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Biomedical subjects

E M Riley

Publications and source records attributed to E M Riley.

At least 19 recordsLinked to original sources
PubMed2006

Vitamin A supplementation increases ratios of proinflammatory to anti-inflammatory cytokine responses in pregnancy and lactation.

Vitamin A supplementation reduces child mortality in populations at risk of vitamin A deficiency and may also reduce maternal mortality. One possible explanation for this is that vitamin A deficiency is associated with altered immune function and cytokine dysregulation. Vitamin A deficiency in pregnancy may thus compound the pregnancy-associated bias of cellular immune responses towards Th-2-like responses and exacerbate susceptibility to intracellular pathogens. We assessed mitogen and antigen-induced cytokine responses during pregnancy and lactation in Ghanaian primigravidae receiving either vitamin A supplementation or placebo. This was a double-blind, randomized, placebo-controlled trial of weekly vitamin A supplementation in pregnant and lactating women. Pregnancy compared to postpartum was associated with a suppression of cytokine responses, in particular of the proinflammatory cytokines interferon (IFN)-gamma and tumour necrosis factor (TNF)-alpha. Mitogen-induced TNF-alpha responses were associated with a decreased risk of peripheral parasitaemia during pregnancy. Furthermore, vitamin A supplementation was significantly associated with an increased ratio of mitogen-induced proinflammatory cytokine (IFN-gamma) to anti-inflammatory cytokine (IL-10) during pregnancy and in the postpartum period. The results of this study indicate that suppression of proinflammatory type 1 immune responses and hence immunity to intracellular infections, resulting from the combined effects of pregnancy and vitamin A deficiency, might be ameliorated by vitamin A supplementation.

Cytokines↗
PubMed2005

Estimating medium- and long-term trends in malaria transmission by using serological markers of malaria exposure.

The implementation and evaluation of malaria control programs would be greatly facilitated by new tools for the rapid assessment of malaria transmission intensity. Because acquisition and maintenance of antimalarial antibodies depend on exposure to malaria infection, such antibodies might be used as proxy measures of transmission intensity. We have compared the prevalence of IgG antibodies with three Plasmodium falciparum asexual stage antigens in individuals of all ages living at varying altitudes encompassing a range of transmission intensities from hyper- to hypoendemic in northeastern Tanzania, with alternative measures of transmission intensity. The prevalence of antibodies to merozoite surface protein-1(19) was significantly more closely correlated with altitude than either point-prevalence malaria parasitemia or single measures of hemoglobin concentration. Analysis of age-specific seroprevalence rates enabled differentiation of recent (seasonal) changes in transmission intensity from longer-term transmission trends and, using a mathematical model of the annual rate of seroconversion, estimation of the longevity of the antibody response. Thus, serological tools allow us to detect variations in malaria transmission over time. Such tools will be invaluable for monitoring trends in malaria endemicity and the effectiveness of malaria control programs.

Adult↗
PubMed2005

Glycosylphosphatidylinositols in malaria pathogenesis and immunity: potential for therapeutic inhibition and vaccination.

Glycosylphosphatidylinositols (GPIs) are found in the outer cell membranes of all eukaryotes. GPIs anchor a diverse range of proteins to the surface of Plasmodium falciparum, but may also exist free of protein attachment. In vitro and in vivo studies have established GPIs as likely candidate toxins in malaria, consistent with the prevailing paradigm that attributes induction of inflammatory cytokines, fever and other pathology to parasite toxins released when schizonts rupture. Although evolutionarily conserved, sufficient structural differences appear to exist that impart upon plasmodial GPIs the ability to activate second messengers in mammalian cells and elicit immune responses. In populations exposed to P. falciparum, the antibody response to purified GPIs is characterised by a predominance of immunoglobulin (Ig)G over IgM and an increase in the prevalence, level and persistence of responses with increasing age. It remains unclear, however, if these antibodies or other cellular responses to GPIs mediate anti-toxic immunity in humans; anti-toxic immunity may comprise either reduction in the severity of disease or maintenance of the malaria-tolerant state (i.e. persistent asymptomatic parasitaemia). P. falciparum GPIs are potentially amenable to specific therapeutic inhibition and vaccination; more needs to be known about their dual roles in malaria pathogenesis and protection for these strategies to succeed.

Animals↗
PubMed2003

The war between the malaria parasite and the immune system: immunity, immunoregulation and immunopathology.

Throughout history malaria has proved to be a significant threat to human health. Between 300 and 500 million clinical cases occur each year worldwide, approximately 2 million of which are fatal, primarily in children. The vast majority of malaria-related deaths are due to infection with Plasmodium falciparum; P. vivax causes severe febrile illness but is rarely fatal. Following repeated exposure to infection, people living in malaria endemic areas gradually acquire mechanisms to limit the inflammatory response to the parasite that causes the acute febrile symptoms (clinical immunity) as well as mechanisms to kill parasites or inhibit parasite replication (antiparasite immunity). Children, who have yet to develop protective immune mechanisms are thus at greater risk of clinical malaria, severe disease and death than adults. However, two epidemiological observations indicate that this is, perhaps, an oversimplified model. Firstly, cerebral malaria - a common manifestation of severe malaria - typically occurs in children who have already acquired a significant degree of antimalarial immunity, as evidenced by lower mean parasite densities and resistance to severe anaemia. One potential explanation is that cerebral malaria is, in part, an immune-mediated disease in which immunological priming occurs during first infection, eventually leading to immunopathology on re-infection. Secondly, among travelers from nonendemic areas, severe malaria is more common - and death rates are higher - in adults than in children. If severe malaria is an immune-mediated disease, what might be priming the immune system of adults from nonendemic areas to cause immunopathology during their first malaria infection, and how do adults from endemic areas avoid severe immunopathology? In this review we consider the role of innate and adaptive immune responses in terms of (i) protection from clinical malaria (ii) their potential role in immunopathology and (iii) the subsequent development of clinical immunity. We conclude by proposing a model of antimalarial immunity which integrates both the immunological and epidemiological data collected to date.

Adult↗
PubMed2003

Does apolipoprotein E polymorphism influence susceptibility to malaria?

Outcome of infection varies greatly among people, and in the case of three very different viruses, it is determined by apolipoprotein E (APOE) genotype. APOE might affect outcome of malaria infection also, since apoE protein and the protozoon (like the viruses) share cell entry mediators (heparan sulphate proteoglycans and/or specific apoE receptors). APOE polymorphisms give rise to protein variants that differ in binding strength to these mediators; thus, the extent of competition between apoE and protozoon for cell entry, and hence magnitude of protozoan damage, might depend on apoE isoform. Genotypes of infants infected with malaria were examined. It was found that APOE epsilon 2 homozygotes became infected at an earlier age than those carrying the other genotypes, the difference being statistically significant. Parasite densities, all of which were low, did not differ significantly. This effect, although based on small numbers, suggests that APOE epsilon 2 may be a risk factor for early infection.

Animals↗
PubMed2002

Absolute levels and ratios of proinflammatory and anti-inflammatory cytokine production in vitro predict clinical immunity to Plasmodium falciparum malaria.

The relationship between malaria-related outcomes and cytokine production in whole blood cultures associated with cellular immune responses and immunity to Plasmodium falciparum malaria was examined in a study in southern Ghana. Production of malaria-specific interferon (IFN)-gamma was associated with reduced risk of fever and clinical malaria. Protective IFN-gamma responses were induced by live schizonts but not by dead parasites. Production of malaria-specific tumor necrosis factor (TNF)-alpha was associated with reduced risk of fever during follow-up. Baseline levels of TNF-alpha and phytohemagglutinin (PHA)-induced interleukin (IL)-10 were positively associated with hemoglobin concentration. IL-12 production was associated with reduced risk of parasitemia. PHA-induced transforming growth factor-beta production was associated with reduced risk of fever during follow-up. High ratios of proinflammatory to anti-inflammatory cytokines were associated with increased risk of fever and higher hemoglobin concentrations. Thus, absolute levels and ratios of proinflammatory and anti-inflammatory cytokines influence susceptibility to infection, clinical disease, and anemia. These data contradict data from cross-sectional clinical studies and indicate a need for detailed analysis of the relationship between cellular immunity to malaria and resistance to disease.

Adolescent↗
PubMed2001

Frequent and persistent, asymptomatic Plasmodium falciparum infections in African infants, characterized by multilocus genotyping.

To determine the duration and complexity of naturally acquired Plasmodium falciparum infections in small children, a longitudinal cohort study of 143 newborns was conducted in coastal Ghana. On average, children experienced 2 episodes of infection in their first 2 years of life, the median duration of an asymptomatic infection was <4 weeks, and estimates of the mean number of parasite genotypes per infection were 1.15-2.28. Nevertheless, 40% of the children experienced infections lasting </=12 weeks, and both the duration and complexity of infections increased with age. The longest period of continual infection was 64 weeks, and the maximum persistence of a single parasite genotype was 40 weeks. Thus, malaria infections in infants <5 months old tend to be asymptomatic and rapidly cleared; persistent asymptomatic parasitemia is more common in children >5 months old. The ability of very young children to clear or control malaria infections indicates the presence of effective innate or immune antiparasite mechanisms.

Age Factors↗
PubMed2001

Changes in cytokine production associated with acquired immunity to Plasmodium falciparum malaria.

Individuals living in malaria-endemic areas eventually develop clinical immunity to Plasmodium falciparum. That is, they are able to limit blood parasite densities to extremely low levels and fail to show symptoms of infection. As the clinical symptoms of malaria infection are mediated in part by pro-inflammatory cytokines it is not clear whether the acquisition of clinical immunity is due simply to the development of antiparasitic mechanisms or whether the ability to regulate inflammatory cytokine production is also involved. We hypothesize that there is a correlation between risk of developing clinical malaria and the tendency to produce high levels of proinflammatory cytokines in response to malaria infection. In order to test this hypothesis, we have compared the ability of peripheral blood mononuclear cells from malaria-naive and malaria-exposed adult donors to proliferate and to secrete IFN-gamma in response to P. falciparum schizont extract (PfSE). In order to determine how PfSE-induced IFN-gamma production is regulated, we have also measured production of IL-12p40 and IL-10 from PfSE-stimulated PBMC and investigated the role of neutralizing antibody to IL-12 in modulating IFN-gamma production. We find that cells from naive donors produce moderate amounts of IFN-gamma in response to PfSE and that IFN-gamma production is strongly IL-12 dependent. Cells from malaria-exposed donors living in an area of low malaria endemicity produce much higher levels of IFN-gamma and this response is also at least partially IL-12 dependent. In complete contrast, cells from donors living in an area of very high endemicity produce minimal amounts of IFN-gamma. No significant differences were detected between the groups in IL-10 production, suggesting that this cytokine does not play a major role in regulating malaria-induced IFN-gamma production. The data from this study thus strongly support the hypothesis that down-regulation of inflammatory cytokine production may be a component of acquired clinical immunity to malaria but the mechanism by which this is achieved remains to be elucidated.

Adult↗
PubMed2001

Do maternally acquired antibodies protect infants from malaria infection?

Neonates and infants are relatively protected from clinical malaria, but the mechanism of this protection is not well understood. Maternally derived antibodies are commonly believed to provide protection against many infectious diseases, including malaria, for periods of up to 6-9 months but several recent epidemiological studies have produced conflicting results regarding a protective role of passively acquired antimalarial antibodies. In this article, we review the epidemiological evidence for resistance of young infants to malaria, summarize the data on antimalarial antibody levels and specificity and their association with protection from malaria infection or clinical disease, and explore alternative explanations for resistance to malaria in infants.

Antibodies, Protozoan↗
PubMed2000

Plasma antibodies from malaria-exposed pregnant women recognize variant surface antigens on Plasmodium falciparum-infected erythrocytes in a parity-dependent manner and block parasite adhesion to chondroitin sulfate A.

In areas of intense Plasmodium falciparum transmission, clinical immunity is acquired during childhood, and adults enjoy substantial protection against malaria. An exception to this rule is pregnant women, in whom malaria is both more prevalent and severe than in nonpregnant women. Pregnancy-associated malaria (PAM) in endemic areas is concentrated in the first few pregnancies, indicating that protective immunity to PAM is a function of parity. The placenta is often heavily infected in PAM, and placental parasites show a striking preference for chondroitin sulfate A (CSA) as an adhesion receptor. Plasma Abs from malaria-exposed multiparous women are able to interfere with binding of P. falciparum parasites to CSA in vitro, and acquisition of Abs interfering with CSA-specific parasite sequestration thus appears to be a critical element in acquired protection against PAM. Here we show that adults from an area of hyperendemic P. falciparum transmission generally possessed low levels of Abs specifically recognizing surface Ags expressed by a CSA-adhering parasite isolate, while unselected isolates were well recognized. In marked contrast, most third-trimester pregnant women from that area had very high plasma levels of such Abs. Plasma levels of Abs specifically recognizing the CSA-adhering isolate strongly depended on parity, whereas recognition of CSA-nonadhering isolates did not. Finally, we demonstrate a clear correlation between plasma levels of Abs recognizing the CSA-specific isolate and the ability to interfere with its sequestration to CSA in vitro. Our study supports the hypothesis that Abs inhibiting CSA-specific parasite sequestration are important in acquisition of protection against PAM.

Adult↗
PubMed2000

Neuropsychological functioning in first-episode psychosis--evidence of specific deficits.

Neuropsychological impairment is ubiquitous in schizophrenia even at the first presentation of psychotic symptoms. We sought to elucidate the nature of the neuropsychological profile at the onset of the illness by examining the neuropsychological functioning of 40 patients experiencing their first episode of psychosis and 22 matched controls. All participants completed a battery of neuropsychological tasks designed to assess attention, verbal learning/memory, non-verbal memory, spatial ability, psychomotor speed, and executive function. First-episode patients showed significant impairment on tasks of executive function, including those requiring the ability to form and initiate a strategy, to inhibit prepotent responses, and to shift cognitive set, and also on tasks of verbal fluency. Memory impairments were seen on verbal learning and delayed non-verbal memory only. Impairment on tasks of psychomotor speed suggests that there may be a significant amount of cognitive slowing even at the first onset of psychosis. We suggest that our patients may be experiencing difficulty in specific aspects of executive functions, including the ability to form and execute a strategy, and these difficulties may be mediating the deficits observed on tasks of verbal learning.

Adolescent↗
PubMed2000

Maintaining the immunological balance in parasitic infections: a role for TGF-beta?

Transforming growth factor beta (TGF-beta) is an important regulator of inflammation, being proinflammatory at low concentrations and anti-inflammatory at high concentrations. As such, TGF-beta might be important in maintaining the balance between control and clearance of infectious organisms on the one hand and prevention of immune-mediated pathology on the other. In this article, Fakhereldin Omer, Jørgen Kurtzhals and Eleanor Riley review the immunoregulatory properties of TGF-beta in the context of parasitic infections. Data from murine malaria infections suggest that TGF-beta modifies the severity of the disease, and a number of potential protective mechanisms are discussed. Evidence is accumulating that TGF-beta is important for the regulation of other host-parasite interactions and that parasites might directly influence TGF-beta-dependent pathways via the synthesis of TGF-beta or TGF-beta-receptor homologues.

Animals↗
PubMed2000

Analysis of human antibodies to erythrocyte binding antigen 175 of Plasmodium falciparum.

Invasion of human erythrocytes by Plasmodium falciparum merozoites is a multistep process. For many strains of the parasite, part of this process requires that the erythrocyte binding antigen 175 (EBA-175) of the merozoite binds to sialic acid residues of glycophorin A on the erythrocyte surface, a receptor-ligand interaction which represents a potential target for inhibition by antibodies. This study characterizes the reactivity of naturally acquired human antibodies with four recombinant proteins representing parts of EBA-175 (region II, regions III to V, and the dimorphic C and F segment region) in populations in which the organism is endemic. Serum immunoglobulin G (IgG) recognizing the recombinant proteins is predominantly of the IgG1 and IgG3 subclasses, and its prevalence increases with age. In a large population study in The Gambia, serum positivity for IgG or IgG1 and IgG3 subclass antibodies to each of the EBA-175 recombinant antigens was not significantly associated with subsequent protection from clinical malaria. However, there was a trend indicating that individuals with high levels of IgG to region II may have some protection.

Adult↗
PubMed2000

Lack of association between maternal antibody and protection of African infants from malaria infection.

Maternally derived antibodies are believed to protect infants against infection, but there is little direct evidence for a protective role of passively acquired antibodies against malaria. A longitudinal study of malaria infection in 143 infants was conducted in a region of southern Ghana where Plasmodium falciparum is endemic. Infants born in the high-transmission season were less likely to become infected in the first 20 weeks of life than children born in the low-transmission season. Plasma, obtained at birth, was tested for immunoglobulin G (IgG) and IgG subclasses to P. falciparum schizonts and recombinant circumsporozoite antigen, MSP-1(19), MSP-2, AMA-1, and Pf155 (also called ring-infected erythrocyte surface antigen). Antibody levels at birth were not associated with resistance to malaria infection. On the contrary, antibodies at birth were positively associated with infection, indicating that high levels of maternally derived antibodies represent a marker for intensity of exposure to malaria infection in infants. However, all five children who experienced high-density infections (>100 parasites/microl of blood) were seronegative for MSP-1(19) at the time of infection.

Adolescent↗
PubMed2000

Linkage of exogenous T-cell epitopes to the 19-kilodalton region of Plasmodium yoelii merozoite surface protein 1 (MSP1(19)) can enhance protective immunity against malaria and modulate the immunoglobulin subclass response to MSP1(19).

The degree of protection against Plasmodium yoelii asexual blood stages induced by immunization of mice with the 19-kDa region of merozoite surface protein 1 (MSP1(19)) is H-2 dependent. As a strategy to improve the protection, mouse strains with disparate H-2 haplotypes were immunized with glutathione S-transferase (GST)-MSP1(19) proteins including either a universal T-cell epitope from tetanus toxin (P2) or an I-A(k)-restricted T-cell epitope (P8) from Plasmodium falciparum Pf332. In H-2(k) mice which are poorly protected following immunization with GST-MSP1(19), GST-P2-MSP1(19) significantly improved the protection. In mice partially (H-2(k/b)) or well protected by GST-MSP1(19) (H-2(d) and H-2(b)), P2 did not further increase the protection. However, the protection of H-2(k/b) mice and to some extent H-2(k) mice was improved by immunization with GST-P8-MSP1(19). The magnitudes of immunoglobulin G1 (IgG1) and IgG2a responses in mice immunized with the GST-MSP1(19) variants correlated with low peak parasitemia, indicating a protective capacity of these IgG subclasses. In H-2(k) mice immunized with GST-P2-MSP1(19), both IgG1 and IgG2a responses were significantly enhanced. The epitope P2 appeared to have a general ability to modulate the IgG subclass response since all four mouse strains displayed elevated IgG2a and/or IgG2b levels after immunization with GST-P2-MSP1(19). In contrast, GST-P8-MSP1(19) induced a slight enhancement of IgG responses in H-2(k/b) and H-2(k) mice without any major shift in IgG subclass patterns. The ability to improve the protective immunity elicited by P. yoelii MSP1(19) may have implications for improvement of human vaccines based on P. falciparum MSP1(19).

Animals↗
PubMed2000

The London School of Hygiene and Tropical Medicine: a new century of malaria research.

The global malaria situation has scarcely improved in the last 100 years, despite major advances in our knowledge of the basic biology, epidemiology and clinical basis of the disease. Effective malaria control, leading to a significant decrease in the morbidity and mortality attributable to malaria, will require a multidisciplinary approach. New tools--drugs, vaccine and insecticides--are needed but there is also much to be gained by better use of existing tools: using drugs in combination in order to slow the development of drug resistance; targeting resources to areas of greatest need; using geographic information systems to map the populations at risk and more sophisticated marketing techniques to distribute bed nets and insecticides. Sustainable malaria control may require the deployment of a highly effective vaccine, but there is much that can be done in the meantime to reduce the burden of disease.

Animals↗