Biomedical subjects

Eleanor M Riley

Publications and source records attributed to Eleanor M Riley.

33 records · Page 2Linked to original sources

PubMed2004

The fine specificity, but not the invasion inhibitory activity, of 19-kilodalton merozoite surface protein 1-specific antibodies is associated with resistance to malarial parasitemia in a cross-sectional survey in The Gambia.

In a cross-sectional survey of 187 Gambian children and adults, we have analyzed prevalence, fine specificity, and 19-kilodalton merozoite surface protein 1 (MSP-1(19))-specific erythrocyte invasion inhibitory activity of antibodies to MSP-1(19) but find no significant association between any of these parameters and prevalence or density of malarial parasitemia, except that, after correcting for total anti-MSP-1(19) antibody levels, individuals with anti-MSP-1(19) antibodies that compete with an invasion inhibitory monoclonal antibody (12.10) were significantly less likely to have malaria infections with densities of > or =1,000 parasites/microl than were individuals without such antibodies. This association persisted after correction for age and ethnic origin.

Adolescent↗

PubMed2004

Fine specificity of serum antibodies to Plasmodium falciparum merozoite surface protein, PfMSP-1(19), predicts protection from malaria infection and high-density parasitemia.

Antibodies to the C terminus of the Plasmodium falciparum merozoite surface protein, PfMSP-1(19), may inhibit merozoite invasion or block the effects of inhibitory antibodies. Here, using a competition enzyme-linked immunosorbent assay and antibody binding to wild-type and mutated recombinant proteins, we show that there are marked variations between individuals in the fine specificity of naturally acquired anti-MSP-1(19) antibodies. Furthermore, although neither the prevalence nor the concentration of total anti-MSP-1(19) antibodies was associated with resistance to malaria in African children, significant associations were observed between antibody fine specificity and subsequent risk of infection and high-density parasitemia during a follow-up period. Thus, the fine specificity of naturally acquired human anti-MSP-1(19) antibodies is crucial in determining their function. Future field studies, including the evaluation of PfMSP-1 vaccine trials, should include assays that explore antibody fine specificity as well as titer.

Adolescent↗

PubMed2003

Uninfected erythrocytes inhibit Plasmodium falciparum-induced cellular immune responses in whole-blood assays.

Whole-blood assays (WBAs) have been successfully used as a simple tool for immuno-epidemiological field studies evaluating cellular immune responses to mycobacterial and viral antigens. Rather unexpectedly, we found very poor cytokine responses to malaria antigens in WBAs in 2 immuno-epidemiological studies carried out in malaria endemic populations in Africa. We have therefore conducted a detailed comparison of cellular immune responses to live (intact) and lysed malaria-infected erythrocytes in WBAs and in peripheral blood mononuclear cell (PBMC) cultures. We observed profound inhibition of both proliferative and interferon-gamma responses to malarial antigens in WBAs as compared with PBMC cultures. This inhibition was seen only for malaria antigens and could not be overcome by increasing either antigen concentration or responder cell numbers. Inhibition was mediated by intact erythrocytes and occurred early in the culture period, suggesting that failure of antigen uptake might underlie the lack of T-cell responses. In support of this hypothesis, we have shown that intact uninfected erythrocytes specifically inhibit phagocytosis of infected red blood cells by peripheral blood monocytes. We propose that specific biochemical interactions with uninfected erythrocytes inhibit the phagocytosis of malaria-infected erythrocytes and that this may impede T-cell recognition in vivo.

Adult↗

PubMed2003

Activation of transforming growth factor beta by malaria parasite-derived metalloproteinases and a thrombospondin-like molecule.

Much of the pathology of malaria is mediated by inflammatory cytokines (such as interleukin 12, interferon gamma, and tumor necrosis factor alpha), which are part of the immune response that kills the parasite. The antiinflammatory cytokine transforming growth factor (TGF)-beta plays a crucial role in preventing the severe pathology of malaria in mice and TGF-beta production is associated with reduced risk of clinical malaria in humans. Here we show that serum-free preparations of Plasmodium falciparum, Plasmodium yoelii 17XL, and Plasmodium berghei schizont-infected erythrocytes, but not equivalent preparations of uninfected erythrocytes, are directly able to activate latent TGF-beta (LatTGF-beta) in vitro. Antibodies to thrombospondin (TSP) and to a P. falciparum TSP-related adhesive protein (PfTRAP), and synthetic peptides from PfTRAP and P. berghei TRAP that represent homologues of TGF-beta binding motifs of TSP, all inhibit malaria-mediated TGF-beta activation. Importantly, TRAP-deficient P. berghei parasites are less able to activate LatTGF-beta than wild-type parasites and their replication is attenuated in vitro. We show that activation of TGF-beta by malaria parasites is a two step process involving TSP-like molecules and metalloproteinase activity. Activation of LatTGF-beta represents a novel mechanism for direct modulation of the host response by malaria parasites.

Amino Acid Sequence↗

PubMed2003

Activation of a subset of human NK cells upon contact with Plasmodium falciparum-infected erythrocytes.

Human NK cells are the earliest source of the protective cytokine IFN-gamma when PBMC from nonimmune donors are exposed to Plasmodium falciparum-infected RBC (iRBC) in vitro. In this study, we show that human NK cells form stable conjugates with iRBC but not with uninfected RBC and that induction of IFN-gamma synthesis is dependent on direct contact between the NK cell and the iRBC. NK cells respond to iRBC only in the presence of a source of IL-12/IL-18 and the subset of NK cells that preferentially respond to iRBC express high levels of the lectin-like receptor CD94/NKG2A. There is heterogeneity between donors in their ability to respond to iRBC. DNA analysis has revealed considerable heterogeneity of killer Ig-like receptor (KIR) genotype among the donor population and has identified 21 new KIR allelic variants in the donors of African and Asian descent. Importantly, we find evidence for significant associations between KIR genotype and NK responsiveness to iRBC. This emphasizes the need for large-scale population-based studies to address associations between KIR genotype and susceptibility to malaria.

Adult↗

PubMed2003

Differential induction of TGF-beta regulates proinflammatory cytokine production and determines the outcome of lethal and nonlethal Plasmodium yoelii infections.

Transforming growth factor-beta is an essential moderator of malaria-induced inflammation in mice. In this study, we show that the virulence of malaria infections is dependent upon the cellular source of TGF-beta and the timing of its production. C57BL/6 mice infected with a nonlethal (Py17X) strain of Plasmodium yoelii produce TGF-beta from 5 days postinfection; this correlates with resolution of parasitemia, down-regulation of TNF-alpha, and full recovery. In contrast, infection with the lethal strain Py17XL induces high levels of circulating TGF-beta within 24 h; this is associated with delayed and blunted IFN-gamma and TNF-alpha responses, failure to clear parasites, and 100% mortality. Neutralization of early TGF-beta in Py17XL infection leads to a compensatory increase in IL-10 production, while simultaneous neutralization of TGF-beta and IL-10R signaling leads to up-regulation of TNF-alpha and IFN-gamma, prolonged survival in all, and ultimate resolution of infection in 40% of Py17XL-infected animals. TGF-beta production can be induced in an Ag-specific manner from splenocytes of infected mice, and by cross-linking surface CTLA-4. CD25(+) and CD8(+) cells are the primary source of TGF-beta following Py17X stimulation of splenocytes, whereas Py17XL induces significant production of TGF-beta from adherent cells. In mice immunized against Py17XL, the early TGF-beta response is inhibited and is accompanied by significant up-regulation of IFN-gamma and TNF-alpha and rapid resolution of challenge infections.

Animals↗

PubMed2003

Serological responses among individuals in areas where both schistosomiasis and malaria are endemic: cross-reactivity between Schistosoma mansoni and Plasmodium falciparum.

We examined specific immunoglobulin G1 (IgG1) and IgG3 responses to Plasmodium falciparum schizont and Schistosoma mansoni egg and worm antigens in individuals from Kenya, Uganda, and the Sudan who had been exposed to malaria and schistosomiasis. A strong correlation between malaria- and schistosome-specific IgG3 responses was observed. This association appears to result from the presence of cross-reactive components of the 2 parasites that bind IgG3 antibodies, rather than to be mediated by immunological cross-regulation or specific regulatory mechanisms induced by either parasite. Cross-reactivity of IgG3 antibodies was confirmed in a Brazilian cohort of individuals living in an area where schistosomiasis is endemic but no malaria occurs and in a Pakistani cohort from an area where malaria is endemic but no schistosomiasis occurs. An IgG3 interaction with antigens from both parasites was observed in individuals from both cohorts, but not in uninfected European control subjects. The immunological and biological implications of this observation require further exploration.

Adolescent↗

PubMed2003

Associations between anti-Schistosoma mansoni and anti-Plasmodium falciparum antibody responses and hepatosplenomegaly, in Kenyan schoolchildren.

Schoolchildren from 2 areas of Kenya, Kangundo and Kambu, have contrasting prevalences of hepatosplenomegaly, despite having similar prevalences and intensities of Schistosoma mansoni infection. However, in individual children, S. mansoni infection intensity is positively correlated with organomegaly. In a previous study, hepatosplenomegaly was associated with Th1-type anti-schistosome cytokine responses. Although the high-morbidity Kambu area had higher malaria transmission than did low-morbidity Kangundo, hepatosplenomegaly was not associated with clinical malaria or with patent malarial parasitemia. However, chronic exposure to malaria might be involved. Here, retrospectively, we assayed plasma from this original study, for anti-Plasmodium falciparum and anti-S. mansoni antibodies, to test whether greater exposure to Plasmodium was a cofactor for hepatosplenomegaly. We found that hepatosplenic children had significantly higher levels of anti-P. falciparum antibodies, compared with nonhepatosplenic children, a finding that strongly suggests that some experience of P. falciparum influenced the development of hepatosplenomegaly in these S. mansoni-infected children.

Animals↗

PubMed2003

Genetic diversity and antigenic polymorphism in Plasmodium falciparum: extensive serological cross-reactivity between allelic variants of merozoite surface protein 2.

Diversity in the surface antigens of malaria parasites is generally assumed to be a mechanism for immune evasion, but there is little direct evidence that this leads to evasion of protective immunity. Here we show that alleles of the highly polymorphic merozoite surface protein 2 (MSP-2) can be grouped (within the known dimorphic families) into distinct serogroups; variants within a serogroup show extensive serological cross-reactivity. Cross-reactive epitopes are immunodominant, and responses to them may be boosted at the expense of responses to novel epitopes (original antigenic sin). The data imply that immune selection explains only some of the diversity in the msp-2 gene and that MSP-2 vaccines may need to include only a subset of the known variants in order to induce pan-reactive antibodies.

Alleles↗

PubMed2003

Lack of gender-specific antibody recognition of products from domains of a var gene implicated in pregnancy-associated Plasmodium falciparum malaria.

Gender-specific and parity-dependent acquired antibody recognition is characteristic of variant surface antigens (VSA) expressed by chondroitin sulfate A (CSA)-adherent Plasmodium falciparum involved in pregnancy-associated malaria (PAM). However, antibody recognition of recombinant products of a specific VSA gene (2O2var1) implicated in PAM and transcribed by a CSA-adhering parasite line did not have these characteristics. Furthermore, we could not demonstrate preferential transcription of 2O2var1 in the CSA-adhering line versus the unselected, parental isolate. Our data call for circumspection regarding the molecular identity of the parasite ligand mediating adhesion to CSA in PAM.

Animals↗

PubMed2002

Innate immune response to malaria: rapid induction of IFN-gamma from human NK cells by live Plasmodium falciparum-infected erythrocytes.

To determine the potential contribution of innate immune responses to the early proinflammatory cytokine response to Plasmodium falciparum malaria, we have examined the kinetics and cellular sources of IFN-gamma production in response to human PBMC activation by intact, infected RBC (iRBC) or freeze-thaw lysates of P. falciparum schizonts. Infected erythrocytes induce a more rapid and intense IFN-gamma response from malaria-naive PBMC than do P. falciparum schizont lysates correlating with rapid iRBC activation of the CD3(-)CD56(+) NK cell population to produce IFN-gamma. IFN-gamma(+) NK cells are detectable within 6 h of coculture with iRBC, their numbers peaking at 24 h in most donors. There is marked heterogeneity between donors in magnitude of the NK-IFN-gamma response that does not correlate with mitogen- or cytokine-induced NK activation or prior malaria exposure. The NK cell-mediated IFN-gamma response is highly IL-12 dependent and appears to be partially IL-18 dependent. Exogenous rIL-12 or rIL-18 did not augment NK cell IFN-gamma responses, indicating that production of IL-12 and IL-18 is not the limiting factor explaining differences in NK cell reactivity between donors or between live and dead parasites. These data indicate that NK cells may represent an important early source of IFN-gamma, a cytokine that has been implicated in induction of various antiparasitic effector mechanisms. The heterogeneity of this early IFN-gamma response between donors suggests a variation in their ability to mount a rapid proinflammatory cytokine response to malaria infection that may, in turn, influence their innate susceptibility to malaria infection, malaria-related morbidity, or death from malaria.

Adult↗

PubMed2002

Cerebral malaria: the contribution of studies in animal models to our understanding of immunopathogenesis.

Cerebral malaria is a serious and often fatal complication of Plasmodium falciparum infections. The precise mechanisms involved in the onset of neuropathology remain unknown, but parasite sequestration in the brain, metabolic disturbances and host immune responses are all thought to be involved. This review outlines the current state of knowledge of cerebral disease in humans, and discusses the contribution of studies of animal models to elucidation of the underlying mechanisms.

Animals↗

PubMed2002

Protective immune responses to the 42-kilodalton (kDa) region of Plasmodium yoelii merozoite surface protein 1 are induced by the C-terminal 19-kDa region but not by the adjacent 33-kDa region.

Vaccination of mice with the 42-kDa region of Plasmodium yoelii merozoite surface protein 1 (MSP1(42)) or its 19-kDa C-terminal processing product (MSP1(19)) can elicit protective antibody responses in mice. To investigate if the 33-kDa N-terminal fragment (MSP1(33)) of MSP1(42) also induces protection, the gene segment encoding MSP1(33) was expressed as a glutathione S-transferase (GST) fusion protein. C57BL/6 and BALB/c mice were immunized with GST-MSP1(33) and subsequently challenged with the lethal P. yoelii YM blood stage parasite. GST-MSP1(33) failed to induce protection, and all mice developed patent parasitemia at a level similar to that in naive or control (GST-immunized) mice; mice immunized with GST-MSP1(19) were protected, as has been shown previously. Specific prechallenge immunoglobulin G (IgG) antibody responses to MSP1 were analyzed by enzyme-linked immunosorbent assay and immunofluorescence. Despite being unprotected, several mice immunized with MSP1(33) had antibody titers (of all IgG subclasses) that were comparable to or higher than those in mice that were protected following immunization with MSP1(19). The finding that P. yoelii MSP1(33) elicits strong but nonprotective antibody responses may have implications for the design of vaccines for humans based on Plasmodium falciparum or Plasmodium vivax MSP1(42).

Animals↗

PubMed2002

Regulation of antigen-specific immunoglobulin G subclasses in response to conserved and polymorphic Plasmodium falciparum antigens in an in vitro model.

Cytophilic antibodies (Abs) play a critical role in protection against Plasmodium falciparum blood stages, yet little is known about the parameters regulating production of these Abs. We used an in vitro culture system to study the subclass distribution of antigen (Ag)-specific immunoglobulin G (IgG) produced by peripheral blood mononuclear cells (PBMCs) from individuals exposed to P. falciparum or unexposed individuals. PBMCs, cultivated with or without cytokines and exogenous CD40/CD40L signals, were stimulated with a crude parasite extract, recombinant vaccine candidates derived from conserved Ags (19-kDa C terminus of merozoite surface protein 1 [MSP1(19)], R23, and PfEB200), or recombinant Ags derived from the polymorphic Ags MSP1 block 2 and MSP2. No P. falciparum-specific Ab production was detected in PBMCs from unexposed individuals. PBMCs from donors exposed frequently to P. falciparum infections produced multiple IgG subclasses when they were stimulated with the parasite extract but usually only one IgG subclass when they were stimulated with a recombinant Ag. Optimal Ab production required addition of interleukin-2 (IL-2) and IL-10 for all antigenic preparations. The IgG subclass distribution was both donor and Ag dependent and was only minimally influenced by the exogenous cytokine environment. In vitro IgG production and subclass distribution correlated with plasma Abs to some Ags (MSP1(19), R23, and MSP2) but not others (PfEB200 and the three MSP1 block 2-derived Ags). Data presented here suggest that intrinsic properties of the protein Ag itself play a major role in determining the subclass of the Ab response, which has important implications for rational design of vaccine delivery.

Adult↗

PubMed2002

Prevalence and boosting of antibodies to Plasmodium falciparum glycosylphosphatidylinositols and evaluation of their association with protection from mild and severe clinical malaria.

Glycosylphosphatidylinositols (GPIs), the anchor molecules of some membrane proteins of Plasmodium species, have been implicated in the induction of immunopathology during malaria infections. Hence, neutralization of GPIs by antibodies may reduce the severity of clinical attacks of malaria. To test this hypothesis, we have assessed the levels of anti-GPI antibodies in plasma from children and adults living in areas of seasonal malaria transmission in The Gambia. In a prospective study of susceptibility to clinical or asymptomatic infection, the levels of anti-GPI antibodies were measured before and after the transmission season. Samples were also obtained from children recruited into a hospital-based study of severe malaria. We find that in malaria-exposed individuals both the prevalence and the concentration of anti-GPI antibodies increase with age and that antibody levels are significantly higher at the end of the malaria transmission season than at the start of the season. Antibody levels are also higher in children with asymptomatic infections (i.e., those with a degree of clinical immunity) than in children who developed clinical malaria and high parasitemia, although this difference is not statistically significant. Importantly, antibodies appear to be rapidly boosted by clinical malaria infection, but children under the age of two years are seronegative for anti-GPI antibodies, even during an acute infection. While GPIs may be involved in the pathogenesis of human malaria, the data from this study do not provide any strong evidence to support the notion that anti-GPI antibodies confer resistance to mild or severe malarial disease. Further case-control studies, ideally of a prospective nature, are required to elucidate the role of antiglycolipid antibodies in protection from severe malaria.

Adolescent↗