Glycobiology and Malaria Parasite Biology

The Glycobiology and Malaria Parasite Biology research group, led by Dr Luis Izquierdo at the Barcelona Institute for Global Health (ISGlobal), focuses on the glycobiology of Plasmodium falciparum, the parasite responsible for malaria. The group explores the molecular intricacies of glycan biosynthesis and modifications in P. falciparum to identify new therapeutic, diagnostic, and vaccine opportunities. Glycans, carbohydrate chains ubiquitous on cell surfaces, play critical roles in parasite biology, including survival, virulence, immune evasion, and host-pathogen interactions.

Understanding these processes at a molecular level is pivotal to the group’s mission of disrupting the parasite's life cycle and uncovering innovative targets for antimalarial interventions. Their work delves deeply into the biology of parasite glycosylation, a process central to the modification of proteins and lipids, which shapes the parasite’s ability to survive, infect its host and evade the immune response.

Research Lines

The team’s efforts are structured around three key areas:

1. Parasite Glycobiology: Investigating the synthesis and biological function of glycoconjugates, such as glycosylphosphatidylinositol (GPI) anchors, which are critical for protein anchoring and parasite survival. Over 30 GPI-anchored proteins and free GPIs in P. falciparum are essential for virulence and pathogenesis, underscoring the potential of the biosynthetic route as a source of therapeutic targets.
2. Drug Target Validation: Identifying and validating enzymes and pathways essential for glycan biosynthesis, such as the Hexosamine Biosynthetic Pathway (HBP). A notable discovery is ApiGNA1, a parasite-specific enzyme with significant differences from its counterpart in humans, making it a promising target for selective antimalarial drugs.
3. Immune Responses to Glycans and Their Implications for Vaccine Design: Evaluating the impact of parasite glycans on immune responses and vaccine-related antigens. For instance, glycan modifications may influence protein antigenicity potentially impacting immune recognition. Recent studies also highlight the protective role of anti-α-gal antibodies, which exhibit cytotoxic effects on P. falciparum sporozoites and may hold promise for developing conjugate vaccines targeting malaria.

Current Focus and Impact

The group’s work has described the biosynthesis and roles of glycosylation precursors across various parasite life stages, advancing the understanding of P. falciparum biology. Key findings highlight the critical role of pathways like the HBP and N-glycosylation in the survival of the asexual blood stages of P. falciparum, which are responsible for the clinical symptoms of malaria. Moreover, ongoing research is extending these insights to explore the significance of these pathways in other essential stages of the parasite's complex life cycle, such as the transmission and liver stages, to uncover additional vulnerabilities.

Additionally, the team collaborates nationally and internationally and employs multidisciplinary approaches, combining glycobiology, enzymology, genetics, and immunology. By bridging fundamental research with applied science, they aim to translate their discoveries into practical solutions, such as novel antimalarials, diagnostic tools, and vaccines.

In summary, the group’s pioneering efforts in parasite glycobiology and related processes illuminate critical aspects of P. falciparum biology, driving the development of innovative strategies to combat malaria. Their research could lay the foundation for breakthroughs in addressing one of the world’s most challenging infectious diseases.

Collaborations

• Institute of Biocomputation and Physics of Complex Systems (BIFI), University of Zaragoza, Spain: Ramón Hurtado-Guerrero
• Department of Parasitology, Institute of Biomedical Sciences of the University of São Paulo, Brazil: Alejandro M Katzin
• Department of Biochemistry and Molecular Biology and Huck Center for Malaria Research, Pennsylvania State University, USA: Manuel Llinás
• Laboratory of Biochemistry, Institut Químic de Sarrià, Spain: Antoni Planas
• Biomedical Sciences Research Complex (BSRC), University of St Andrews, UK: Terry K Smith
• Institute for Systems Biology, Seattle, Washington, USA: Kristian E. Swearingen
• Center for Tropical and Emerging Global Diseases, University of Georgia, USA: Vasant Muralidharan

Publications from 2023 and 2024

• Alberione MP, González-Ruiz V, Rudaz S, Soldati-Favre D, Izquierdo L, Kloehn J. N-acetylglucosamine supplementation fails to bypass the critical acetylation of glucosamine-6-phosphate required for Toxoplasma gondii replication and invasion. Plos Pathogens. 2024 Jun 20;20(6):e1011979. 10.1371/journal.ppat.1011979
• Aguilar R, Jiménez A, Santano R, Vidal M, Maiga-Ascofare O, Strauss R, Bonney J, Agbogbatey M, Goovaerts O, Boham EEA, Adu EA, Cuamba I, Ramírez-Morros A, Dutta S, Angov E, Zhan B, Izquierdo L, Santamaria P, Mayor A, Gascón J, Ruiz-Comellas A, Molinos-Albert LM, Amuasi JH, Awuah AA, Adriaensen W, Dobaño C, Moncunill G. Malaria and other infections induce polyreactive antibodies that impact SARS-CoV-2 seropositivity estimations in endemic settings. Journal of Medical Virology. 2024. Jun;96(6):e29713. 10.1002/jmv.29713
• Jairoce C, Macià D, Torres-Yaguana JP, Mayer L, Vidal M, Santano R, Hurtado-Guerrero R, Reiter K, Narum DL, Lopez-Gutierrez B, Hamerly T, Sacarlal J, Aguilar R, Dinglasan RR, Moncunill G, Izquierdo L, Dobaño C. RTS,S/AS02A Malaria Vaccine-Induced IgG Responses Equally Recognize Native-Like Fucosylated and Nonfucosylated Plasmodium falciparum Circumsporozoite Proteins. The Journal of Infectious Disseases. 2024 Mar 14;229(3):795-799. 10.1093/infdis/jiad471
• Martín Pérez C, Aguilar R, Jiménez A, Salmerón G, Canyelles M, Rubio R, Vidal M, Cuamba I, Barrios D, Díaz N, Santano R, Serra P, Santamaria P, Izquierdo L, Trilla A, Vilella A, Barroso S, Tortajada M, García-Basteiro AL, Moncunill G, Dobaño C. Correlates of protection and determinants of SARS-CoV-2 breakthrough infections 1 year after third dose vaccination. BMC Medicine. 2024 Mar 8;22(1):103. 10.1186/s12916-024-03304-3
• Crispim M, Verdaguer IB, Hernández A, Kronenberger T, Fenollar À, Yamaguchi LF, Alberione MP, Ramirez M, de Oliveira SS, Katzin AM, Izquierdo L. Beyond the MEP Pathway: A novel kinase required for prenol utilization by malaria parasites. PLoS Pathogens. 2024 Jan 26;20(1):e1011557. 10.1371/journal.ppat.1011557
• Natama HM, Moncunill G, Vidal M, Rouamba T, Aguilar R, Santano R, Rovira-Vallbona E, Jiménez A, Somé MA, Sorgho H, Valéa I, … Izquierdo L, Mens PF, Schalling HDFH, Tinto H, Rosanas-Urgell A, Dobaño C. Associations between prenatal malaria exposure, maternal antibodies at birth, and malaria susceptibility during the first year of life in Burkina Faso. Infection and Immunity. 2023 Oct 17;91(10):e00268-23. 10.1128/iai.00268-23
• Izquierdo L. The glycobiology of plasmodium falciparum: New approaches and recent advances. Biotechnology Advances. 2023 Sept;66:108178. 10.1016/j.biotechadv.2023.108178
• Kogevinas M, Karachaliou M, Espinosa A, Aguilar R, Castaño-Vinyals G, Garcia-Aymerich J, Carreras A, Cortés B, … Izquierdo L, Cirach M, Nieuwenhuijsen M, Dadvand P, Straif K, Moncunill G, de Cid R, Dobaño C, Tonne C. Long-Term Exposure to Air Pollution and COVID-19 Vaccine Antibody Response in a General Population Cohort (COVICAT Study, Catalonia). Environmental Health Perspectives. 2023 Apr;131(4):047001. 10.1289/EHP11989
• Aguilar R, Li X, Crowell CS, Burrell T, Vidal M, Rubio R, Jiménez A… Izquierdo L, Tortajada M, Angulo A, Soutschek E, Engel P, García-Basteiro A, Busch DH, Moncunill G, Protzer U, Dobaño C, Gerhard M. RBD-Based ELISA and Luminex Predict Anti-SARS-CoV-2 Surrogate-Neutralizing Activity in Two Longitudinal Cohorts of German and Spanish Health Care Workers. Microbiology Spectrum. 2023 Jan:e03165-22. 10.1128/spectrum.03165-22