Prof James McCarthy, Lab Head | WEHI Researcher Profile

Q: Development of transmission blocking drugs

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.

Q: Going bananas for sex

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.

Q: The Renovators Dream: Malaria host cell remodelling

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.

About

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:
– How parasites renovate their RBC home to drive virulence and transmission
– How the parasite makes the banana-shaped sexual blood stage gametocyte
– How this shape helps them survive in the host and be efficiently transmitted
– How parasites behave inside the human host in vivo
– How effective specific drugs and vaccines are at blocking transmission of gametocytes from infected humans to Anopheles mosquitos.
– 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.

Education

Joint appointments

Grants and funding

Publications

Selected publications from Prof James McCarthy

Williams E, Hocking JS, Fairley CK, Chen MY, Williamson DA, McCarthy JS, Jamrozik E. Rationale and Ethical Assessment of an Oropharyngeal Gonorrhea Controlled Human Infection Model. The Journal of Infectious Diseases. 2025;231(4):10.1093/infdis/jiaf029

Hla TK, Osowicki J, Marsh JA, Salman S, Page-Sharp M, Yoo O, Azzopardi K, Morici M, Batty KT, Barr RK, Enkel SL, Kado J, Hatchuel L, Fulurija A, McCarthy JS, Snelling TL, Steer AC, Carapetis J, Manning L. Establishing the lowest penicillin concentration to prevent pharyngitis due to Streptococcus pyogenes using a human challenge model (CHIPS): a randomised, double-blind, placebo-controlled trial. The Lancet Microbe. 2025;:10.1016/j.lanmic.2024.101038

Muhi S, Schmidt S, Marshall JL, O’Brien DP, Johnson PDR, McCarthy JS, Jamrozik E, Osowicki J, Stinear TP. Perceptions of a Buruli ulcer controlled human infection model: How, who, and why?. PLOS Neglected Tropical Diseases. 2025;19(2):10.1371/journal.pntd.0012593

Abd-Rahman AN, Kaschek D, Kümmel A, Webster R, Potter AJ, Odedra A, Woolley SD, Llewellyn S, Webb L, Marquart L, Chalon S, Gaaloul ME, McCarthy JS, Möhrle JJ, Barber BE. Characterizing the pharmacological interaction of the antimalarial combination artefenomel-piperaquine in healthy volunteers with induced blood-stage Plasmodium falciparum to predict efficacy in patients with malaria. BMC Medicine. 2024;22(1):10.1186/s12916-024-03787-0

Mukhiya R, Fleischmann WA, Loughland JR, Chan J-A, de Labastida Rivera F, Andrew D, Beeson JG, McCarthy JS, Barber BE, Lopez JA, Engwerda C, Thomson-Luque R, Boyle MJ. Heterogeneity of the human immune response to malaria infection and vaccination driven by latent cytomegalovirus infection. EBioMedicine. 2024;109:10.1016/j.ebiom.2024.105419

Persson KEM, Horton JL, Kurtovic L, McCarthy JS, Anders RF, Beeson JG. Declining Antibody Affinity Over Time After Human Vaccination With a Plasmodium falciparum Merozoite Vaccine Candidate. The Journal of Infectious Diseases. 2024;230(3):10.1093/infdis/jiae259

Tully MK, Dini S, Flegg JA, McCarthy JS, Price DJ, Simpson JA. Evaluation of a Bayesian hierarchical pharmacokinetic–pharmacodynamic model for predicting parasitological outcomes in Phase 2 studies of new antimalarial drugs. Antimicrobial Agents and Chemotherapy. 2024;68(9):10.1128/aac.00863-24

Puchner KP, Bottazzi ME, Periago V, Grobusch M, Maizels R, McCarthy J, Lee B, Gaspari E, Diemert D, Hotez P. Vaccine value profile for Hookworm. Vaccine. 2024;42(19):10.1016/j.vaccine.2023.05.013

Woolley SD, Grigg MJ, Marquart L, Gower JSE, Piera K, Nair AS, Amante FM, Rajahram GS, William T, Frazer DM, Chalon S, McCarthy JS, Anstey NM, Barber BE. Longitudinal changes in iron homeostasis in human experimental and clinical malaria. EBioMedicine. 2024;105:10.1016/j.ebiom.2024.105189

Muhi S, Buultjens AH, Porter JL, Marshall JL, Doerflinger M, Pidot SJ, O’Brien DP, Johnson PDR, Lavender CJ, Globan M, McCarthy J, Osowicki J, Stinear TP. Mycobacterium ulcerans challenge strain selection for a Buruli ulcer controlled human infection model. PLOS Neglected Tropical Diseases. 2024;18(5):10.1371/journal.pntd.0011979