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Nat Microbiol. 2019 Jun 17. doi: 10.1038/s41564-019-0474-x. [Epub ahead of print]

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

Author information

1
Section of Paediatrics, Imperial College, London, UK.
2
Institute for Molecular Bioscience, University of Queensland, Brisbane, Queensland, Australia.
3
QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.
4
Medical Research Council Unit, Fajara, The Gambia at the London School of Hygiene and Tropical Medicine, Fajara, The Gambia.
5
Department of Immunopathology, Sanquin Research and Landsteiner Laboratory, Amsterdam University Medical Centre, University of Amsterdam, Amsterdam, The Netherlands.
6
Department of Pediatric Hematology, Immunology and Infectious Diseases, Emma Children's Hospital, Amsterdam University Medical Centre, Amsterdam, The Netherlands.
7
Centre for Infectious Disease Control, National Institute for Public Health and the Environment, Bilthoven, The Netherlands.
8
Department of Blood Cell Research, Sanquin Research and Landsteiner Laboratory, Amsterdam University Medical Centre, University of Amsterdam, Amsterdam, The Netherlands.
9
The Roslin Institute and the Royal (Dick) School of Veterinary Studies, University of Edinburgh, Edinburgh, UK.
10
Department of Immunology and Infection, London School of Hygiene and Tropical Medicine, London, UK.
11
Centre of Immunobiology, Institute of Infection, Immunity & Inflammation, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, UK.
12
MRC Centre for Global Infectious Disease Analysis, Imperial College, London, UK.
13
Department of Pathogen Molecular Biology, London School of Hygiene and Tropical Medicine, London, UK.
14
F. Hoffmann-La Roche Ltd., Basel, Switzerland.
15
Section of Paediatrics, Imperial College, London, UK. a.cunnington@imperial.ac.uk.

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.

PMID:
31209307
DOI:
10.1038/s41564-019-0474-x

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