Geoffrey I Mcfadden

• BSc (Hons), PhD
• Professor (Full) at University of Melbourne

Vaccination with radiation-attenuated sporozoites (RAS) can provide highly effective protection against malaria in both humans and mice. To extend understanding of malaria immunity and inform the development of future vaccines, we studied the protective response elicited by this vaccine in C57BL/6 mice. We reveal that successive doses of Plasmodium...

Plasmodium falciparum causes most malaria deaths. Its developmental transitions and environmental adaptation are partially regulated by epigenetic mechanisms. Plasmodium falciparum GCN5 (PfGCN5) is an epigenetic regulator that acetylates lysines and can also bind to acetylated lysine residues on histones via its bromodomain (BRD). Here, we showed t...

Pathogenic protists are responsible for many diseases that significantly impact human and animal health across the globe. Almost all protists possess mitochondria or mitochondrion-related organelles, and many contain plastids. These endosymbiotic organelles are crucial to survival and provide well-validated and widely utilised drug targets in paras...

Dendritic cells (DC) are pivotal for initiating adaptive immunity, a process triggered by the activation of DC via pathogen products or damage. Here, we describe an additional layer to this process, essential when pathogen-derived signals alone cannot directly achieve full DC activation. Immunisation with sporozoites from Plasmodium leads to CD8 T...

Vaccination with radiation-attenuated sporozoites (RAS) can provide highly effective protection against malaria in both humans and mice. To extend understanding of malaria immunity and inform the development of future vaccines, we studied the protective response elicited by this vaccine in C57BL/6 mice. We reveal that successive doses of Plasmodium...

With resistance to most antimalarials increasing, it is imperative that new drugs are developed. We previously identified an aryl acetamide compound, MMV006833 (M-833), that inhibited the ring-stage development of newly invaded merozoites. Here, we select parasites resistant to M-833 and identify mutations in the START lipid transfer protein (PF3D7...

Antimalarials are now used in combination with partner drugs to stem parasite drug resistance. Partners are often older, safe, cheap drugs, but resistance is already circulating for many, which raises the risk of selecting for multidrug resistance. If the partner drug(s) could be refractory to the spread of resistance, better resistance control cou...

With resistance to most antimalarials increasing, it is imperative that new antimalarial drugs are developed to replace or complement front-line artemisinin therapies. We: bioRxiv preprint previously identified an aryl acetamide compound, MMV006833 (M-833), that inhibited ring development of newly invaded merozoites. Here, we selected parasites res...

Malaria is caused by Plasmodium species transmitted by Anopheles mosquitoes. Following a mosquito bite, Plasmodium sporozoites migrate from skin to liver, where extensive replication occurs, emerging later as merozoites that can infect red blood cells and cause symptoms of disease. As liver tissue-resident memory T cells (Trm cells) have recently b...

With emerging resistance to frontline treatments, it is vital that new antimalarial drugs are identified to target Plasmodium falciparum. We have recently described a compound, MMV020291, as a specific inhibitor of red blood cell (RBC) invasion, and have generated analogues with improved potency. Here, we generated resistance to MMV020291 and perfo...

The symbiotic partnership between corals and dinoflagellate algae is crucial to coral reefs. Corals provide their algal symbionts with shelter, carbon dioxide and nitrogen. In exchange, the symbiotic algae supply their animal hosts with fixed carbon in the form of glucose. But how glucose is transferred from the algal symbiont to the animal host is...

Tissue resident memory T cells (TRM cells) can provide effective tissue surveillance and can respond rapidly to infection. Vaccination strategies aimed at generating TRM cells have shown promise against a range of pathogens. We have previously shown that the choice of adjuvant critically influences CD8+ TRM cell formation in the liver. However, the...

Introduction The spread of artemisinin resistant Plasmodium falciparum parasites is of global concern and highlights the need to identify new antimalarials for future treatments. Azithromycin, a macrolide antibiotic used clinically against malaria, kills parasites via two mechanisms: ‘delayed death’ by inhibiting the bacterium-like ribosomes of the...

With emerging resistance to frontline treatments, it is vital that new antimalarial drugs are identified to target Plasmodium falciparum . We have recently described a compound, MMV020291, as a specific inhibitor of red blood cell invasion, and have generated analogues with improved potency. Here, we identify actin and profilin as putative targets...

Malaria parasites are diheteroxenous, requiring two hosts-a vertebrate and a mosquito-to complete their life cycle. Mosquitoes are the definitive host where malaria parasite sex occurs, and vertebrates are the intermediate host, supporting asexual amplification and more significant geographic spread. In this review, we examine the roles of a single...

Self-adjuvanting vaccines consisting of peptide epitopes conjugated to immune adjuvants are a powerful way of generating antigen-specific immune responses. We previously showed that a Plasmodium-derived peptide conjugated to a rearranged form of α-galactosylceramide (α-GalCer) could stimulate liver-resident memory T (TRM) cells that were effective...

Chromerids are a group of alveolates, found in corals, that show peculiar morphological and genomic features. These organisms are evolutionary placed in-between symbiotic dinoflagellates and parasitic apicomplexans. There are two known species of chromerids: Chromera velia and Vitrella brassicaformis. Here, the biochemical composition of C. velia c...

Malaria is a devastating parasitic disease caused by parasites from the genus Plasmodium. Therapeutic resistance has been reported against all clinically available antimalarials, threatening our ability to control the disease and therefore there is an ongoing need for the development of novel antimalarials. Towards this goal, we identified the 2-(N...

The algal cell wall is an important cellular component that functions in defense, nutrient utilization, signaling, adhesion, and cell‐cell recognition — processes important in the cnidarian–dinoflagellate symbiosis. The cell wall of symbiodiniacean dinoflagellates is not well characterized. Here, we present a method to isolate cell walls of Symbiod...

Symbiodiniaceae algae are often photosymbionts of reef-building corals. The establishment of their symbiosis resembles a microbial infection where eukaryotic pattern recognition receptors (e.g. lectins) are thought to recognize a specific range of taxon-specific microbial-associated molecular patterns (e.g. glycans). The present study used the sea...

Thorough understanding of the role of CD4 T cells in immunity can be greatly assisted by the study of responses to defined specificities. This requires knowledge of Plasmodium-derived immunogenic epitopes, of which only a few have been identified, especially for the mouse C57BL/6 background. We recently developed a TCR transgenic mouse line, termed...

A highly protective vaccine will greatly facilitate achieving and sustaining malaria elimination. Understanding mechanisms of antibody-mediated immunity is crucial for developing vaccines with high efficacy. Here, we identify key roles in humoral immunity for Fcγ-receptor (FcγR) interactions and opsonic phagocytosis of sporozoites. We identify a ma...

Malaria is still one of the most important global infectious diseases. Emergence of drug resistance and a shortage of new efficient antimalarials continue to hamper a malaria eradication agenda. Malaria parasites are highly sensitive to changes in the redox environment. Understanding the mechanisms regulating parasite redox could contribute to the...

Malaria remains a major cause of mortality in the world and an efficient vaccine is the best chance of reducing the disease burden. Vaccination strategies for the liver stage of disease that utilise injection of live radiation‐attenuated sporozoites (RAS) confer sterile immunity, which is mediated by CD8⁺ memory T cells, with liver‐resident memory...

Background Resistance to front-line antimalarials (artemisinin combination therapies) is spreading, and development of new drug treatment strategies to rapidly kill Plasmodium spp. malaria parasites is urgently needed. Azithromycin is a clinically used macrolide antibiotic proposed as a partner drug for combination therapy in malaria, which has als...

The antibiotic actinonin kills malaria parasites (Plasmodium falciparum) by interfering with apicoplast function. Early evidence suggested that actinonin inhibited prokaryote-like post-translational modification in the apicoplast; mimicking its activity against bacteria. However, Amberg Johnson et al. (2017) identified the metalloprotease TgFtsH1 a...

The antibiotic actinonin kills malaria parasites (Plasmodium falciparum) by interfering with apicoplast function. Early evidence suggested that actinonin inhibited prokaryote-like post-translational modification in the apicoplast; mimicking its activity against bacteria. However, Amberg Johnson et al. (2017) identified the metalloprotease TgFtsH1 a...

The antibiotic actinonin kills malaria parasites (Plasmodium falciparum) by interfering with apicoplast function. Early evidence suggested that actinonin inhibited prokaryote-like post-translational modification in the apicoplast; mimicking its activity against bacteria. However, Amberg Johnson et al. (2017) identified the metalloprotease TgFtsH1 a...

Liver resident-memory CD8 ⁺ T cells (T RM cells) can kill liver-stage Plasmodium -infected cells and prevent malaria, but simple vaccines for generating this important immune population are lacking. Here, we report the development of a fully synthetic self-adjuvanting glycolipid-peptide conjugate vaccine designed to efficiently induce liver T RM ce...

Malaria is still one of the most important global infectious diseases. Emergence of drug resistance and a shortage of new efficient anti-malarials continue to hamper a malaria eradication agenda. Malaria parasites are highly sensitive to changes in redox environment. Understanding the mechanisms regulating parasite redox could contribute to the des...

The antibiotic actinonin kills malaria parasites (Plasmodium falciparum) by interfering with apicoplast function. Early evidence suggested that actinonin inhibited prokaryote-like post-translational modification in the apicoplast; mimicking its activity against bacteria. However, Amberg Johnson et al. (2017) identified the metalloprotease TgFtsH1 a...

Liver resident-memory CD8+ T cells (TRM cells) can kill liver-stage Plasmodium-infected cells and prevent malaria, but simple vaccines for generating this important immune population are lacking. Here, we report the development of a fully synthetic self-adjuvanting glycolipid-peptide conjugate vaccine designed to efficiently induce liver TRM cells....

The sea anemone, Exaiptasia diaphana, previously known as Exaiptasia pallida or Aiptasia pallida, has become increasingly popular as a model for cnidarian-microbiome symbiosis studies due to its relatively rapid growth, ability to reproduce sexually and asexually, and symbiosis with diverse prokaryotes and the same microalgal symbionts (family Symb...

Apicomplexan parasites are unicellular eukaryotic pathogens that must obtain and combine lipids from both host cell scavenging and de novo synthesis to maintain parasite propagation and survival within their human host. Major questions on the role and regulation of each lipid source upon fluctuating host nutritional conditions remain unanswered. Ch...

The mutualistic symbiosis between cnidarians and photosynthetic dinoflagellates supports one of the most diverse ecosystems on the planet, coral reefs. Cnidarian-Symbiodiniaceae symbioses are broadly species-specific, but little is known about the mechanisms underpinning this specificity. Here, we explored the ability of three genotypes of the sea...

Apicomplexan parasites such as Toxoplasma gondii possess an unusual heme biosynthesis pathway whose enzymes localize to the mitochondrion, cytosol or apicoplast, a non-photosynthetic plastid present in most apicomplexans. To characterize the involvement of the apicoplast in the T. gondii heme biosynthesis pathway, we investigated the role of the ap...

Abstract Coral–dinoflagellate symbiosis underpins the evolutionary success of corals reefs. Successful exchange of molecules between the cnidarian host and the Symbiodiniaceae algae enables the mutualistic partnership. The algae translocate photosynthate to their host in exchange for nutrients and shelter. The photosynthate must traverse multiple m...

The sea anemone, Exaiptasia diaphana, commonly known as Exaiptasia pallida or Aiptasia pallida, has become increasingly popular as a model for cnidarian-microbiome symbiosis studies due to its relatively rapid growth, ability to reproduce sexually and asexually, and symbiosis with diverse prokaryotes and the same microalgal symbionts (family Symbio...

Prasinophytes (Chlorophyta) are a diverse, paraphyletic group of planktonic microalgae for which benthic species are largely unknown. Here, we report a sand‐dwelling, marine prasinophyte with several novel features observed in clonal cultures established from numerous locations around Australia. The new genus and species, which we name Microrhizoid...

Background: In multicellular organisms, alternative splicing is central to tissue differentiation and identity. Unicellular protists lack multicellular tissue but differentiate into variable cell types during their life cycles. The role of alternative splicing in transitions between cell types and establishing cellular identity is currently unknow...

Zanthoxylum zanthoxyloides, syn. Fagara zanthoxyloides, is a tree growing in West Africa and is used in traditional medicine against a variety of diseases, including malaria. In the work reported here, root bark and stem bark extracts of this tree, as well as compounds isolated from the extracts, have been investigated for activity in vitro against...

Insecticide-impregnated bed nets have saved millions from fatal malaria, but their effectiveness is waning due to mosquito insecticide resistance. A new strategy (Paton et al., Nature, 2019) to deliver parasiticidal compounds into mosquitoes to kill transmission-stage parasites could enhance the effectiveness of bed nets and get around the perennia...

Liver resident-memory CD8+ T cells (TRM cells) provide important protection against liver-stage Plasmodium infections. Here, we show that a glycolipid-peptide conjugate vaccine designed to be cleaved in vivo to release the NKT cell agonist a-galactosylceramide (a-GalCer), together with a CD8+ T cell malarial epitope, efficiently induced intrahepati...

Apicomplexan parasites are unicellular eukaryotes responsible for major human diseases including malaria and toxoplasmosis. Apicomplexan parasites must obtain and combine lipids both from host cell scavenging and de novo synthesis to maintain parasite propagation and survival within their human host. Major questions on the actual role for each lipi...

Alternative splicing is a widespread, essential, and complex component of gene regulation. Apicomplexan parasites have long been recognized to produce alternatively spliced transcripts for some genes and can produce multiple protein products that are essential for parasite growth. Recent approaches are now providing more wide-ranging surveys of the...

Apicomplexan parasites including Toxoplasma gondii and Plasmodium spp. manufacture a complex arsenal of secreted proteins used to interact with and manipulate their host environment. These proteins are organised into three principle exocytotic compartment types according to their functions: micronemes for extracellular attachment and motility, rhop...

Liver tissue-resident memory T (Trm) cells migrate throughout the sinusoids and are capable of protecting against malaria sporozoite challenge. To gain an understanding of liver Trm cell development, we examined various conditions for their formation. Although liver Trm cells were found in naive mice, their presence was dictated by antigen specific...

Plastids are key organelles in both photosynthetic and nonphotosynthetic organisms. In photosynthetic organisms, plastids can be readily purified using differential centrifugations due to the high density of photosynthetic membranes or thylakoids. The apicomplexan plastid (the apicoplast) is an essential nonphotosynthetic plastid that lacks thylako...

Significance Malaria parasites require certain host nutrients for growth and survival. In this project, we examined the role of the human vitamin biotin in all stages of the malaria life cycle. We cultured blood- and liver-stage malaria parasites in the absence of biotin and found that, whereas blood-stage replication was unaffected, liver-stage pa...

Malaria parasites alternate between intracellular and extracellular stages and successful egress from the host cell is crucial for continuation of the life cycle. We investigated egress of Plasmodium berghei gametocytes, an essential process taking place within a few minutes after uptake of a blood meal by the mosquito. Egress entails the rupture o...

Malaria parasites contain a relict plastid, the apicoplast, which is considered an excellent drug target due to its bacterial-like ancestry. Numerous parasiticidals have been proposed to target the apicoplast, but few have had their actual targets substantiated. Isopentenyl pyrophosphate (IPP) production is the sole required function of the apicopl...

We describe an MHC class II (I-A(b))-restricted TCR transgenic mouse line that produces CD4(+) T cells specific for Plasmodium species. This line, termed PbT-II, was derived from a CD4(+) T cell hybridoma generated to blood-stage Plasmodium berghei ANKA (PbA). PbT-II cells responded to all Plasmodium species and stages tested so far, including rode...

Background The clinical symptoms of malaria are caused by the asexual replication of Plasmodium parasites in the blood of the vertebrate host. To spread to new hosts, however, the malaria parasite must differentiate into sexual forms, termed gametocytes, which are ingested by a mosquito vector. Sexual differentiation produces either female or male...

The malaria-causing parasite, Plasmodium, contains a unique non-photosynthetic plastid known as the apicoplast. The apicoplast is an essential organelle bound by four membranes. Although membrane transporters are attractive drug targets, only two transporters have been characterised in the malaria parasite apicoplast membranes. We selected 27 candi...

The cryptomonad nucleomorph is a vestigial nucleus of a eukaryotic red alga engulfed by a phagotrophic protist and retained as a photosynthetic endosymbiont. This review recounts the initial discovery and subsequent characterisation of the cryptomonad nucleomorph focusing on the key role of Peter Sitte and his protégés in our understanding of secon...

Actin has important roles in Plasmodium parasites but its exact function in different life stages is not yet fully elucidated. Here we report the localization of ubiquitous actin I in gametocytes of the rodent model parasite P. berghei. Using an antibody specifically recognizing F-actin and deconvolution microscopy we detected actin I in a punctate...

Symbiosis is an evolutionary strategy that facilitates the survival of most species across a diversity of habitats. The foundation of coral reefs relies on the endosymbiosis between reef-building corals and photosynthetic dinoflagellates in the genus Symbiodinium. The algae transfer up to 95% of their photosynthate to their host, promoting coral gr...

Initial host-symbiont recognition is constituted by a complex series of inter-partner molecular signalling events, also known as winnowing stages. This study aims to investigate the first steps in the establishment of symbiosis between the coral model Exaiptasia pallida and Symbiodinium dinoflagellates, using three main approaches.

Table S1. The Full Results of the Screen Including Vector IDs, RGR Measurements, Confidence Limits, and Phenotype Calls, Related to Figure 1 The latest data are also available to browse interactively or download as a customisable CSV at http://plasmogem.sanger.ac.uk

Table S3. Genes Clustered by Location or Function, Related to Figures 2, 4, 6, and S4

Table S5. Two-Way and Three-Way Orthologs for P. berghei, T. gondii, and P. falciparum and Available Phenotype Data, Related to Figure 3

Table S2. The Data Underpinning the Comparison of Gene Properties in the Screen Compared with the Genome, Related to Figure S1

Conserved Plasmodium genes of unknown function which belong to the ookinete cluster (cluster 9), but have a barseq phenotype in asexual blood stages are highlighted and may be filtered in column L. The expression data were from RNA sequencing experiments reported by Otto et al. (2014).

The file archive includes an R-markdown document, which will reproduce all bioinformatic procedures conducted.

Table S6. Phases at which P. berghei Genes Were Gained, with Phenotyping Data, Related to Figure 5 This includes genes which are required for normal asexual blood stage growth and that belong to groups of orthologs acquired by the ancestral hematozoan, suggesting they may be important for the intraerythrocytic lifestyle of malaria parasites.

Table S8. Summary of the Phenotyping Data, Gene Identifiers, and Known or Putative Functions of the Transporters Shown in Figure 6B, Related to Figure 6

Table S7. All GO Enrichment Data Including which Genes Are Responsible for Enrichment, Related to Figures 6 and S4

The genomes of malaria parasites contain many genes of unknown function. To assist drug development through the identification of essential genes and pathways, we have measured competitive growth rates in mice of 2,578 barcoded Plasmodium berghei knockout mutants, representing >50% of the genome, and created a phenotype database. At a single stage...