Modelling pathogen load dynamics to elucidate mechanistic determinants of host-Plasmodium falciparum interactions

Georgiadou, A. et al. (2019) Modelling pathogen load dynamics to elucidate mechanistic determinants of host-Plasmodium falciparum interactions. Nature Microbiology, 4, pp. 1592-1602. (doi: 10.1038/s41564-019-0474-x) (PMID:31209307)

Abstract

During infection, increasing pathogen load stimulates both protective and harmful aspects of the host response. The dynamics of this interaction are hard to quantify in humans, but doing so could improve understanding of the mechanisms of disease and protection. We sought to model the contributions of the parasite multiplication rate and host response to observed parasite load in individual subjects infected with Plasmodium falciparum malaria, using only data obtained at the time of clinical presentation, and then to identify their mechanistic correlates. We predicted higher parasite multiplication rates and lower host responsiveness in cases of severe malaria, with severe anaemia being more insidious than cerebral malaria. We predicted that parasite-growth inhibition was associated with platelet consumption, lower expression of CXCL10 and type 1 interferon-associated genes, but increased cathepsin G and matrix metallopeptidase 9 expression. We found that cathepsin G and matrix metallopeptidase 9 directly inhibit parasite invasion into erythrocytes. The parasite multiplication rate was associated with host iron availability and higher complement factor H levels, lower expression of gametocyte-associated genes but higher expression of translation-associated genes in the parasite. Our findings demonstrate the potential of using explicit modelling of pathogen load dynamics to deepen understanding of host–pathogen interactions and identify mechanistic correlates of protection.

• Item Type: Articles
• Additional Information: This work was supported by the Medical Research Council (MRC) UK via core funding to the malaria research programme at the MRC Unit, The Gambia; the UK MRC and the UK Department for International Development (DFID) under the MRC/DFID Concordat agreement that is also part of the EDCTP2 program supported by the European Union (MR/L006529/1 to A.J.C.); a Wellcome Trust Value In People Award to A.J.C. and the European Union’s seventh Framework program under EC-GA no. 279185 (EUCLIDS; www.euclids-project.eu).
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Otto, Professor Thomas
• Authors: Georgiadou, A., Lee, H. J., Walther, M., van Beek, A. E., Fitriani, F., Wouters, D., Kuijpers, T. W., Nwakanma, D., D'Alessandro, U., Riley, E. M., Otto, T. D., Ghani, A., Levin, M., Coin, L. J., Conway, D. J., Bretscher, M. T., and Cunnington, A. J.
• College/School: College of Medical Veterinary and Life Sciences > School of Infection & Immunity
• Research Centre: College of Medical Veterinary and Life Sciences > School of Infection & Immunity > Centre for Immunobiology
• Journal Name: Nature Microbiology
• Publisher: Nature Publishing Group
• ISSN: 2058-5276
• ISSN (Online): 2058-5276
• Published Online: 17 June 2019
• Copyright Holders: Copyright © The Authors, under exclusive licence to Springer Nature Limited 2019
• First Published: First published in Nature Microbiology 4:1592-1602
• Publisher Policy: Reproduced in accordance with the publisher copyright policy