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

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Title: Modelling pathogen load dynamics to elucidate mechanistic determinants of host-Plasmodium falciparum interactions
Authors: Georgiadou, A
Lee, HJ
Walther, M
Van Beek, A
Fitriani, F
Wouters, D
Kuijpers, T
Nwakanma, D
D'Alessandro, U
Riley, E
Otto, T
Ghani, A
Levin, M
Coin, L
Conway, D
Bretscher, M
Cunnington, A
Item Type: Journal Article
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 mechanisms of disease and protection. We sought to model the contributions of parasite multiplication rate and host response to observed parasite load in individual subjects 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 severe malaria cases, with severe anemia 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. 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.
Issue Date: 17-Jun-2019
Date of Acceptance: 30-Apr-2019
URI: http://hdl.handle.net/10044/1/70353
ISSN: 2058-5276
Publisher: Nature Research
Journal / Book Title: Nature Microbiology
Sponsor/Funder: Medical Research Council (MRC)
Bill & Melinda Gates Foundation
Funder's Grant Number: MR/L006529/1
OPP1068440
Publication Status: Accepted
Embargo Date: 2019-12-17
Appears in Collections:Department of Medicine
Faculty of Medicine
Epidemiology, Public Health and Primary Care



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