Our research is aimed at understanding the unique biology of the malaria parasite Plasmodium falciparum, with a particular focus on virulence and transmission.
We are investigating:
In these projects, we will use CRISPR gene editing to create transgenic malaria parasites, which we will study by combing proteomics, molecular and cellular biology techniques with super resolution microscopy to define the molecular players driving gametocyte development and transmission.
This in vitro work will be complimented by ex vivo examination of samples from experimental human malaria infection studies, which are focused on identifying and confirming the activity of candidate transmission blocking drugs and vaccines.
A combined in vitro and in vivo approach to understanding how gametocytes mature will inform the development of effective means of combating this debilitating disease.
Professor McCarthy holds a joint appointment as Director of the Victorian Infectious Diseases Service at the Royal Melbourne Hospital, and Professor of Medicine at the Doherty Institute where he leads the Translational Models of Infectious Diseases group that focusses on human infection challenge models to develop drugs and vaccines.
Australia, University of Melbourne, MBBS
Australia, University of Melbourne, MD
The Royal Melbourne Hospital
The Doherty Institute
International Fellow, American Society of Tropical Medicine and Hygiene
Fellow, Australian Academy of Health and Medical Sciences
Sornchai Looareesuwan Medal for significant achievements in malaria research
2018-22, Grant – Tropical diseases: Translating discoveries into better health, NHMRC
2018-22, Practitioner Fellowship – Translational Studies in Malaria, NHMRC
2017-22, CRE Grant, NHMRC Centre for Research Excellence in Malaria Elimination
2014-18, Support of Clinical Trial Infrastructure, Bill and Melinda Gates Foundation
2017, An innovative antimalarial treatment – Proof of Efficacy in Malaria Human Challenge Model, Wellcome Trust Translation Fund Award
Assigners Panel, NHMRC, 2018
Editorial Board, International Journal of Parasitology
1. Collins KA, Abd-Rahman AN, Marquart L, Ballard E, Gobeau N, Griffin P, Chalon S, Mohrle JJ, McCarthy JS. Antimalarial activity of artefenomel against asexual parasites and transmissible gametocytes during experimental blood-stage Plasmodium vivax infection. J Infect Dis. 2020 Jun 1;jiaa287. PMID: 32479608
2. Collins KA, Wang CY, Adams M, Mitchell H, Robinson GJ, Rampton M, Elliott S, Odedra A, Khoury D, Ballard E, Shelper TB, Lucantoni L, Avery VM, Chalon S, Moehrle JJ, McCarthy JS. A Plasmodium vivax experimental human infection model for evaluating efficacy of interventions. J Clin Invest. 2020;130(6):2920-7. PMID: 32045385
3. Prajapati SK, Ayanful-Torgby R, Pava Z, Barbeau MC, Acquah FK, Cudjoe E, Kakaney C, Amponsah JA, Obboh E, Ahmed AE, Abuaku BK, McCarthy JS, Amoah LE, Williamson KC. The transcriptome of circulating sexually committed Plasmodium falciparum ring stage parasites forecasts malaria transmission potential. Nat Commun. 2020;11(1):6159. PMID: 33268801
4. Vijay R, Guthmiller JJ, Sturtz AJ, Surette FA, Rogers KJ, Sompallae RR, Li F, Pope RL, Chan JA, de Labastida Rivera F, Andrew D, Webb L, Maury WJ, Xue HH, Engwerda CR, McCarthy JS, Boyle MJ, Butler NS. Infection-induced plasmablasts are a nutrient sink that impairs humoral immunity to malaria. Nat Immunol. 2020;21(7):790-801. PMID: 32424361
5. Watts RE, Odedra A, Marquart L, Webb L, Abd-Rahman AN, Cascales L, Chalon S, Rebelo M, Pava Z, Collins KA, Pasay C, Chen N, Peatey CL, Mohrle JJ, McCarthy JS. Safety and parasite clearance of artemisinin-resistant Plasmodium falciparum infection: A pilot and a randomised volunteer infection study in Australia. PLoS Med. 2020;17(8):e1003203. PMID: 32822347
6. Cao P, Collins KA, Zaloumis S, Wattanakul T, Tarning J, Simpson JA, McCarthy J, McCaw JM. Modeling the dynamics of Plasmodium falciparum gametocytes in humans during malaria infection. Elife. 2019 Oct 29;8:e49058. PMID: 31658944
7. Collins KA, Wang CY, Adams M, Mitchell H, Rampton M, Elliott S, Reuling IJ, Bousema T, Sauerwein R, Chalon S, Mohrle JJ, McCarthy JS. A controlled human malaria infection model enabling evaluation of transmission-blocking interventions. J Clin Invest. 2018;128(4):1551-62. PMID: 29389671
8. Rutledge GG, Bohme U, Sanders M, Reid AJ, Cotton JA, Maiga-Ascofare O, Djimde AA, Apinjoh TO, Amenga-Etego L, Manske M, Barnwell JW, Renaud F, Ollomo B, Prugnolle F, Anstey NM, Auburn S, Price RN, McCarthy JS, Kwiatkowski DP, Newbold CI, Berriman M, Otto TD. Plasmodium malariae and P. ovale genomes provide insights into malaria parasite evolution. Nature. 2017;542(7639):101-4. PMID: 28117441
9. Farid R, Dixon MW, Tilley L, McCarthy JS. Initiation of gametocytogenesis at very low parasite density in Plasmodium falciparum infection. J Infect Dis. 2017;215(7):1167-74. PMID: 28498997
The gametocyte stages of development represent a bottleneck in the malaria lifecycle with only a proportion (~10%) of the parasite population committing to sexual development.
This makes the gametocyte an attractive drug target, as disruption of gametocyte development by a drug or vaccine would stop transmission. Using a combination of in vitro and ex vivo experiments and examination of ex vivo samples from experimental malaria infection studies, we will investigate the effects these drugs and vaccines have on male and female gametocytes.
In addition, we will directly test how drug treatment affects transmission by mosquitos. The development and study of transmission-blocking drugs and vaccines will be essential in the fight to eliminate malaria.
Team member: Matthew Dixon
Gametocyte maturation and development is critical for survival within the host and disease transmission. Inhibition of this development would ablate disease transmission. This transformation sees an amoeboid-shaped asexual stage parasite morph into a banana-shaped sexual stage parasite, which is essential to disease transmission.
Despite the importance of this stage of the parasite we understand very little about its unique biology. This unique shape is driven by the assembly of a membrane complex termed the inner membrane complex and the elaboration of a dense microtubule cytoskeleton that drives the unique gametocyte shape.
In this project we are interested in determining the cellular and molecular players driving this shape change and how this influences survival within the host and mosquito transmission.
Team member: Matthew Dixon
The ability of the malaria parasite to survive within the host relies on its ability to renovate its RBC home.
This renovation is facilitated by the export of proteins into the host cell, where they modify the RBC’s properties making them rigid and prone to clearance by the spleen. To avoid clearance the parasite builds a multi-protein complex at the RBC surface called the virulence complex consisting of the knob protein KAHRP and the adhesin (PfEMP1).
We are interested in understanding how this complex is assembled and defining its molecular structure.
Team members: Matthew Dixon, Mohini Shibu