Plasmodium falciparum genetic crosses in a humanized mouse model

Vaughan, Ashley M.; Pinapati, Richard S.; Cheeseman, Ian H.; Camargo, Nelly; Fishbaugher, Matthew; Checkley, Lisa A.; Nair, Shalini; Hutyra, Carolyn A.; Nosten, François; Anderson, Timothy J.; Ferdig, Michael T.; Kappe, Stefan H. I.

doi:10.1038/nmeth.3432

Cited by 73 publications

(102 citation statements)

References 26 publications

Supporting

Mentioning

102

Contrasting

Order By: Relevance

“…Analyses of experimental crosses indicate that the mean relatedness between F 1 progeny is approximately normally distributed with a mean of 0.52 and a standard deviation of 0.08 [26]. In our data (Fig.…”

Section: Discussionmentioning

confidence: 58%

Genetic relatedness analysis reveals the cotransmission of genetically related Plasmodium falciparum parasites in Thiès, Senegal

et al. 2017

View full text Add to dashboard Cite

BackgroundAs public health interventions drive parasite populations to elimination, genetic epidemiology models that incorporate population genomics can be powerful tools for evaluating the effectiveness of continued intervention. However, current genetic epidemiology models may not accurately simulate the population genetic profile of parasite populations, particularly with regard to polygenomic (multi-strain) infections. Current epidemiology models simulate polygenomic infections via superinfection (multiple mosquito bites), despite growing evidence that cotransmission (a single mosquito bite) may contribute to polygenomic infections.MethodsHere, we quantified the relatedness of strains within 31 polygenomic infections collected from patients in Thiès, Senegal using a hidden Markov model to measure the proportion of the genome that is inferred to be identical by descent.ResultsWe found that polygenomic infections can be composed of highly related parasites and that superinfection models drastically underestimate the relatedness of strains within polygenomic infections.ConclusionsOur findings suggest that cotransmission is a major contributor to polygenomic infections in Thiès, Senegal. The incorporation of cotransmission into existing genetic epidemiology models may enhance our ability to characterize and predict changes in population structure associated with reduced transmission intensities and the emergence of important phenotypes like drug resistance that threaten to undermine malaria elimination activities.Electronic supplementary materialThe online version of this article (doi:10.1186/s13073-017-0398-0) contains supplementary material, which is available to authorized users.

show abstract

Section: Discussionmentioning

confidence: 58%

Genetic relatedness analysis reveals the cotransmission of genetically related Plasmodium falciparum parasites in Thiès, Senegal

et al. 2017

View full text Add to dashboard Cite

show abstract

“…We cannot exclude defects in metabolism of artesunate, or alternative pathways to generate ART-R. We are currently analyzing a genetic cross (Vaughan et al 2015) involving one such non- kelch13 ART-R parasite to investigate this further.…”

Section: Discussionmentioning

confidence: 99%

Population Parameters Underlying an Ongoing Soft Sweep in Southeast Asian Malaria Parasites

et al. 2016

Self Cite

View full text Add to dashboard Cite

Multiple kelch13 alleles conferring artemisinin resistance (ART-R) are currently spreading through Southeast Asian malaria parasite populations, providing a unique opportunity to observe an ongoing soft selective sweep, investigate why resistance alleles have evolved multiple times and determine fundamental population genetic parameters for Plasmodium. We sequenced kelch13 (n = 1,876), genotyped 75 flanking SNPs, and measured clearance rate (n = 3,552) in parasite infections from Western Thailand (2001–2014). We describe 32 independent coding mutations including common mutations outside the kelch13 propeller associated with significant reductions in clearance rate. Mutations were first observed in 2003 and rose to 90% by 2014, consistent with a selection coefficient of ∼0.079. ART-R allele diversity rose until 2012 and then dropped as one allele (C580Y) spread to high frequency. The frequency with which adaptive alleles arise is determined by the rate of mutation and the population size. Two factors drive this soft sweep: (1) multiple kelch13 amino-acid mutations confer resistance providing a large mutational target—we estimate the target is 87–163 bp. (2) The population mutation parameter (Θ = 2Neμ) can be estimated from the frequency distribution of ART-R alleles and is ∼5.69, suggesting that short term effective population size is 88 thousand to 1.2 million. This is 52–705 times greater than Ne estimated from fluctuation in allele frequencies, suggesting that we have previously underestimated the capacity for adaptive evolution in Plasmodium. Our central conclusions are that retrospective studies may underestimate the complexity of selective events and the Ne relevant for adaptation for malaria is considerably higher than previously estimated.

show abstract

“…Complete P. falciparum replication has been possible using human liver chimeric Fah null Rag2 null IL2rg null (FRG) NOD and thymidine kinase (TK) NOG mice engrafted with human hepatocytes and infused with human RBCs (65, 66). Humanized mice are now being used to study P. falciparum genetic traits and phenotypes associated with severity of disease (67) and for testing the efficacy of new therapeutics that block entry of the virus into hepatocytes (68). …”

Section: Infectious Disease In Humanized Micementioning

confidence: 99%

Humanized Mouse Models of Clinical Disease

Walsh

Kenney

Jangalwe

et al. 2017

Annu. Rev. Pathol. Mech. Dis.

443

384

View full text Add to dashboard Cite

Immunodeficient mice engrafted with functional human cells and tissues, i.e., “humanized mice”, have become increasingly important as small pre-clinical animal models for the study of human diseases. Since the description of immunodeficient mice bearing mutations in the IL2 receptor common gamma chain (IL2rgnull) in the early 2000’s, investigators have been able to engraft murine recipients with human hematopoietic stem cells that develop into functional human immune systems. These mice can also be engrafted with human tissues such as islets, liver, skin, and most solid and hematologic cancers. Humanized mice are permitting significant progress in studies of human infectious disease, cancer, regenerative medicine, graft versus host disease, allergies, and immunity. Ultimately, use of humanized mice may lead to the implementation of truly “personalized” medicine in the clinic. This review discusses recent progress in the development and use of humanized mice, and highlights their utility for the study of human diseases.

show abstract

Plasmodium falciparum genetic crosses in a humanized mouse model

Cited by 73 publications

References 26 publications

Genetic relatedness analysis reveals the cotransmission of genetically related Plasmodium falciparum parasites in Thiès, Senegal

Genetic relatedness analysis reveals the cotransmission of genetically related Plasmodium falciparum parasites in Thiès, Senegal

Population Parameters Underlying an Ongoing Soft Sweep in Southeast Asian Malaria Parasites

Humanized Mouse Models of Clinical Disease

Contact Info

Product

Resources

About