Walter and Eliza Hall Institute of Medical Research

About: Walter and Eliza Hall Institute of Medical Research is a nonprofit organization based out in Melbourne, Victoria, Australia. It is known for research contribution in the topics: Antigen & Immune system. The organization has 5012 authors who have published 10620 publications receiving 873561 citations.

The genome of the simian and human malaria parasite Plasmodium knowlesi

Abstract: Plasmodium knowlesi is an intracellular malaria parasite whose natural vertebrate host is Macaca fascicularis (the 'kra' monkey); however, it is now increasingly recognized as a significant cause of human malaria, particularly in southeast Asia. Plasmodium knowlesi was the first malaria parasite species in which antigenic variation was demonstrated, and it has a close phylogenetic relationship to Plasmodium vivax, the second most important species of human malaria parasite (reviewed in ref. 4). Despite their relatedness, there are important phenotypic differences between them, such as host blood cell preference, absence of a dormant liver stage or 'hypnozoite' in P. knowlesi, and length of the asexual cycle (reviewed in ref. 4). Here we present an analysis of the P. knowlesi (H strain, Pk1(A+) clone) nuclear genome sequence. This is the first monkey malaria parasite genome to be described, and it provides an opportunity for comparison with the recently completed P. vivax genome and other sequenced Plasmodium genomes. In contrast to other Plasmodium genomes, putative variant antigen families are dispersed throughout the genome and are associated with intrachromosomal telomere repeats. One of these families, the KIRs, contains sequences that collectively match over one-half of the host CD99 extracellular domain, which may represent an unusual form of molecular mimicry.

The follicular dendritic cell: long term antigen retention during immunity.

Abstract: The obligatory need for antigen in the induction of a specific immune response has long been recognized. However, much less in known about the possible continuing requirement for antigen for the maintenance of adequate levels of immunity. If immunity is to be protective, the maintenance of an adequate level of immunity, cellular and/or humoral, is as important as is its induction. There is a vast body of evidence demonstrating that once a satisfactory degree of immunity has been produced, it tends to be maintained by the continued production of antibody as well as by a well developed capacity to respond rapidly and accurately to a fresh antigenic challenge. In humoral immunity it has long been known that antibody levels can be maintained for very long periods even in the absence of fresh exogenous immunogenic stimulation. The possible role of retained antigen in regular restimulation of specific memory cells has been postulated and it has been suggested that small quantities of antigen are retained as antigen-antibody complexes at certain strategic sites such as lymphoid organs (Graf & Uhr 1969, Bystryn et al. 1970, 1971, Kitces et al.

Open Source Drug Discovery with the Malaria Box Compound Collection for Neglected Diseases and Beyond.

Abstract: A major cause of the paucity of new starting points for drug discovery is the lack of interaction between academia and industry. Much of the global resource in biology is present in universities, whereas the focus of medicinal chemistry is still largely within industry. Open source drug discovery, with sharing of information, is clearly a first step towards overcoming this gap. But the interface could especially be bridged through a scale-up of open sharing of physical compounds, which would accelerate the finding of new starting points for drug discovery. The Medicines for Malaria Venture Malaria Box is a collection of over 400 compounds representing families of structures identified in phenotypic screens of pharmaceutical and academic libraries against the Plasmodium falciparum malaria parasite. The set has now been distributed to almost 200 research groups globally in the last two years, with the only stipulation that information from the screens is deposited in the public domain. This paper reports for the first time on 236 screens that have been carried out against the Malaria Box and compares these results with 55 assays that were previously published, in a format that allows a meta-analysis of the combined dataset. The combined biochemical and cellular assays presented here suggest mechanisms of action for 135 (34%) of the compounds active in killing multiple life-cycle stages of the malaria parasite, including asexual blood, liver, gametocyte, gametes and insect ookinete stages. In addition, many compounds demonstrated activity against other pathogens, showing hits in assays with 16 protozoa, 7 helminths, 9 bacterial and mycobacterial species, the dengue fever mosquito vector, and the NCI60 human cancer cell line panel of 60 human tumor cell lines. Toxicological, pharmacokinetic and metabolic properties were collected on all the compounds, assisting in the selection of the most promising candidates for murine proof-of-concept experiments and medicinal chemistry programs. The data for all of these assays are presented and analyzed to show how outstanding leads for many indications can be selected. These results reveal the immense potential for translating the dispersed expertise in biological assays involving human pathogens into drug discovery starting points, by providing open access to new families of molecules, and emphasize how a small additional investment made to help acquire and distribute compounds, and sharing the data, can catalyze drug discovery for dozens of different indications. Another lesson is that when multiple screens from different groups are run on the same library, results can be integrated quickly to select the most valuable starting points for subsequent medicinal chemistry efforts.