Biomedical subjects

Peter C Bull

Publications and source records attributed to Peter C Bull.

9 recordsLinked to original sources

PubMed2006

The frequency of BDCA3-positive dendritic cells is increased in the peripheral circulation of Kenyan children with severe malaria.

The ability of Plasmodium falciparum-infected erythrocytes to adhere to host endothelial cells via receptor molecules such as ICAM-1 and CD36 is considered a hallmark for the development of severe malaria syndromes. These molecules are also expressed on leukocytes such as dendritic cells. Dendritic cells are antigen-presenting cells that are crucial for the initiation of adaptive immune responses. In many human diseases, their frequency and function is perturbed. We analyzed the frequency of peripheral blood dendritic cell subsets and the plasma concentrations of interleukin-10 (IL-10) and IL-12 in Kenyan children with severe malaria and during convalescence and related these parameters to the adhesion phenotype of the acute parasite isolates. The frequency of CD1c(+) dendritic cells in children with acute malaria was comparable to that in healthy controls, but the frequency of BDCA3(+) dendritic cells was significantly increased. Analysis of the adhesion phenotypes of parasite isolates revealed that adhesion to ICAM-1 was associated with the frequency of peripheral blood CD1c(+) dendritic cells, whereas the adhesion of infected erythrocytes to CD36 correlated with high concentrations of IL-10 and low concentrations of IL-12 in plasma.

Animals↗

PubMed2005

Plasmodium falciparum variant surface antigen expression patterns during malaria.

The variant surface antigens expressed on Plasmodium falciparum-infected erythrocytes are potentially important targets of immunity to malaria and are encoded, at least in part, by a family of var genes, about 60 of which are present within every parasite genome. Here we use semi-conserved regions within short var gene sequence "tags" to make direct comparisons of var gene expression in 12 clinical parasite isolates from Kenyan children. A total of 1,746 var clones were sequenced from genomic and cDNA and assigned to one of six sequence groups using specific sequence features. The results show the following. (1) The relative numbers of genomic clones falling in each of the sequence groups was similar between parasite isolates and corresponded well with the numbers of genes found in the genome of a single, fully sequenced parasite isolate. In contrast, the relative numbers of cDNA clones falling in each group varied considerably between isolates. (2) Expression of sequences belonging to a relatively conserved group was negatively associated with the repertoire of variant surface antigen antibodies carried by the infected child at the time of disease, whereas expression of sequences belonging to another group was associated with the parasite "rosetting" phenotype, a well established virulence determinant. Our results suggest that information on the state of the host-parasite relationship in vivo can be provided by measurements of the differential expression of different var groups, and need only be defined by short stretches of sequence data.

Amino Acid Sequence↗

PubMed2005

Plasmodium falciparum antigenic variation: relationships between in vivo selection, acquired antibody response, and disease severity.

BACKGROUND: Variant surface antigens (VSA) on Plasmodium falciparum-infected erythrocytes are potentially important targets of immunity to malaria. We previously identified a VSA phenotype--VSA with a high frequency of antibody recognition (VSA(FoRH))--that is associated with young host age and severe malaria. We hypothesized that VSA(FoRH) are positively selected by host molecules such as intercellular adhesion molecule 1 (ICAM1) and CD36 and dominate in the absence of an effective immune response. Here, we assessed, in 115 Kenyan children, the potential role played by in vivo selection pressures in either favoring or selecting against VSA(FoRH) among parasites that cause malaria. METHODS: We tested for associations between VSA(FoRH) and (1) the repertoire of VSA antibodies carried by children at the time of acute malaria and (2) polymorphisms in ICAM1 (K29M) and CD36 (T188G) that could potentially reduce the positive selection of VSA(FoRH). RESULTS: An expected negative association between VSA antibody repertoire and VSA(FoRH) was observed in children with nonsevere malaria. However, this association did not extend to children with severe malaria, many of whom apparently had well-developed VSA antibody responses despite being infected by parasites expressing VSA(FoRH). There was no evidence for involvement of CD36 or ICAM1 in positive selection of VSA(FoRH). On the contrary, a weak positive association between carriage of the CD36 (T188G) allele and VSA(FoRH) was observed in children with severe malaria. CONCLUSION: The association between the VSA(FoRH) parasite phenotype and severe malaria cannot be explained simply in terms of the total repertoire of VSA antibodies carried at the time of acute disease.

Amino Acid Substitution↗

PubMed2004

Protection against clinical malaria by heterologous immunoglobulin G antibodies against malaria-infected erythrocyte variant surface antigens requires interaction with asymptomatic infections.

Erythrocytes infected with mature stages of Plasmodium falciparum express variant surface antigens (VSAs) of parasite origin, including P. falciparum erythrocyte membrane protein 1. Anti-VSA antibodies protect against clinical malaria caused by parasites bearing VSAs to which they are specific (homologous), but their role in protecting against heterologous infection is unclear. Here, we report that, among 256 Kenyan children involved in a 1-year active case surveillance study, asymptomatic parasitemia was associated with an enlarged repertoire of anti-VSA immunoglobulin G (IgG) antibodies specific to apparently heterologous parasite isolates, as measured by flow cytometry. Together, asymptomatic infection and anti-VSA IgG were associated with reduced odds of experiencing an episode of clinical malaria during follow-up, whereas, independently, they were associated with increased susceptibility. These results support previous findings and underline the importance of considering the parasitological status of study participants when examining the role that immune responses to VSAs and other malaria antigens play.

Animals↗

PubMed2004

Transient cross-reactive immune responses can orchestrate antigenic variation in malaria.

The malaria parasite Plasmodium falciparum has evolved to prolong its duration of infection by antigenic variation of a major immune target on the surface of the infected red blood cell. This immune evasion strategy depends on the sequential, rather than simultaneous, appearance of immunologically distinct variants. Although the molecular mechanisms by which a single organism switches between variants are known in part, it remains unclear how an entire population of parasites within the host can synchronize expression to avoid rapidly exhausting the variant repertoire. Here we show that short-lived, partially cross-reactive immune responses to parasite-infected erythrocyte surface antigens can produce a cascade of sequentially dominant antigenic variants, each of which is the most immunologically distinct from its preceding types. This model reconciles several previously unexplained and apparently conflicting epidemiological observations by demonstrating that individuals with stronger cross-reactive immune responses can, paradoxically, be more likely to sustain chronic infections. Antigenic variation has always been seen as an adaptation of the parasite to evade host defence: we show that the coordination necessary for the success of this strategy might be provided by the host.

Age Distribution↗

PubMed2004

The use of cryopreserved mature trophozoites in assessing antibody recognition of variant surface antigens of Plasmodium falciparum-infected erythrocytes.

Mature stages of Plasmodium falciparum insert variant antigens (VSA) into the surface of infected erythrocytes, and antibodies against such antigen provide variant-specific protection against malaria. Because mature P. falciparum trophozoites normally sequester away from the peripheral circulation, parasites for anti-VSA antibody studies are obtained from patients as ring trophozoites, cryopreserved, and cultured to maturity when required. However, this process is associated with problems of poor recovery from cryopreservation, growth failure and variations in time different isolates take to mature after recovery. We therefore assessed the use of cryopreserved mature trophozoites in anti-VSA assays. Cryopreservation of parasites did not alter their anti-VSA antibody reactivity phenotype as determined by agglutination assays or flow cytometry. We have therefore demonstrated that cryopreserved mature trophozoites are suitable for use in anti-VSA antibody assays. The use of cryopreserved mature trophozoites could help to circumvent the problems associated with recovery of cryopreserved ring trophozoites.

Agglutination↗

PubMed2002

Plasmodium falciparum infections are associated with agglutinating antibodies to parasite-infected erythrocyte surface antigens among healthy Kenyan children.

Antibodies to the highly diverse variant surface antigens (VSAs) expressed on Plasmodium falciparum-infected erythrocytes are thought to play a role in the development of naturally acquired immunity to malaria. It has been suggested that children gradually acquire immunity through the piecemeal acquisition of antibodies to a large number of VSAs over several years of exposure. However, in a cross-sectional survey of Kenyan children before the malaria-transmission season, the proportion of children with antibodies recognizing randomly sampled VSAs was found to be strikingly higher among children with microscopically detectable P. falciparum infection, compared with those without detectable infection. We suggest that parasitization status may be an important consideration in longitudinal assessments of the protective role of some anti-parasite immune responses and support this suggestion with data from a prospective study of VSA antibodies in a group of children who subsequently had severe malaria.

Agglutination Tests↗

PubMed2002

The role of antibodies to Plasmodium falciparum-infected-erythrocyte surface antigens in naturally acquired immunity to malaria.

Plasmodium falciparum, the most virulent species of human malaria parasite, causes 1-3 million deaths per year. Because this parasite is susceptible to naturally acquired host immunity the main burden of diseases falls on young children. The mechanism of this immunity is still unclear. However, the parasite makes a considerable investment in the insertion of highly polymorphic antigens (parasite-infected-erythrocyte surface antigens, PIESA) on the infected erythrocyte surface, and these antigens are potentially important immune targets.

Animals↗

PubMed2002

Naturally acquired immunoglobulin (Ig)G subclass antibodies to crude asexual Plasmodium falciparum lysates: evidence for association with protection for IgG1 and disease for IgG2.

There is longstanding evidence for a role of immunoglobulin (Ig)G in protection against malarial disease and infection. IgG1 and IgG3 have been shown to be particularly efficient at associating with monocytes in potentially protective mechanisms (i.e. antibody-dependent cellular inhibition, opsonization and phagocytosis). Conversely, there is some evidence that IgG2 (and possibly IgG4) antibodies may be antagonistic to this protection. The protective effect of IgG subclass antibody activity present before the beginning of a malaria transmission season (preseason antibody levels) against severe malaria has not been tested in longitudinal studies. We measured IgG class and subclass antibody levels specific to crude Plasmodium falciparum lysates by enzyme linked immunosorbent assay in a case-control study of 76 children on the coast of Kenya. The mean optical density values for both IgG class and subclass antibodies were not significantly different between the children who developed severe malaria and those who remained healthy during an observation period of two malaria transmission seasons. However, elevated levels of IgG1 in relation to levels of IgG2 and IgG4 antibodies were associated with protection from severe malaria (P = 0.02). Conversely, elevated levels of IgG2 in relation to IgG1 and IgG3 antibodies were associated with a higher risk of developing severe malaria (P = 0.006).

Animals↗