Imperial College London
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Dr Athina Georgiadou

Faculty of Medicine, Department of Infectious Disease

Imperial College Research Fellow
 
 
 
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Contact

 

a.georgiadou

 
 
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Location

 

246St Mary's Research BuildingSt Mary's Campus

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Summary

 

Publications

Citation

BibTex format

@unpublished{Bretscher:2018:10.1101/321463,
author = {Bretscher, MT and Georgiadou, A and Lee, HJ and Walther, M and van, Beek AE and Fitriani, F and Wouters, D and Kuijpers, TW and Nwakanma, D and DAlessandro, U and Riley, EM and Levin, M and Coin, LJ and Ghani, A and Conway, DJ and Cunnington, AJ},
doi = {10.1101/321463},
title = {Estimating parasite load dynamics to reveal novel resistance mechanisms to human malaria},
url = {http://dx.doi.org/10.1101/321463},
year = {2018}
}
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RIS format (EndNote, RefMan)

TY  - UNPB
AB  - <jats:title>Abstract</jats:title><jats:p>Improved methods are needed to identify host mechanisms which directly protect against human infectious diseases in order to develop better vaccines and therapeutics<jats:sup>1,2</jats:sup>. Pathogen load determines the outcome of many infections<jats:sup>3</jats:sup>, and is a consequence of pathogen multiplication rate, duration of the infection, and inhibition or killing of pathogen by the host (resistance). If these determinants of pathogen load could be quantified then their mechanistic correlates might be determined. In humans the timing of infection is rarely known and treatment cannot usually be withheld to monitor serial changes in pathogen load and host response. Here we present an approach to overcome this and identify potential mechanisms of resistance which control parasite load in<jats:italic>Plasmodium falciparum</jats:italic>malaria. Using a mathematical model of longitudinal infection dynamics for orientation, we made individualized estimates of parasite multiplication and growth inhibition in Gambian children at presentation with acute malaria and used whole blood RNA-sequencing to identify their correlates. We identified novel roles for secreted proteases cathepsin G and matrix metallopeptidase 9 (MMP9) as direct effector molecules which inhibit<jats:italic>P. falciparum</jats:italic>growth. Cathepsin G acts on the erythrocyte membrane, cleaving surface receptors required for parasite invasion, whilst MMP9 acts on the parasite. In contrast, the type 1 interferon response and expression of<jats:italic>CXCL10</jats:italic>(IFN-γ-inducible protein of 10 kDa, IP-10) were detrimental to control of parasite growth. Natural variation in iron status and plasma levels of complement factor H were determinants of parasite multiplication rate. Our findings demonstrate the importance of accounting for the dynamic interaction between host
AU  - Bretscher,MT
AU  - Georgiadou,A
AU  - Lee,HJ
AU  - Walther,M
AU  - van,Beek AE
AU  - Fitriani,F
AU  - Wouters,D
AU  - Kuijpers,TW
AU  - Nwakanma,D
AU  - DAlessandro,U
AU  - Riley,EM
AU  - Levin,M
AU  - Coin,LJ
AU  - Ghani,A
AU  - Conway,DJ
AU  - Cunnington,AJ
DO  - 10.1101/321463
PY  - 2018///
TI  - Estimating parasite load dynamics to reveal novel resistance mechanisms to human malaria
UR  - http://dx.doi.org/10.1101/321463
ER  -
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