Within-host competition can delay evolution of drug resistance in malaria

In the malaria parasite P. falciparum, drug resistance generally evolves first in low-transmission settings, such as Southeast Asia and South America. Resistance takes noticeably longer to appear in the high-transmission settings of sub-Saharan Africa, although it may spread rapidly thereafter. Here, we test the hypothesis that competitive suppression of drug-resistant parasites by drug-sensitive parasites may inhibit evolution of resistance in high-transmission settings, where mixed-strain infections are common. We employ a cross-scale model, which simulates within-host (infection) dynamics and between-host (transmission) dynamics of sensitive and resistant parasites for a population of humans and mosquitoes. Using this model, we examine the effects of transmission intensity, selection pressure, fitness costs of resistance, and cross-reactivity between strains on the establishment and spread of resistant parasites. We find that resistant parasites, introduced into the population at a low frequency, are more likely to go extinct in high-transmission settings, where drug-sensitive competitors and high levels of acquired immunity reduce the absolute fitness of the resistant parasites. Under strong selection from antimalarial drug use, however, resistance spreads faster in high-transmission settings than low-transmission ones. These contrasting results highlight the distinction between establishment and spread of resistance and suggest that the former but not the latter may be inhibited in high-transmission settings. Our results suggest that within-host competition is a key factor shaping the evolution of drug resistance in P. falciparum.

[1]  Mehul Dhorda,et al.  The spread of artemisinin-resistant Plasmodium falciparum in the Greater Mekong subregion: a molecular epidemiology observational study , 2017, The Lancet. Infectious diseases.

[2]  Sebastian Bonhoeffer,et al.  A combined within-host and between-hosts modelling framework for the evolution of resistance to antimalarial drugs , 2016, Journal of The Royal Society Interface.

[3]  S. P. Kachur,et al.  Within-host competition and drug resistance in the human malaria parasite Plasmodium falciparum , 2016, Proceedings of the Royal Society B: Biological Sciences.

[4]  Tran Dang Nguyen,et al.  Optimum population-level use of artemisinin combination therapies: a modelling study , 2015, The Lancet. Global health.

[5]  Caroline O. Buckee,et al.  Dissecting the determinants of malaria chronicity: why within-host models struggle to reproduce infection dynamics , 2015, Journal of The Royal Society Interface.

[6]  E. Klein The impact of heterogeneous transmission on the establishment and spread of antimalarial drug resistance. , 2014, Journal of theoretical biology.

[7]  A. Manjurano,et al.  Trends in chloroquine resistance marker, Pfcrt-K76T mutation ten years after chloroquine withdrawal in Tanzania , 2013, Malaria Journal.

[8]  A. Read,et al.  Quantifying variation in the potential for antibody-mediated apparent competition among nine genotypes of the rodent malaria parasite Plasmodium chabaudi , 2013, Infection, genetics and evolution : journal of molecular epidemiology and evolutionary genetics in infectious diseases.

[9]  S. P. Kachur,et al.  The silent threat: asymptomatic parasitemia and malaria transmission , 2013, Expert review of anti-infective therapy.

[10]  Martin Walker,et al.  Predicting mosquito infection from Plasmodium falciparum gametocyte density and estimating the reservoir of infection , 2013, eLife.

[11]  E. Klein Antimalarial drug resistance: a review of the biology and strategies to delay emergence and spread. , 2013, International journal of antimicrobial agents.

[12]  Mercedes Pascual,et al.  Population structuring of multi-copy, antigen-encoding genes in Plasmodium falciparum , 2012, eLife.

[13]  David L. Smith,et al.  Superinfection and the evolution of resistance to antimalarial drugs , 2012, Proceedings of the Royal Society B: Biological Sciences.

[14]  Andrew F. Read,et al.  Enhanced Transmission of Drug-Resistant Parasites to Mosquitoes following Drug Treatment in Rodent Malaria , 2012, PloS one.

[15]  David L. Smith,et al.  Ross, Macdonald, and a Theory for the Dynamics and Control of Mosquito-Transmitted Pathogens , 2012, PLoS pathogens.

[16]  N. Savill,et al.  Causes of Variation in Malaria Infection Dynamics: Insights from Theory and Data , 2011, The American Naturalist.

[17]  S. Huijben,et al.  The fitness of drug‐resistant malaria parasites in a rodent model: multiplicity of infection , 2011, Journal of evolutionary biology.

[18]  Pierre Baldi,et al.  The Stability and Complexity of Antibody Responses to the Major Surface Antigen of Plasmodium falciparum Are Associated with Age in a Malaria Endemic Area* , 2011, Molecular & Cellular Proteomics.

[19]  T. Antão,et al.  Environmental, pharmacological and genetic influences on the spread of drug-resistant malaria , 2011, Proceedings of the Royal Society B: Biological Sciences.

[20]  T. Antão Evolutionary parasitology applied to control and elimination policies. , 2011, Trends in parasitology.

[21]  M. Pascual,et al.  Transmission Intensity and Drug Resistance in Malaria Population Dynamics: Implications for Climate Change , 2010, PloS one.

[22]  Silvie Huijben,et al.  CHEMOTHERAPY, WITHIN‐HOST ECOLOGY AND THE FITNESS OF DRUG‐RESISTANT MALARIA PARASITES , 2010, Evolution; international journal of organic evolution.

[23]  David L. Smith,et al.  Prospective strategies to delay the evolution of anti-malarial drug resistance: weighing the uncertainty , 2010, Malaria Journal.

[24]  J. Barnwell,et al.  Origin and Evolution of Sulfadoxine Resistant Plasmodium falciparum , 2010, PLoS pathogens.

[25]  Toshihiro Mita,et al.  Spread and evolution of Plasmodium falciparum drug resistance. , 2009, Parasitology international.

[26]  M. C. Bolla,et al.  Competitive facilitation of drug-resistant Plasmodium falciparum malaria parasites in pregnant women who receive preventive treatment , 2009, Proceedings of the National Academy of Sciences.

[27]  H. Babiker,et al.  Impaired fitness of drug-resistant malaria parasites: evidence and implication on drug-deployment policies , 2009, Expert review of anti-infective therapy.

[28]  P. Tsukayama,et al.  Dynamics of Malaria Drug Resistance Patterns in the Amazon Basin Region following Changes in Peruvian National Treatment Policy for Uncomplicated Malaria , 2009, Antimicrobial Agents and Chemotherapy.

[29]  Marc Lipsitch,et al.  No coexistence for free: neutral null models for multistrain pathogens. , 2009, Epidemics.

[30]  Denise L. Doolan,et al.  Acquired Immunity to Malaria , 2009, Clinical Microbiology Reviews.

[31]  L. Rivière,et al.  Antigenic variation in Plasmodium falciparum. , 2008, Annual review of microbiology.

[32]  Troy Day,et al.  Linking within- and between-host dynamics in the evolutionary epidemiology of infectious diseases. , 2008, Trends in ecology & evolution.

[33]  David L. Smith,et al.  Clinically immune hosts as a refuge for drug-sensitive malaria parasites , 2008, Malaria Journal.

[34]  N. Arinaminpathy,et al.  The effects of a partitioned var gene repertoire of Plasmodium falciparum on antigenic diversity and the acquisition of clinical immunity , 2008, Malaria Journal.

[35]  S. Huijben,et al.  Competitive release and facilitation of drug-resistant parasites after therapeutic chemotherapy in a rodent malaria model , 2007, Proceedings of the National Academy of Sciences.

[36]  L. Hviid Development of vaccines against Plasmodium falciparum malaria: taking lessons from naturally acquired protective immunity. , 2007, Microbes and infection.

[37]  A. Read,et al.  Dynamics of Multiple Infection and Within‐Host Competition in Genetically Diverse Malaria Infections , 2005, The American Naturalist.

[38]  W. Watkins,et al.  Intensity of malaria transmission and the evolution of drug resistance. , 2005, Acta tropica.

[39]  A. Read,et al.  Competitive release of drug resistance following drug treatment of mixed Plasmodium chabaudi infections , 2004, Malaria Journal.

[40]  B. Sharp,et al.  Intercontinental Spread of Pyrimethamine-Resistant Malaria , 2004, Science.

[41]  Mario Recker,et al.  Transient cross-reactive immune responses can orchestrate antigenic variation in malaria , 2004, Nature.

[42]  U. d’Alessandro,et al.  History, Dynamics, and Public Health Importance of Malaria Parasite Resistance , 2004, Clinical Microbiology Reviews.

[43]  N. Speybroeck,et al.  Intensity of transmission and spread of gene mutations linked to chloroquine and sulphadoxine-pyrimethamine resistance in falciparum malaria. , 2003, International journal for parasitology.

[44]  J. Kublin,et al.  Reemergence of chloroquine-sensitive Plasmodium falciparum malaria after cessation of chloroquine use in Malawi. , 2003, The Journal of infectious diseases.

[45]  I. Hastings Malaria control and the evolution of drug resistance: an intriguing link. , 2003, Trends in parasitology.

[46]  David A. Fidock,et al.  Chloroquine Resistance in Plasmodium falciparum Malaria Parasites Conferred by pfcrt Mutations , 2002, Science.

[47]  John C. Wootton,et al.  Genetic diversity and chloroquine selective sweeps in Plasmodium falciparum , 2002, Nature.

[48]  M. D. Wilson,et al.  Novel Plasmodium falciparum clones and rising clone multiplicities are associated with the increase in malaria morbidity in Ghanaian children during the transition into the high transmission season , 2001, Parasitology.

[49]  K. Dietz,et al.  Plasmodium falciparum parasitaemia described by a new mathematical model , 2001, Parasitology.

[50]  J. T. Williams,et al.  Microsatellite markers reveal a spectrum of population structures in the malaria parasite Plasmodium falciparum. , 2000, Molecular biology and evolution.

[51]  U. d’Alessandro,et al.  Modelling a predictable disaster: the rise and spread of drug-resistantmalaria. , 2000, Parasitology today.

[52]  K. Dietz,et al.  Review of intra-host models of malaria. , 1999, Parassitologia.

[53]  G. Killeen,et al.  Short report: entomologic inoculation rates and Plasmodium falciparum malaria prevalence in Africa. , 1999, The American journal of tropical medicine and hygiene.

[54]  D. Arnot,et al.  Unstable malaria in Sudan: the influence of the dry season. Clone multiplicity of Plasmodium falciparum infections in individuals exposed to variable levels of disease transmission. , 1998, Transactions of the Royal Society of Tropical Medicine and Hygiene.

[55]  I. Hastings,et al.  A model for the origins and spread of drug-resistant malaria , 1997, Parasitology.

[56]  THE WORLD HEALTH ORGANIZATION , 1954 .

[57]  T. Adak,et al.  Open Access RESEARCH , 2010 .