10 is still unknown. In this article, we demonstrate that T cell-derived IL-10 is necessary for the control of pathology during acute malaria, as mice bearing specific deletion of Il10 in T cells fully reproduce the phenotype observed in Il10(-)(/)(-) mice, with significant weight loss, decline in temperature, and increased mortality. Furthermore, we show that IFN-γ(+) Th1 cells are the main producers of IL-10 throughout acute infection, expressing high levels of CD44 and ICOS, and low levels of CD127. Although Foxp3(+) regulatory CD4(+) T cells produce IL-10 during infection, highly activated IFN-γ(+) Th1 cells were shown to be the essential and sufficient source of IL-10 to guarantee protection against severe immune-mediated pathology. Finally, in this model of malaria, we demonstrate that the generation of protective IL10(+)IFN-γ(+) Th1 cells is dependent on IL-27 signaling and independent of IL-21.

                Author and article information

                European Journal of Microbiology and Immunology
                Akadémiai Kiadó
                1 March 2015
                26 March 2015
                : 5
                : 1 ( otherID: VRG7W6904000 )
                : 131-141
                [ 1 ] Université de Lomé Centre Hospitalier Universitaire Lomé Togo
                [ 2 ] Centre Hospitalier Régional (CHR) Sokodé Togo
                [ 3 ] Onchocerciasis Reference Laboratory Institut National d’Hygiène Sokodé Togo
                [ 4 ] University Clinics of Tübingen Institute of Tropical Medicine Tübingen Germany
                Original Article


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