title: Effect of mature blood-stage Plasmodium parasite sequestration on pathogen biomass in mathematical and in vivo models of malaria.
abstract: Parasite biomass and microvasculature obstruction are strongly associated with disease severity and death in Plasmodium falciparum-infected humans. This is related to sequestration of mature, blood-stage parasites (schizonts) in peripheral tissue. The prevailing view is that schizont sequestration leads to an increase in pathogen biomass, yet direct experimental data to support this are lacking. Here, we first studied parasite population dynamics in inbred wild-type (WT) mice infected with the rodent species of malaria, Plasmodium berghei ANKA. As is commonly reported, these mice became moribund due to large numbers of parasites in multiple tissues. We then studied infection dynamics in a genetically targeted line of mice, which displayed minimal tissue accumulation of parasites. We constructed a mathematical model of parasite biomass dynamics, incorporating schizont-specific host clearance, both with and without schizont sequestration. Combined use of mathematical and in vivo modeling indicated, first, that the slowing of parasite growth in the genetically targeted mice can be attributed to specific clearance of schizonts from the circulation and, second, that persistent parasite growth in WT mice can be explained solely as a result of schizont sequestration. Our work provides evidence that schizont sequestration could be a major biological process driving rapid, early increases in parasite biomass during blood-stage Plasmodium infection.
authors.affiliation: Complex Systems in Biology Group, Centre for Vascular Research, University of New South Wales, Kensington, New South Wales, Australia.
authors.forename: David S
authors.initials: DS
authors.lastname: Khoury
authors.forename: Deborah
authors.initials: D
authors.lastname: Cromer
authors.forename: Shannon E
authors.initials: SE
authors.lastname: Best
authors.forename: Kylie R
authors.initials: KR
authors.lastname: James
authors.forename: Peter S
authors.initials: PS
authors.lastname: Kim
authors.forename: Christian R
authors.initials: CR
authors.lastname: Engwerda
authors.forename: Ashraful
authors.initials: A
authors.lastname: Haque
authors.forename: Miles P
authors.initials: MP
authors.lastname: Davenport
mesh_terms: D000818:Animals; D018533:Biomass; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D004912:Erythrocytes / Q000378:metabolism / Q000469:parasitology*; D005260:Female; D005434:Flow Cytometry; D008163:Luminescent Measurements; D008288:Malaria / Q000097:blood / Q000469:parasitology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008954:Models, Biological; D010962:Plasmodium berghei / Q000254:growth & development* / Q000472:pathogenicity; D052939:Schizonts / Q000469:parasitology
chemical_list: D016207:Cytokines