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

Athina Georgiadou, Hyun Jae Lee , Michael Walther, Anna E. van Beek , Fadlila Fitriani, Diana Wouters, Taco W Kuijpers, Davis Nwakanma, Umberto D'Alessandro, Eleanor Riley, Thomas Dan Otto, Azra C. Ghani, Michael Levin, Lachlan Coin, David J. Conway, Michael T Bretscher, Aubrey J Cunnington

Research output: Contribution to journalArticlepeer-review

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.
Original languageEnglish
JournalNature Microbiology
DOIs
Publication statusPublished - 17 Jun 2019

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