Malaria? ?remains? ?endemic? ?in? ?sub-Saharan? ?Africa? ?in? ?large? ?part? ?due? ?to? ?continued? ?evolution? ?and? ?spread? ?of? ?drug resistance? ?which? ?undermines? ?ongoing? ?large-scale? ?control? ?and? ?elimination? ?efforts.? ?We? ?will? ?leverage high-throughput? ?genotyping? ?of? ?parasites? ?using? ?a? ?state-of-the-art? ?panel? ?of? ?molecular? ?inversion? ?probes? ?(MIPs)? ?for targeted? ?sequencing? ?of? ?thousands? ?of? ?resistance? ?and? ?neutral? ?loci? ?across? ?thousands? ?of? ?infections? ?covering? ?the entire? ?Democratic? ?Republic? ?of? ?Congo? ?(DRC)? ?and? ?select? ?areas? ?in? ?bordering? ?countries.? ?This? ?will? ?provide? ?us? ?a? ?map with? ?an? ?unprecedented? ?scale? ?and? ?resolution? ?to? ?define? ?the? ?evolution? ?and? ?spread? ?of? ?antimalarial? ?resistance mutations.? ?In? ?this? ?project,? ?we? ?will? ?first? ?develop? ?our? ?genotyping? ?panel? ?which? ?should? ?provide? ?a? ?high-resolution? ?tool for? ?studying? ?all? ?known? ?drug? ?resistance? ?loci? ?and? ?general? ?parasite? ?population? ?structure? ?in? ?this? ?and? ?other? ?settings. Applying? ?this? ?to? ?well? ?annotated? ?samples? ?from? ?across? ?the? ?DRC? ?and? ?bordering? ?countries,? ?we? ?will? ?define? ?the prevalence? ?of? ?drug? ?resistance? ?mutations? ?and? ?define? ?them? ?based? ?on? ?their? ?genetic? ?haplotypes? ?which? ?act? ?as? ?a unique? ?fingerprints.? ?We? ?will? ?then? ?map? ?these? ?drug? ?resistance? ?haplotypes? ?and? ?study? ?their? ?spread? ?and? ?spatial associations? ?and? ?further? ?examine? ?their? ?epidemiologic? ?associations? ?and? ?interactions.? ?Onto? ?this? ?detailed? ?spatial map,? ?we? ?will? ?? ?examine? ?specific? ?locales? ?of? ?interest? ?for? ?temporal? ?changes.? ?? ?These? ?focal? ?regions? ?in? ?the? ?DRC represent? ?diverse? ?ecologic? ?and? ?demographic? ?features? ?that? ?likely? ?impact? ?resistance? ?spread? ?and? ?evolution including? ?areas? ?with? ?minimal? ?health? ?care? ?infrastructure? ?and? ?ongoing? ?regions? ?of? ?conflict.? ?Our? ?final? ?work? ?will? ?be? ?to apply? ?more? ?sophisticated? ?models? ?to? ?the? ?rich? ?sequence? ?data? ?in? ?order? ?to? ?estimate? ?the? ?flow? ?of? ?parasites? ?and resistance? ?mutations? ?within? ?and? ?between? ?the? ?DRC.? ?This? ?includes? ?the? ?development? ?of? ?new? ?? ?population? ?structure models? ?(MALECOT)? ?incorporating? ?parasite? ?infections? ?that? ?have? ?multiple? ?strains? ?allowing? ?for? ?a? ?better understanding? ?of? ?the? ?full? ?dataset? ?as? ?in? ?polyclonal? ?infections? ?are? ?often? ?the? ?majority? ?in? ?endemic? ?African? ?countries. This? ?model? ?should? ?be? ?broadly? ?applicable? ?to? ?other? ?studies? ?of? ?malaria? ?or? ?infections? ?with? ?mixed? ?strains.? ?We? ?will also? ?leverage? ?? ?spatially? ?explicit? ?models? ?to? ?define? ?general? ?parasite? ?flow? ?in? ?both? ?relative? ?and? ?absolute? ?terms comparing? ?and? ?contrasting? ?to? ?the? ?flow? ?of? ?resistant? ?parasites.? ?This? ?work? ?will? ?provide? ?the? ?patterns? ?of? ?general? ?gene flow? ?and? ?barriers? ?on? ?the? ?spread? ?of? ?specific? ?drug? ?resistance? ?alleles? ?and? ?haplotypes.? ?In? ?summary,? ?not? ?only? ?will this? ?project? ?enhance? ?our? ?understanding? ?of? ?malaria? ?landscape? ?genetics? ?and? ?the? ?evolution? ?and? ?spread? ?of antimalarial? ?resistance,? ?it? ?will? ?provide? ?tools? ?and? ?analysis? ?framework? ?for? ?improving? ?public? ?health? ?interventions that? ?will? ?directly? ?inform? ?the? ?DRC? ?National? ?Malaria? ?Control? ?Program.

Public Health Relevance

PROJECT? ?NARRATIVE Falciparum? ?malaria? ?remains? ?a? ?major? ?global? ?public? ?health? ?problem? ?and? ?the? ?continued? ?evolution? ?and? ?spread? ?of drug? ?resistance? ?impedes? ?control? ?efforts? ?in? ?endemic? ?countries? ?such? ?as? ?the? ?Democratic? ?Republic? ?of? ?Congo.? ?To better? ?understand? ?the? ?evolution? ?and? ?spread? ?of? ?drug? ?resistance? ?this? ?project? ?will? ?genotype? ?thousands? ?of? ?malaria infections? ?from? ?across? ?the? ?entire? ?country? ?to? ?define? ?all? ?known? ?resistance? ?genes? ?and? ?determine? ?barriers? ?and corridors? ?of? ?gene? ?flow? ?that? ?can? ?be? ?targeted? ?in? ?public? ?health? ?interventions.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI139520-03
Application #
9728882
Study Section
Clinical Research and Field Studies of Infectious Diseases Study Section (CRFS)
Program Officer
Joy, Deirdre A
Project Start
2018-06-21
Project End
2023-05-31
Budget Start
2019-06-01
Budget End
2020-05-31
Support Year
3
Fiscal Year
2019
Total Cost
Indirect Cost
Name
Brown University
Department
Pathology
Type
Schools of Medicine
DUNS #
001785542
City
Providence
State
RI
Country
United States
Zip Code
02912