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Archived Comments for: Epidemiological models for the spread of anti-malarial resistance

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  1. How can resistance spread in the absence of drug pressure?

    Ian Hastings, Liverpool School of Tropical Medicine

    7 September 2004

    Koella & Antia [1] employed an epidemiological approach to investigate how antimalarial drug resistance spreads through a population, and reached the seemingly anomalous conclusion that resistance could spread even if it was selectively disadvantageous (i.e. natural selection was acting against the metabolic disruption presumed to occur as a result of the mutation) and no drug was being deployed. This indicates that some other force besides drug selection must be present in their model and capable of overcoming the cost of resistance, so driving resistance into a population. This additional force appears to be human immunity. Their model split humans into five types: uninfected-susceptible, uninfected-immune, infected with sensitive parasites (infected-sensitive), infected with resistant parasites (infected-resistant), infected with both types (infected-mixed). At low frequencies of resistance the proportion of humans in the infected-resistant and infected-mixed are negligible, so only three types need be considered i.e. uninfected-susceptible, uninfected-immune, and infected-sensitive. According to their model, a resistant form can invade both uninfected-susceptible and infected-sensitive while a sensitive form can infect only the uninfected-sensitive host. This ability of resistant parasites to infect an additional type of person is presumably sufficient to establish it at low frequencies in the population even in the absence of drug pressure. The implicit assumption in the model is that the resistant and sensitive parasites differ in their immune profiles and are regulated independently, so that a human infected with sensitive parasites can be superinfected with a resistant form, but not with another sensitive form; this is unlikely for reasons discussed below. One way around this assumption would be to allow superinfection of the same parasite type but limit the number of infections to two, so there would be two extra infection classes: infected-double-sensitive and infected-double-resistant. The latter would again be negligible so a resistant parasite could infect uninfected-susceptible and infected-single-sensitive and the sensitive form could infect exactly the same classes. This establishes a level playing field with respect to infection opportunities and it will be interesting to discover whether resistant forms can still invade in the absence of drug pressure.

    The original epidemiological model may be valid in organisms where sexual recombination is sufficiently low that distinct antigenic ‘strains’ may be stable. However, this is implausible for highly sexual organisms such as P. falciparum where frequent recombination will randomise the immune profiles around the drug resistance gene [2,3] ensuring resistance is not associated with a distinct antigenic profile. Exceptions may occur if the resistant mutation is closely physically linked to a strongly-immunogenic gene, or if the resistant mutation is itself recognised by host immunity [4] but neither mechanism seems compelling The high rate of genetic recombination makes any physical linkage between resistant and immune genes transitory, and in any case could only drive resistance if the immune variant is actively spreading through the population so that resistance can ‘hitchhike’ along with it. The possibility that the resistance gene(s) are themselves immunogenic cannot be disproved but it seems unlikely. Three genes have been implicated in encoding resistance. The crt gene encodes resistance to chloroquine, and dhfr and dhps encode resistance to pyrimethamine and sulphadoxine, respectively. The crt encodes a parasite vacuole transporter protein and dhfr and dhps encode enzymes of the parasite folate pathway so none of them a priori seem likely to be strongly exposed to human immunity; certainly none have been identified as possible vaccine candidates. Thus the second model allowing superinfection irrespective of resistance phenotype seems more plausible and it would be useful to compare results from both models to try and elucidate the exact mechanism responsible for superinfection's ability to maintain resistance in the absence of drug pressure. The other conclusions [1] on the role of natural selection in establishing a threshold level of drug use that must be exceeded before resistance can spread, and of population sub-division and migration in maintaining variability in the population, are not affected by these arguments on parasite immunity and constitute a valuable contribution to understanding the dynamics of antimalarial drug resistance.

    Reference List

    1. Koella JC, Antia R: Epidemiological models for the spread of anti-malarial resistance. Malaria Journal 2003, 2: 3.

    2. Hastings IM: Population genetics and the detection of immunogenic and drug resistant loci in Plasmodium. Parasitol 1996, 112: 155-164.

    3. Hastings IM, Wedgwood-Oppenheim BA: Sex, strains and virulence. Parasitol Today 1997, 13: 375-383.

    4. Koella JC: Epidemiological evidence for an association between chloroquine resistance of Plasmodium falciparum and its immunological properties. Parasitol Today 1993, 9: 105-108.

    Competing interests