Diagnostic Evasion in Plasmodium falciparum Towards Hrp2-Sensitive Rapid Diagnostic Tests via pfhrp2 Gene Deletions

Open Access
Author:
Hollenbeak, Asher
Area of Honors:
Biochemistry and Molecular Biology
Degree:
Bachelor of Science
Document Type:
Thesis
Thesis Supervisors:
  • Maciej F Boni, Thesis Supervisor
  • Lorraine C Santy, Honors Advisor
Keywords:
  • malaria
  • rapid diagnostic tests
  • diagnostic
  • Plasmodium
  • falciparum
  • Linkage
  • Disequilibrium
Abstract:
Plasmodium falciparum is considered to be the species responsible for the most human deaths due to malaria, as well as the most prevalent Plasmodium species globally. Antimalarial drugs and diagnostic tests are important components of malaria control and elimination strategies, but P. falciparum strains have evolved genotypes that are resistant to antimalarial drugs, and undetectable by Histidine Rich Protein 2 (Hrp2) based rapid diagnostic tests (RDTs). Hrp2 based RDTs are capable of diagnosing the presence of P. falciparum with high sensitivity using anti-Hrp2 antibodies. Pfhrp2 gene deletions in P. falciparum strains prevent the production and secretion of Hrp2, preventing detection by RDTs. In this study the epidemiological patterns of pfhrp2 gene deletions were investigated, as well as how pfhrp2 gene deletions evolve in conjunction with known drug resistance loci. A deterministic series of 131 ordinary differential equations were constructed in order to represent the disease progression of malaria caused by P. falciparum. The model accounted for host immunity, antimalarial resistance mutations, pfhrp2 gene deletions, fitness differences between genotypes, drug coverage, diagnostic coverage, and varying transmission levels. It was found that when regarding diagnostic evasive strains of P. falciparum, physical coverage does not effectively explain the disease dynamics, and the effective coverage must be accounted for. The introduction of RDTs can increase the long-term prevalence of P. falciparum without a secondary diagnostic test. Negative linkage disequilibrium was found between diagnostic evasive genotypes and drug resistant genotypes, indicating that diagnostic evasive and drug resistant genotypes do not assort the way two drug resistant genotypes do. Thus, if RDTs are implemented into a population, measures should be taken to monitor the spread of pfhrp2 gene deletions, and understand how pfhrp2 gene deletions affect drug resistance spread.