Congratulations to Walter and Eliza Hall Institute scientists who have been publishing their malaria research work.
Wai-Hong Tham published a very nice story with Professor Alan Cowman, head of the institute's Infection and Immunity division, and Dr. Danny Wilson, Sash Lopaticki, Jason Corbin, Dr. Dave Richard, James Beeson and collaborators at the University of Edinburgh. The research was published in the journal Proceedings of the National Academy of Sciences and is summarised here:
Identification of a key pathway used by malaria parasites to infect human cells For decades, it has been known that malaria parasites use glycophorins as a means of entry into red blood cells. We recently identified a novel pathway which serves as the major alternative avenue for invasion that does not depend on glycophorins. This invasion pathway depends on the binding of Plasmodium falciparum parasite ligand PfRh4 to Complement Receptor 1 (CR1).
James Beesons' group has also published some work as part of their WEHI-PNGIMR:
"Isolation of viable Plasmodium falciparum merozoites to define erythrocyte invasion events and advance vaccine and drug development." Boyle MJ, Wilson DW, Richards JS, Riglar DT, Tetteh KK, Conway DJ, Ralph SA, Baum J, Beeson JG. Proc Natl Acad Sci U S A. 2010 Aug 10;107(32):14378-83.
Members from the Beeson lab, in collaboration with Baum and Ralph groups have developed a novel method for the isolation of P. falciparum merozoites at high purity and yield which maintain invasive capacity. Isolated merozoites can be utilized to test investigate invasion biology, test invasion inhibitory compounds and be fixed during invasion for microscopy studies of invasion mechanisms. This work was published in PNAS in August and it is hoped that the new isolation technique will allow a new method for malaria parasitologists to answer basic biological questions about how the P. falciparum merozoite invades and how human immune system targets this stage of the parasites life-cycle.
Richards JS, et al. 2010. "Association between naturally acquired antibodies to erythrocyte-binding antigens of Plasmodium falciparum and protection from malaria and high-density parasitemia." Clinical Infectious Diseases, 51:e50-60.
Antibodies targeting blood stage antigens are important in protection against malaria, but the principle targets remain unclear.
Erythrocyte-binding antigens (EBAs) are important erythrocyte invasion ligands used by merozoites and may be targets of protective immunity, but there are limited data examining their potential importance.
Jack Richards and his collaborators examined antibodies among 206 Papua New Guinean children who were treated with antimalarials at enrolment and observed prospectively for 6 months for reinfection and malaria. Immunoglobulin (Ig) G, IgG subclasses, and IgM to different regions of EBA175, EBA140, and EBA181 expressed as recombinant proteins were assessed in comparison with several other merozoite antigens.
High levels of IgG to each of the EBAs were strongly associated with protection from symptomatic malaria and high density parasitemia, but not with risk of reinfection per se. The predominant IgG subclasses were either IgG1 or IgG3, depending on the antigen. The predominance of
IgG1 versus IgG3 reflected structural features of specific regions of the proteins. IgG3 was most strongly associated with protection, even for those antigens that had an IgG1 predominant response. The EBAs appear important targets of acquired protective immunity. These findings support their further development as vaccine candidates.
Reiling et al, "Evidence that the erythrocyte invasion ligand PfRh2 is a target of protective immunity against Plasmodium falciparum malaria."Journal of Immunology, 2010
Antibodies targeting blood stage antigens of Plasmodium falciparum are important in acquired immunity to malaria, but major targets remain unclear. The P. falciparum reticulocyte-binding homologues (PfRh) are key ligands used by merozoites during invasion of erythrocytes. PfRh2a and PfRh2b are functionally-important members of this family and may be targets of protective immunity, but their potential role in human immunity has not been examined. We expressed eight different recombinant proteins covering the whole of the PfRh2 common region and the PfRh2a and PfRh2b-specific regions. Antibodies were measured among a cohort of 206 Papua New Guinean children who were followed prospectively for 6 months for re-infection and malaria. At baseline, antibodies were associated with increasing age and active infection. High levels of IgG to all PfRh2 protein constructs were strongly associated with protection from symptomatic malaria and high density parasitemia. The predominant IgG subclasses were IgG1 and IgG3, with little IgG2 and IgG4 detected. To further understand the significance of PfRh2 as an immune target, we analysed PfRh2 sequences and found that polymorphisms are concentrated in an N-terminal region of the protein, and appear to be under diversifying selection suggesting immune pressure. Cluster analysis grouped the sequences into 4 main groups, suggesting that many of the haplotypes identified may be antigenically similar. These findings provide evidence suggesting that PfRh2 is an important target of protective immunity in humans, and that antibodies act by controlling blood-stage paraitemia, and support its potential for vaccine development.