Population-size dependency of Atovaquone resistance in P. chabaudi malaria

Open Access
Author:
Bram, Joshua T
Area of Honors:
Biology
Degree:
Bachelor of Science
Document Type:
Thesis
Thesis Supervisors:
  • Stephen Wade Schaeffer, Thesis Supervisor
  • Andrew Fraser Read, Honors Advisor
Keywords:
  • drug resistance
  • malaria
  • evolutionary rescue
  • Atovaquone
  • emergence
  • spread
Abstract:
In choosing treatment regimens that best manage drug resistance, it is important to understand the differences between the origin of resistance and the spread of resistance through microbial populations. It is well known that once resistance has arisen, strong drug use places selective pressure on microbes and leads to the proliferation of resistant phenotypes, often over short treatment periods. However, we know little about the factors that contribute to the origin of drug resistance, particularly within hosts. In this study using an in vivo rodent malaria model, we test the basic population genetics principle that mutational events occur more frequently in larger populations, and this contributes to increased rates of evolution (i.e. rate of resistance emergence). Mice were inoculated with equal parasite counts and subsequently drug treated at varying time points to simulate different population sizes, allowing us to examine the effects of population size on resistance emergence. Using the rodent malaria model and the antimalarial Atovaquone, we found that resistance emergence does depend on parasite population size: proportion of mice harboring resistant parasites increased with parasite densities at the onset of treatment. Thus, treatment of larger parasite populations is more likely to lead to resistance emergence. We hypothesize that this may be due to an increased genetic load found within large populations, increasing the probability of the parasite population containing a resistance-conferring allele.