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Infection and Immunity cquired immunity2


Infection and Immunity cquired immunity2

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									         Infection and Immunity
                               Malaria and Leishmaniasis are two parasitic diseases that infect more than
                               15% of humanity. Children are particularly vulnerable. Drug resistance to
                               both diseases is increasing, so our goal is to improve methods of
                               preventing and treating these diseases by understanding the parasite’s
                               basic mechanisms of immunology, cell biology and genetics. The successful
                               development of vaccines and novel chemotherapeutic treatments hinges
                               on our deeper knowledge of these key determinants of the outcome of
                               the relationship between the host and the invasive organism. Our ability
                               to understand and affect disease outcomes in patients with malaria was
                               greatly increased with the appointment of James Beeson, a public health
                               physician and scientist with extensive experience in malarial countries
                               such as Kenya and Malawi. Through a collaborative project with The
                               National Institute for Malaria, Parasitology and Entomology (NIMPE) in
                               Vietnam, our Division and Medicine at The University of Melbourne also
                               provides expertise and staff training in laboratory protocols in Hanoi, and
                               helps with field studies in several provinces. The project has achieved its
                               first year goals and continues to provide valuable data on drug resistance,
                               as well as strengthening NIMPE’s capacity for research and surveillance
                               activities. Central to our activities is the identification of parasite proteins
                               essential for the organism’s survival or pathogenesis in the host. These are
                               possible drug targets. Analysis of GDP-Mannose Pyrophosphorylase
                               (GDP-PM) from leishmania shows that deletion of the gene that encodes
                               it results in an avirulent organism that does not cause disease in mice. Its
                               expression and crystallisation is a first step towards the development of
                               new anti-leishmanial treatments. Similarly for malaria, we have shown that
                               the Serine-rich antigen (SERA) is not only essential for the parasite’s
                               growth in human red blood cells but also that it is a protease. The
                               expression of an active domain of this enzyme is a precursor to
     Research Focus            development of inhibitors that lead to antimalarial drug development. To
                               understand how the parasites cause disease in humans we must determine
     Functional genomics       the events contributing to death in the case of malaria. We identified
     Pathogenesis of disease   changes in the expression of 30,000 mouse genes after malarial infection.
                               Distinct subsets of host genes are expressed differently due to infection
     Acquired immunity         and this may underlie the development of malarial syndromes such as
                               anemia, metabolic dysregulation and the inflammatory cascade.
     Parasite cell biology

                                                             From left:
                                                             Dr Louis Schofield, Dr Brendan Crabb, Dr Emanuela Handman,
                                                             Dr James Beeson, Professor Alan Cowman (Head)

                                       The Walter and Eliza Hall Institute of Medical Research Annual Report 2003 • 2004

Functional Genomics

Position effect variegation and perinuclear compartmentalisation are linked to regulation of subtelomeric
virulence genes in Plasmodium falciparum
MT Duraisingh, TS Voss, AJ Marty, JK Thompson, RT Good, BS Crabb and AF Cowman, in collaboration with M Duffy (Medicine, The
University of Melbourne)
The malaria parasite Plasmodium falciparum undergoes antigenic    consequently, as there could be up to seven chromosome ends
variation to evade host responses through switching expression    per cluster, this would bring a number of var genes within this
of variant surface proteins encoded by the var gene family. domain. Even if only one chromosome end occupied the “active
The var gene family is located in the subtelomeric regions of     site”, because multiple var genes are often present on the one
the 14 chromosomes. The overall structure of P falciparum         end, it would be important to have additional tiers of regulation
chromosome ends is highly conserved with distinct blocks of       to ensure mutually exclusive expression and this is consistent
repeated DNA defined as telomere associated repeat elements       with maintenance of the silent state for the var gene adjacent
(TAREs) 1 to 6 found immediately internal to the telomere         to the active hDHFR locus. Current evidence suggests that var
repeat tract. Subtelomeric var genes represent the most telomere- gene non-coding regions harbour important boundary elements
proximal genes and are located directly downstream of TARE6, that may insulate them from derepressed chromatin in an active
the largest block of repeat sequences.                            compartment of the nucleus.
We have inserted a drug resistance
gene cassette adjacent to a
subtelomeric var in P falciparum and
demonstrate reversible silencing of
this gene by epigenetic mechanisms.
Transcriptional activation of the
integrated transgene is associated
with increased sensitivity of local
chromatin to nuclease digestion.
When silenced, the inserted gene
occupies a separate perinuclear
location relative to a second episomally
maintained marker of subtelomeric
expression. However, when both
genes are transcriptionally active they
colocalise at the nuclear periphery.
Using the same strategy we have
shown that a specific subtelomeric
var gene occupies distinct perinuclear
positions depending on its state of
activation. Together, this implies that
perinuclear compartmentalisation
and chromatin modification play
an important role in the epigenetic
regulation of subtelomeric virulence
genes in P falciparum.
Our data indicates that locus
repositioning of subtelomeric var
genes within the nucleus plays an
important role in transcriptional
regulation of this gene family
and maintenance of monoallelic
expression. Expression of a specific       Figure 1. Fluorescent in situ hybridisation (FISH) analysis of P falciparum parasite chromosomes. The colours
var gene would require its physical        represent a chromosome end var2CSA and a plasmid pGEM. These only come together (bottom two rows)
positioning within a nuclear domain        when they are both expressed suggesting that there is a particular location in the nucleus that is permissive for
competent for transcription and            transcription.

                                          Infection and Immunity

     Novel drugs against leishmaniasis target enzymes essential for mannose synthesis and glycosylation
     A Davis, L Kedzierski, A Hodder, J Stewart, B Smith, E Handman, in collaboration with M Perugini (Biochemistry and Molecular
     Biology, The University of Melbourne), T Ilg (Intervet Innovation GmbH, Schwabenheim, Germany)

     The current anti-Leishmania drugs, developed more than 50                      As the first step in the elucidation of the three dimensional
     years ago, are difficult to administer, and toxic, and drug                    structure of the enzyme we have generated crystals and produced a
     resistance is on the rise. We aim to develop drugs to block two                molecular model based on the structure of a bacterial homologue,
     enzymes in the mannose biosynthetic pathway, GDP-Mannose                       the N-acetyl-glucosamine-1-phosphate uridyltransferase
     Pyrophosphorylase (GDP-PM) and Phosphomannomutase                              (figure 2). Circular dichroism has revealed that it is comprised
     (PMM) which are essential for glycosylation in all eukaryotic                  of mixed α/β structures, in agreement with the model. We will
     organisms including Leishmania. Deletion of the two genes in                   use the three-dimensional structures and homology model of
     L mexicana produced avirulent organisms which were taken                       the enzyme for de novo ligand design and in silico screening of
     up by host macrophages but could not survive, suggesting that                  chemical databases. In parallel with the structural studies, we
     the inactivation of these enzymes should lead to cure. We have                 have developed enzyme assays suitable for high throughput
     produced recombinant GDP-MP and shown that its active                          screening of large chemical libraries of drug-like molecules. The
     form is a homo-hexamer that is stable at room temperature and                  two approaches should synergise to identify drug candidates and
     physiological pH.                                                              improve their functional specificity and efficacy.

     Figure 2. Three-dimensional model of the GDP-MP hexamer showing the view down the three-fold axis of the hexameric model.

     Molecular analysis of Plasmodium falciparum from                                resistance transporter (pfcrt, 76T) and multidrug resistance 1
     drug treatment failure patients in Papua New                                    (pfmdr1), were fixed in the population and two markers for
     Guinea                                                                          pyrimethamine resistance, dihydrofolate reductase (dhps) 59R
     GJ Casey, AF Cowman, in collaboration with M Ginny, M Uranoli,                  and 108N, were found at moderate to high levels, overall 60% and
     I Mueller, JC Reeder (Papua New Guinea Institute of Medical                     75%, respectively. No polymorphisms in dihydropteroate synthase
     Research), B Genton (Swiss Tropical Institute, Basel, Switzerland)              (dhps), associated with sulfadoxine resistance, were present. These
                                                                                     findings stress the need for regular monitoring of the effects of
     A study was conducted in Papua New Guinea to analyse Plasmodium
                                                                                     standard drug treatment of uncomplicated malaria in Papua New
     falciparum drug resistance genes in patients with resistant malaria.
     Two markers for 4-aminoquinoline resistance, chloroquine

                                      The Walter and Eliza Hall Institute of Medical Research Annual Report 2003 • 2004

Pathogenesis of Disease

Microarray analysis of the global transcriptional response during fatal malarial pathogenesis
AC Sexton, RT Good, DS Hansen, L Buckingham, L Schofield, with K Simpson (Genetics and Bioinfomatics)
The primary pathophysiological events contributing to malarial       previously unknown transcriptional changes in the host that
fatality are the cerebral syndrome, anaemia and metabolic            may underlie the development of malarial syndromes such as
acidosis. The molecular basis of each has been unclear. In this      anaemia, metabolic dysregulation and the inflammatory cascade.
study, microarray analysis of murine transcriptional responses       Transcriptional profiling may therefore prove useful in elucidating
during the development of severe disease revealed temporal,          causal relationships in pathogenesis and immunity. Generation
organ-specific and pathway-specific patterns. Of approximately       of appropriate clinical samples and extension into other rodent
30,000 mouse genes, 99% have homologues in humans. We                malarias will be important future steps in comparison of malarial
observed only a small minority fluctuating transcriptionally in      pathogenesis across host and parasite taxa. Microarray technology
response to malarial insult. Over 400 genes in the brain and 600     therefore greatly extends the utility of rodent malarias as models
in the spleen displayed transcriptional changes. The intensity       for infection in humans.
data for detectable transcripts from duplicate mice was very
                                                                     Figure 3. Overall results of microarray analyses of brains and spleens. A.
strongly correlated (R2 = 0.99). Dominant patterns revealed          Overall pattern of genes with changing transcript levels in brains (left panels)
strongly suppressed erythropoiesis starting at early time-points     and spleens (right panels) of infected C57BL/6 mice, compared with uninfected
during infection, and highly up-regulated transcription of genes     mice (day 0). Fold change is on the Y-axis and is plotted against time point (days
controlling host glycolysis including lactate dehydrogenase. The     0, 1, 3, and 5) on the X-axis. Blue lines, transcripts increasing (top panels) or
latter presents a mechanism that may contribute to metabolic         decreasing (lower panels) on day 1 only; green lines, changes on day 3 only; red
acidosis. No evidence for hypoxia-mediated regulation of these       lines, changes on day 5 only; aqua lines, genes that changed on day 1 and day
                                                                     3; yellow lines, genes that changed on day 3 and day 5; purple lines, genes that
events was observed, raising the question of which transcriptional
                                                                     changed on day 1 and day 5; and white lines, genes that changed on all 3 days.
pathway regulates expression of glycolytic enzymes in severe         B. Venn diagrams showing numbers of transcripts that increased and decreased,
malaria. Interferon-regulated gene transcripts dominated the         respectively, at each time point in brains and spleens. Colour scheme is as above,
inflammatory response to cytokines. These results demonstrate        except that genes that changed at all 3 days are in black instead of white.

                                                            Infection and Immunity

     Dendritic cell populations in the Leishmania major                                              A leucine rich repeat motif of Leishmania parasite
     infected skin and draining lymph nodes                                                          surface antigen-2 binds to macrophages through
     T Baldwin, J Curtis, E Handman, with M O’Keeffe, D Vremec,                                      the complement receptor 3
     with K Shortman (Immunology)                                                                    L Kedzierski, J Montgomery, D Bullen, J Curtis, E Handman, in
     Using the metacyclic promastigotes-ear infection model of                                       collaboration with E Gardiner (Monash University), A Jimenez-
     cutaneous leishmaniasis we showed that susceptible BALB/c                                       Ruiz (University of Alcala, Madrid, Spain)
     mice have similar populations of dendritic cells, but an increased                              We studied the function of two Leishmania glycoconjugates,
     number of plasmacytoid dendritic cells in the draining lymph                                    surface antigen-2 (PSA-2) and membrane proteophosphoglycan
     nodes compared to resistant C57BL/6 mice. The dendritic cells                                   (PPG) and demonstrated that a series of Leucine Rich Repeats
     emigrating from the infected skin harboured no parasites, and                                   (LRR) shared by PSA-2 and PPG bind to the mouse and the
     those in the lymph nodes did not harbour parasites until three                                  human complement receptor 3 (CR3, Mac-1) in a calcium
     weeks after infection. In contrast, from very early in infection, a                             independent manner. This is the first demonstration of a
     significant percentage of macrophages emigrating from the skin                                  functional role for PSA-2. Our data indicate that in addition to
     were infected indicating that they ferry the parasites to the lymph                             the two known ligands for host macrophages, leishmanolysin
     node where dendritic cells become infected.                                                     and lipophosphoglycan, parasite attachment and invasion of
                                                                                                     macrophages involves a third ligand comprising the LRRs shared
                                                                                                     by PSA-2 and PPG and that these interactions occur via the CR3.

     Acquired Immunity

     A specific type of functional antibodies can play a protective role against blood-stage Plasmodium
     falciparum infection in individuals in a malaria endemic area of Africa
     RA O’Donnell, TF de Koning-Ward, BS Crabb, in collaboration with CC John, AM Moormann, CL King, JW Kazura (Case Western
     Reserve University, Cleveland, OH USA), PO Sumba (Kenya Medical Research Institute, Kisian, Kenya)
      Recognition that individuals living in malaria endemic countries                               individuals were not all equally susceptible to re-infection with
      eventually become clinically immune to the disease has been a                                  P falciparum following drug cure. Using a new neutralisation
      crucial factor driving the development of anti-malarial vaccines.                              assay developed recently by our group here at WEHI that is
      Surprisingly, however, the proteins that are targets of this                                   based on use of transgenic P falciparum parasites, individuals
      clinical immunity remain poorly defined as do the mechanism                                    with high-level MSP-119 specific invasion-inhibitory antibodies
      of action of protective antibodies. One malaria protein that has                               had a significantly reduced risk of blood-stage infection relative
      received considerable attention is the C-terminal fragment of                                  to others in the population. In contrast, high levels of total
      Plasmodium falciparum merozoite surface protein 1 (MSP-119)                                    MSP-119 antibodies as measured by enzyme immunoassay with
     – a protein that has now become a leading candidate for inclusion                               four different recombinant antigens did not correlate with
      in a human malaria vaccine. To examine the potential protective                                protection from infection. These findings implicate an important
      role of antibodies to MSP-119 in persons naturally exposed to                                  protective role for MSP-119-specific invasion inhibitory antibodies
      malaria, we combined with our US and Kenyan collaborators                                      in immunity to blood-stage P falciparum infection, and suggest
      to examine targets of immunity in a highland area of western                                   that the measurement of MSP-119 specific inhibitory antibodies
      Kenya. A treatment time to infection study was performed                                       may serve as an accurate correlate of protection in clinical trials
      over a 10-week period in 76 residents. These semi-immune                                       of MSP-1-based vaccines.
                                                                                                                                   Figure 4. Neutralising but not total

                              �                                                    �                                               antibodies correlate with protection from
                                                                                                                                   re-infection with P falciparum malaria in
                              ����                                                 ����                                            a western Kenyan population. A. Time to
                                                                                                                                   P falciparum infection in individuals with

                                                                                                                                   high-level of total antibodies to MSP-119
                              ����                                                 ����
                                                                                                                                   measured (≥75th percentile) as compared
                                                                                                                                   to low-level total antibodies to PfMSP-119
                              ����                                                 ����                                            (<75th percentile). B. Time to P falciparum
                                                                                                                                   infection in individuals with high-level
                                             ��������������������������                                ��������������
                              ����                                                 ����
                                                                                                                                   neutralising antibodies (so called invasion-
                                             �������������������������                                 ��������������
                                                                                                                                   inhibitory antibodies or IIA) to MSP-119
                                                                                                                                   (≥75th percentile) as compared to low-level
                              ����                                                 ����                                            IIA to MSP-119 (<75th percentile). Panel B
                                     �   �         �         �            �   ��          �      �      �        �      �     ��   shows that far fewer individuals became re-
                                                                                                                                   infected with malaria if they possessed high
                                                                                                                                   levels of MSP-119 IIA at the time of drug
                                                                                                                                   clearance (time point 0).

                                      The Walter and Eliza Hall Institute of Medical Research Annual Report 2003 • 2004

A common function for the double EGF-like                            receptor adaptor MyD88 were much more susceptible to infection
modules of the highly divergent Plasmodium surface                   with L major than wild-types, demonstrating a central role for
proteins                                                             this pathway in control of infection, and suggesting that L major
DR Drew, RA O’Donnell, BS Crabb, with BJ Smith (Structural           possesses a ligand for Toll-like receptors. LPG, but not other
Biology)                                                             surface glycolipids, activated the innate immune system via TLR
                                                                     2. Cytokine induction by LPG required the GPI anchor. LPG also
In this study we addressed whether the diverse epidermal growth
factor (EGF)-like domains that cover the surface of the human        induced the expression of SOCS-1 and 3. Thus, Toll-like receptors
malaria parasite P falciparum are capable of performing the same     are required for resistance to L major and LPG is a Toll-like
biological function. These domains, particularly those from          receptor agonist from this protozoal pathogen.
MSP-1, are amongst the leading vaccine candidates for the control    CD1d-restricted NKT cells contribute to
of blood-stage malaria. Our data shows that the MSP-1 EGF            splenomegaly and enhance parasite-specific
domains can be functionally complemented by radically different      antibody responses in murine malaria
EGF domains. One implication of this work is that this common
                                                                     DS Hansen, M-A Siomos, T de Koning-Ward, B Crabb, L
EGF domain function may be targeted by intervention strategies.
                                                                     Buckingham, L Schofield
In this regard we identified a highly conserved pocket that may be
accessed by small molecule inhibitors.                               CD1d-restricted NKT cells contribute to malarial splenomegaly
                                                                     associated with expansion of the splenic B cell pool, and enhance
MyD88 is essential for clearance of Leishmania                       parasite-specific antibody formation, in response to Plasmodium
major: possible role for lipophosphoglycan and TLR2                  berghei infection. The increased B cell responses correlate
signalling                                                           with the ability of NKT cells to promote the development of
MJ de Veer, JM Curtis, TM Baldwin, A Sexton, E Handman,              TH2 immune responses. In addition, antibody against the GPI-
L Schofield, in collaboration with JA DiDonato (The Lerner           anchored protein Merozoite Surface Protein 1 (MSP-1) were
Research Institute, Cleveland Clinic Foundation, Cleveland, OH       found to be significantly lower in CD1–/– mice compared to wild-
USA), MJ McConville (Biochemistry and Molecular Biology, The         type animals. P berghei-infected MHCII–/– mice also generated
University of Melbourne)                                             antibodies against MSP-1, indicating that IgG production against
Glycosylphosphatidylinositol (GPI)-anchored lipophosphoglycan        GPI-anchored antigens can arise from both MHCII-dependent
(LPG) is a virulence factor of Leishmania. Mice lacking the Toll     and independent pathways during malaria infection.

    Life at WEHI.

                                             Infection and Immunity

     Parasite Cell Biology

     Evidence that the unusual protease domain of Plasmodium falciparum SERA5 functions as an active
     AN Hodder, DR Drew, M Delorenzi, SK Miller, BS Crabb, with RJ Simpson (Joint ProteomicS Laboratory), TP Speed (Genetics and
     Bioinformatics), in collaboration with VC Epa (Health Sciences and Nutrition, CSIRO, Melbourne), R Bourgon (Statistics, University of
     California, CA USA), RL Moritz, DF Frecklington, RN Pike (Biochemistry and Molecular Biology, The University of Melbourne)

     A malaria antigen known as SERA5 has long been of considerable
     interest to malaria researchers because of its very strong expression,
     its apparent important role in blood-stage development and its
     potential as a vaccine and drug target. SERA5 has an unusual
     protease domain, which in most ways is typical of the cysteine
     protease papain family but oddly possesses a serine residue in
     the catalytic position. The prospect that this protein functions
     as a protease has been contentious. Our evidence that SERA5
     retains catalytic activity provides impetus for the identification of
     inhibitors that may have potential as anti-malarial drugs. We also
     detail the evolutionary relationships of SERA family members
     and structurally model the protease domains. These data suggest
     that Plasmodium SERA proteases fall into two classes that are
     likely to have distinct biological roles.
     Figure 5. Molecular modelling reveals that SERA5 folds like a
     cysteine protease: Ribbon diagram the enzyme domains of SERA5 compared
     to caricain, a typical papain-family cysteine protease. The putative active site
     residues are depicted in stick form. In SERA5 these are appropriately positioned
     relative to one another in cleft.

     Selective inhibition of a two-step egress of malaria                               Plasmodium falciparum merozoite surface protein 6
     parasites from the host erythrocyte                                                is a dimorphic antigen
     ME Wickham, AF Cowman, in collaboration with JG Culvernor                          JA Pearce, T Triglia, AN Hodder, AF Cowman, in collaboration
     (Pathology, The University of Melbourne)                                           with DC Jackson (Microbiology and Immunology, The University
     Escape from the host erythrocyte by the invading malaria                           of Melbourne), RF Anders (Biochemistry, La Trobe University)
     parasite is a fundamental step in the course of the disease about                  Merozoite surface protein 1 (MSP1) is implicated in the invasion of
     which little is known. Having developed into 16-32 daughter                        human erythrocytes by forming a complex with MSP6 and MSP7.
     merozoites within the parasitophorous vacuole, release from the                    MSP6 contains dimorphic elements in its protein structure. The
     erythrocyte involves a primary rupture of the parasitophorous                      sequences of eight MSP6 genes indicate that the alleles of each
     vacuole membrane, followed by a secondary rupture of the                           dimorphic form of MSP6 are highly conserved. 3D7-type MSP6
     erythrocyte plasma membrane. Each step can be inhibited by                         alleles are detected in parasites from all malarious regions of the
     different protease inhibitors, implicating the involvement of                      world; K1-type MSP6 alleles have been detected in parasites from
     distinct proteases in each process. Our findings will facilitate                   SE Asia only. Cleavage of MSP6, which produces the p36 fragment
     the identification of the parasite and host molecules involved in                  in 3D7-type MSP6 and associates with MSP1, also occurs in K1-
     merozoite release.                                                                 type MSP6 but at a different site in the protein. Anti-3D7 MSP6
                                                                                        antibodies weakly inhibited erythrocyte invasion by homologous
                                                                                        3D7 merozoites but did not inhibit a parasite line expressing the
                                                                                        K1-type MSP6 allele. Antibodies from hyperimmune individuals
                                                                                        affinity purified on an MSP3 peptide cross-reacted with MSP6;
                                                                                        therefore, MSP6 may also be a target of antibody-dependent
                                                                                        cellular inhibition.

                                            The Walter and Eliza Hall Institute of Medical Research Annual Report 2003 • 2004

Strengthening malaria control and program capacity in Vietnam
J Thompson, T Triglia, A Cowman, with S Thomas (Genetics and Bioinformatics), in collaboration with B Biggs, S Caruana (Medicine,
The University of Melbourne), M Morris, B Hilton-Thorpe (Australian International Health Initiative), LD Cong, LK Thuan, NT Tien,
NV Thanh (National Institute of Malariology, Parasitology and Entomology, Hanoi, Vietnam)

We have instituted a joint program with the National Institute of
Malariology, Parasitology and Entomology (NIMPE) in Hanoi,
together with our colleagues at The University of Melbourne
and the Australian International Health Initiative, to strengthen
both research capacity and the ability to monitor drug resistance
in Vietnam. In Vietnam, half the population live in forests and
mountainous areas where they are at risk of malaria infection.
In these remote areas, there is a significant unmet need for early
and appropriate antimalarial therapy. Drug resistant malaria
has been an increasing problem since the 1980s with levels of
chloroquine resistance ranging from 41–62% and sulphadoxine-
pyrimethamine resistance from 26–100%. Widespread usage of
artemisinin and related drugs has resulted in reduced numbers of
malaria cases since 1991 but has the potential to cause resistance
and lead to a major malaria epidemic. Artesunate is widely
available from local merchants and is often used indiscriminately
                                                                           Mr Nguyen Duc Giang, NIMPE, working in the newly-equipped Hanoi
and in suboptimal dosage for the self-treatment of fever.
                                                                           laboratory, observed by Sonia Caruana, The University of Melbourne and Mr
This program has been developing over the last year and resulted           Troung van Hanh, NIMPE.
in frequent visits from NIMPE scientists to this institute for
both training and research to analyse the prevalence of drug
resistance alleles in malaria parasites in Vietnam. This and other
data analysed at NIMPE has provided important information on
malarial drug resistance in the areas under study. The aim of this
program is to use targeted field and laboratory-based analyses to
assist in informing malaria drug use policies and practices that
will, we hope, reduce morbidity and mortality.

                                                                           Ms Sonia Caruana with children from the Quang Tri District during a
                                                                           familiarisation visit in preparation for the Situational Analysis project in
                                                                           Quang Tri Province.

Training Workshop at NIMPE for regional IMPE doctors. Ms Beth Hilton-
Thorp, Australian International Health Initiative, with Dr Thanh Ngo and
Mrs Pham Thi Xuyen, NIMPE.

                                           Infection and Immunity

     Major Lectures and Exchanges                                                  Institute for Biotechnology, Sydney, 4/04, Speaker
                                                                                   HHMI International Research Fellow Conference, Tallin, Estonia, 6/04, Speaker
     Alan Cowman                                                                   Human Frontiers of Science Program Workshop, Marburg, Germany, 6/04,
     Biology of Parasitism 2003, Woods Hole, MA USA, 8/03, Lecturer                Speaker
     ComBio 2003, Melbourne, 9/03, Session Chair
     Molecular Approaches to Malaria (MAM) 2004, Lorne, Victoria, 2/04,
     2nd International Malaria Meeting, Hopkins Malaria Research Institute,        Staff List
     Baltimore, MD USA, 3/04, Speaker
                                                                                   Alan F Cowman, Division Head
     Washington University, School of Medicine, St Louis, MO USA, 3/04,
     Speaker                                                                       Marian Cravino, Administrative Officer
     Bernhard Nocht Institute for Tropical Medicine, Hamburg, Germany, 5/04,       Alan F Cowman, BSc(Hons) Griffith PhD Melb, Howard Hughes
     Speaker                                                                             International Research Scholar
                                                                                   Jacob Baum, BA(Hons) MA Oxon MSc PhD London
     WHO/TDR Symposium on “Social, economic and biological determinants
                                                                                   Quang Phuc Bui, MD Hanoi, Visiting Scientist (from 10/03 to 12/03)
     of the emergence and spread of drug and insecticide resistance”, Accra,
                                                                                   Tim-Wolf Gilberger, BBiology PhD Hamburg (to 8/03)
     Ghana, 6/04, Speaker
                                                                                   Robert Good, BSc MSc(Prelim) Mon
     HHMI International Research Fellow Conference, Tallin, Estonia, 6/04,         Julie Healer, BSc(Hons) Glasgow M Phil London PhD Edinburgh (from 7/03)
     Speaker                                                                       Ellen Knuepfer, PhD Imperial College (to 2/04)
                                                                                   Matthias Marti, MSc Basel PhD Zurich, Swiss National Science Foundation
     Brendan Crabb
     London School of Hygiene and Tropical Medicine, UK, 9/03, Speaker             Melanie Rug, PhD Heidelberg
     ComBio 2003, Melbourne, 9/03, Speaker/Session chair                           Nicole Struck, BSc(Hons) Hamburg, Visiting Scientist (from 4/04 to 6/04)
     HHMI International Research Fellow Conference, Tallin, Estonia, 6/04,         Till Voss, PhD Basel, Swiss National Science Foundation Fellow
     Speaker                                                                       Gerard Casey, BSc(Hons) Mon
                                                                                   Jennifer Thompson, BSc MSc Melb
     Emanuela Handman                                                              Tony Triglia, BSc(Hons) MSc Melb
     The Annual Scientific Meeting of the Australian Society for Parasitology,
     Darwin, 7/03, Speaker                                                         Christian Flueck, MSc Berne, Visiting Student (from 2/04)
                                                                                   Jodi Thomson, BSc Wisconsin, Visiting Scientist (from 2/04 to 6/04)
     University of California, San Francisco CA USA, 6/04, Speaker                 Janine Stubbs, BSc Tas BSc(Hons) ANU, PhD Student
     Gordon Conference, Bristol, RI USA, 6/04, Speaker                             Malaria Functional Genomics
     Louis Schofield                                                               Alexander Maier, BSc Southern Colorado PhD Heidelberg
     Centenary Institute, Sydney, 7/03, Speaker                                    Louisa McRobert, BSc Glasgow MSc Liverpool PhD Leeds, Visiting Scientist
     Human Frontiers of Science Program Workshop, Geneva, Switzerland, 9/03,           (from 2/04 to 4/04)
     Speaker                                                                       Monica Brown
                                                                                   Matthew O’Neill, BSc(Hons) Melb
     CD1 Tetramer Workshop, NIAID, Bethesda, MD USA, 1/04, Speaker
                                                                                   Brendan S Crabb, BSc(Hons) PhD Melb, Howard Hughes International
     British Society of Parasitology Autumn Symposium, UK, 3/04, Plenary               Research Scholar
     Speaker                                                                       Arlene Dent, BSc PhD MD Indiana, Visiting Scientist (from 2/04)
     New York University Vaccine Symposium, New York, NY USA, 3/04, Speaker        Paul Gilson, BSc(Hons) PhD Melb

     ACKNOWLEDGMENTS                         Hazel and Pip Appel Fund              EM Carty                                 EM Newton Estate
     The Infection and Immunity              PG Keir                               John PG Claridge Estate                  Jessie Reeves Estate
     Division acknowledges the               Overseas:                             RAM del Cott Estate                      Agnes T Robertson Estate
     generous gifts and bequests listed                                            Duncan Crawford Estate                   Stanley L Spencer Estate
                                             Human Frontier Science Program
     elsewhere in this Report and also                                             SG Cubbins Estate                        Colin Syme Fellowship Fund
                                             Organization (France)
     thanks the following organisations,                                           EJ (Ted) Darbyshire Estate               John T Tomasetti Estate
                                             Howard Hughes Medical Institute
     trusts and persons whose major                                                GC Graves Estate                         Tropical Diseases Fund
     grants supported research in this                                             Joan Henderson Estate                    Dorothy Hope Walker Estate
                                             Atlantic Philanthropies Inc.
     Division.                                                                     M Hamilton Estate                        Ita E Westcott Estate
                                             UNDP/World Bank/WHO Special
                                                                                   Olive Maye Hemphill Estate
     Australia:                              Programme for Research and
                                                                                   GAN Highton Estate
     National Health and Medical             Training in Tropical Diseases
                                                                                   EM Holmes Estate
     Research Council                        The Wellcome Trust (UK)
                                                                                   Catherine M Jackson Estate
     Australian Research Council             National Institutes of Health (USA)
                                                                                   Alexia Lyell Bequest
     Fellowships Scheme                      Income from the following Funds       Dr Ian Mackay Fellowship Fund
     Victorian State Government              also supported this Division:         Trevor Geoffrey Mansfield Estate
     Cooperative Research Centre for         JW Ballantyne Estate                  GF Mitchell Fund
     Vaccine Technology                      Jean C Burns Estate                   Edith Moffatt Scholarship Fund
     Australian Agency for International     Isabella A Brown Estate               Ida Alice Moon Estate
     Development (AusAID)                    Catherine Carlson Estate              Alan Ambrose Murray Estate

                                          The Walter and Eliza Hall Institute of Medical Research Annual Report 2003 • 2004

Doron Greenbaum, BA PhD UCSF, Visiting Scientist (from 8/03)          Staff Notes
Tania de Koning-Ward, BSc(Hons) PhD Melb
Damien Drew, BSc Mon BSc(Hons) PhD Melb, Peter Doherty Fellow
Anthony Hodder, BSc(Hons) PhD Mon                                     ARRIVALS
Markus Meissner, PhD Heidelberg, Visiting Scientist (to 7/03)         James Beeson, inaugural Miller Fellow from the Kenya Medical Research
                                                                      Institute, Kilifi, Kenya
Soula Krejany, BSc MSc Melb
                                                                      Arlene Dent, Visiting Scientist from Rainbow Babies & Children’s Hospital,
Rachel Lundie, BA/BSc(Hons) Melb, PhD Student
                                                                      Cleveland, OH USA
Joanne McCoubrie, BSc(Hons) Murdoch, PhD Student (from 2/04)
Allison Marty, BSc(Hons) Melb, Visiting PhD Student                   Christian Flueck, Visiting Scientist from the Swiss Tropical Institute, Basel,
Susanne Miller, BSc(Hons) LaT, PhD Student                            Switzerland
Paul Sanders, BSc(Hons) Melb, PhD Student                             Doron Greenbaum, Visiting Scientist from the University of California, San
Danny Wilson, BSc(Hons) NTU, PhD Student (from 2/04)                  Francisco, CA USA
James Beeson, BMedSc(Hons) MB BS(Hons) Mon PhD Melb, Miller Fellow    Julie Healer, Research Officer from the Department of Medicine, The
(from 6/04)                                                           University of Melbourne
Emanuela Handman, MSc PhD Jerusalem
Tony Davis, BSc(Hons) LaT PhD RMIT                                    DEPARTURES
Lukasz Kedzierski, BSc(Hons) PhD Mon, Peter Doherty Fellow            Quang Phuc Bui, Visiting Scientist, returned to the NIMPE, Hanoi, Vietnam
Beena Kumar, MB BS Madras MD Rohtak (to 1/04)                         Michael De Veer, Research Officer, to the Centre for Animal Biotechnology,
Christiane Radt, MB BS Germany DTMH Lond                              Department of Medicine, The University of Melbourne
Alex Uboldi, BSc(Hons) PhD Witwatersrand
                                                                      Tim-Wolf Gilberger, Research Officer, to the Bernhard Nocht Institute for
Tracey Baldwin, BAppSc RMIT                                           Tropical Medicine, Hamburg, Germany
Joan Curtis
                                                                      Ellen Knuepfer, Research Officer, to the Division of Parasitology, National
Mary Barson, BSc Melb, BSc(Hons) Student (from 2/04)                  Institute for Medical Research, UK
Jim Stewart, BSc Melb, BSc(Hons) Student (to 4/04)
                                                                      Beena Kumar, Research Officer, to the Royal Children’s and Royal Women’s
Louis Schofield, BSc MSc Lond PhD Qld, Howard Hughes International    Hospitals, Melbourne
    Research Scholar
Michael De Veer, PhD Mon (to 4/04)                                    Louisa McRobert, Visiting Scientist, returned to the London School of
Diana Hansen, BBiolSc Buenos Aires PhD Uppsala                        Hygiene & Tropical Medicine, UK
Thomas Nebl, PhD LaT                                                  Markus Meissner, Visiting Scientist, returned to the Imperial College of
Nicole Pettigrew, BAppSc(Hons) PhD RMIT (to 7/03)                     Science and Technology, London, UK
Nicholas Bernard, BA/BSc(Hons) Melb                                   Nicole Pettigrew, Research Officer, to the Royal Children’s Hospital,
John Manzi, BSc(Hons) LaT (from 7/03)                                 Melbourne
Janet Steele, BAppSc RMIT (from 8/03)
Mary-Anne Siomos, BBiolSc(Hons) LaT (to 9/03)
Marta D’Ombrain, BSc(Hons) Melb , PhD Student (from 2/04)
Krystal Evans, BSc(Hons) Wollongong, PhD Student
Catherine Nie, BSc Melb, BSc(Hons) Student (from 2/04)

                                                                      New staff and students (from left): Christian Flueck, Janet Steele,
                                                                      Doron Greenbaum, James Beeson, Danny Wilson, Julie Healer,
                                                                      Quang Phuc Bui, Arlene Dent, John Manzi


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