Clinically immune hosts as a refuge for drug-sensitive malaria parasites

Eili Y Klein,David L Smith,Maciej F Boni,Ramanan Laxminarayan

doi:10.1186/1475-2875-7-67

Eili Y Klein, David L Smith + Show 2 more

Open Access

https://doi.org/10.1186/1475-2875-7-67

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Abstract

BackgroundMutations in Plasmodium falciparum that confer resistance to first-line antimalarial drugs have spread throughout the world from a few independent foci, all located in areas that were likely characterized by low or unstable malaria transmission. One of the striking differences between areas of low or unstable malaria transmission and hyperendemic areas is the difference in the size of the population of immune individuals. However, epidemiological models of malaria transmission have generally ignored the role of immune individuals in transmission, assuming that they do not affect the fitness of the parasite. This model reconsiders the role of immunity in the dynamics of malaria transmission and its impact on the evolution of antimalarial drug resistance under the assumption that immune individuals are infectious.MethodsThe model is constructed as a two-stage susceptible-infected-susceptible (SIS) model of malaria transmission that assumes that individuals build up clinical immunity over a period of years. This immunity reduces the frequency and severity of clinical symptoms, and thus their use of drugs. It also reduces an individual's level of infectiousness, but does not impact the likelihood of becoming infected.ResultsSimulations found that with the introduction of resistance into a population, clinical immunity can significantly alter the fitness of the resistant parasite, and thereby impact the ability of the resistant parasite to spread from an initial host by reducing the effective reproductive number of the resistant parasite as transmission intensity increases. At high transmission levels, despite a higher basic reproductive number, R0, the effective reproductive number of the resistant parasite may fall below the reproductive number of the sensitive parasite.ConclusionThese results suggest that high-levels of clinical immunity create a natural ecological refuge for drug-sensitive parasites. This provides an epidemiological rationale for historical patterns of resistance emergence and suggests that future outbreaks of resistance are more likely to occur in low- or unstable-transmission settings. This finding has implications for the design of drug policies and the formulation of malaria control strategies, especially those that lower malaria transmission intensity.

Highlights

Mutations in Plasmodium falciparum that confer resistance to first-line antimalarial drugs have spread throughout the world from a few independent foci, all located in areas that were likely characterized by low or unstable malaria transmission
Prompt treatment with effective antimalarial drugs could prevent much of the morbidity and mortality associated with clinical malaria, but the evolution of resistance has diminished the therapeutic efficacy of two previous first-line antimalarials, chloroquine (CQ) and sulphadoxine-pyrimethamine (SP)
Genetic evidence suggests that most CQ-resistant parasites in the world today are descended from one of four founder events [4,5] that occurred in Southeast Asia, South America and Papua New Guinea, and spread to other regions, including sub-Saharan Africa

Summary

Introduction

Mutations in Plasmodium falciparum that confer resistance to first-line antimalarial drugs have spread throughout the world from a few independent foci, all located in areas that were likely characterized by low or unstable malaria transmission. Several hypotheses about the de novo mutation rate and the selection pressure resistant parasites face and their relation to transmission intensity have been proposed to explain why CQ resistance originated in what is presumed to be low or unstable transmission areas outside of sub-Saharan Africa, including (a) a lower frequency of resistant alleles in higher transmission areas because of within-host competition [9]; (b) less drug treatment (per parasite) in higher transmission areas [2,9,10]; and (c) a lower frequency of selfing in higher transmission areas, which increases the probability that multilocus resistant genotypes will be broken up by the action of Mendelian segregation [9,11,12]. An additional explanation is that in high transmission areas, where immunity is better developed, mutant parasites are less likely to survive a host immune response [10,13]

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