학술논문
Multiple genetic loci define Ca++ utilization by bloodstream malaria parasites
Document Type
Report
Source
BMC Genomics. January 16, 2019, Vol. 20 Issue 1
Subject
Language
English
ISSN
1471-2164
Abstract
Author(s): Liana Apolis[sup.1,2] , Joanna Olivas[sup.1] , Prakash Srinivasan[sup.1,3] , Ambuj K. Kushwaha[sup.1] and Sanjay A. Desai[sup.1] Background Development of Plasmodium parasites within erythrocytes accounts for most of the clinical [...]
Background Bloodstream malaria parasites require Ca.sup.++ for their development, but the sites and mechanisms of Ca.sup.++ utilization are not well understood. We hypothesized that there may be differences in Ca.sup.++ uptake or utilization by genetically distinct lines of P. falciparum. These differences, if identified, may provide insights into molecular mechanisms. Results Dose response studies with the Ca.sup.++ chelator EGTA (ethylene glycol-bis([beta]-aminoethyl ether)-N,N,N',N'-tetraacetic acid) revealed stable differences in Ca.sup.++ requirement for six geographically divergent parasite lines used in previous genetic crosses, with the largest difference seen between the parents of the HB3 x Dd2 cross. Genetic mapping of Ca.sup.++ requirement yielded complex inheritance in 34 progeny clones with a single significant locus on chromosome 7 and possible contributions from other loci. Although encoded by a gene in the significant locus and a proposed Ca.sup.++ target, PfCRT (P. falciparum chloroquine resistance transporter), the primary determinant of clinical resistance to the antimalarial drug chloroquine, does not appear to contribute to this quantitative trait. Stage-specific application of extracellular EGTA also excluded determinants associated with merozoite egress and erythrocyte reinvasion. Conclusions We have identified differences in Ca.sup.++ utilization amongst P. falciparum lines. These differences are under genetic regulation, segregating as a complex trait in genetic cross progeny. Ca.sup.++ uptake and utilization throughout the bloodstream asexual cycle of malaria parasites represents an unexplored target for therapeutic intervention. Keywords: Malaria, Calcium, Antimalarial drug targets, Linkage analysis, EGTA, Plasmodium falciparum, Merozoite invasion
Background Bloodstream malaria parasites require Ca.sup.++ for their development, but the sites and mechanisms of Ca.sup.++ utilization are not well understood. We hypothesized that there may be differences in Ca.sup.++ uptake or utilization by genetically distinct lines of P. falciparum. These differences, if identified, may provide insights into molecular mechanisms. Results Dose response studies with the Ca.sup.++ chelator EGTA (ethylene glycol-bis([beta]-aminoethyl ether)-N,N,N',N'-tetraacetic acid) revealed stable differences in Ca.sup.++ requirement for six geographically divergent parasite lines used in previous genetic crosses, with the largest difference seen between the parents of the HB3 x Dd2 cross. Genetic mapping of Ca.sup.++ requirement yielded complex inheritance in 34 progeny clones with a single significant locus on chromosome 7 and possible contributions from other loci. Although encoded by a gene in the significant locus and a proposed Ca.sup.++ target, PfCRT (P. falciparum chloroquine resistance transporter), the primary determinant of clinical resistance to the antimalarial drug chloroquine, does not appear to contribute to this quantitative trait. Stage-specific application of extracellular EGTA also excluded determinants associated with merozoite egress and erythrocyte reinvasion. Conclusions We have identified differences in Ca.sup.++ utilization amongst P. falciparum lines. These differences are under genetic regulation, segregating as a complex trait in genetic cross progeny. Ca.sup.++ uptake and utilization throughout the bloodstream asexual cycle of malaria parasites represents an unexplored target for therapeutic intervention. Keywords: Malaria, Calcium, Antimalarial drug targets, Linkage analysis, EGTA, Plasmodium falciparum, Merozoite invasion