Department of Infection Biology, London School of Hygiene and Tropical Medicine, Keppel St, London, WC1E 7HT, UK.
LPHI, MIVEGEC, INSERM, CNRS, IRD, University of Montpellier, 34095, Montpellier, Cedex 5, France.
Commun Biol. 2020 Oct 28;3(1):624. doi: 10.1038/s42003-020-01349-7.
Pathogen multiplication rate is theoretically an important determinant of virulence, although often poorly understood and difficult to measure accurately. We show intrinsic asexual blood stage multiplication rate variation of the major human malaria parasite Plasmodium falciparum to be associated with blood-stage infection intensity in patients. A panel of clinical isolates from a highly endemic West African population was analysed repeatedly during five months of continuous laboratory culture, showing a range of exponential multiplication rates at all timepoints tested, mean rates increasing over time. All isolates had different genome sequences, many containing within-isolate diversity that decreased over time in culture, but increases in multiplication rates were not primarily attributable to genomic selection. New mutants, including premature stop codons emerging in a few isolates, did not attain sufficiently high frequencies to substantially affect overall multiplication rates. Significantly, multiplication rate variation among the isolates at each of the assayed culture timepoints robustly correlated with parasite levels seen in patients at clinical presentation, indicating innate parasite control of multiplication rate that contributes to virulence.
病原体繁殖率理论上是一个重要的毒力决定因素，尽管通常理解不足且难以准确测量。我们发现主要人体疟疾寄生虫疟原虫的内在无性血期繁殖率变化与患者的血液期感染强度有关。从高度流行的西非人群中分析了一组临床分离株，在五个月的连续实验室培养中反复进行分析，在所有测试的时间点均显示出不同的指数繁殖率，平均繁殖率随时间增加。所有分离株都有不同的基因组序列，其中许多包含随时间在培养过程中减少的株内多样性，但繁殖率的增加并非主要归因于基因组选择。新的突变体，包括少数分离株中出现的过早终止密码子，没有达到足够高的频率，无法显著影响总体繁殖率。重要的是，在每个检测的培养时间点，分离株之间的繁殖率变化与患者就诊时的寄生虫水平显著相关，表明寄生虫对繁殖率的固有控制有助于毒力。
