@article{fdi:010091513,
  title = {{P}lasmodium ovale spp dhfr mutations associated with reduced susceptibility to pyrimethamine in sub-{S}aharan {A}frica : a retrospective genetic epidemiology and functional study},
  author = {{J}oste, {V}. and {C}opp{\'e}e, {R}. and {B}ailly, {J}ustine and {R}akotoarivony, {Y}. and {T}oko {T}chokoteu, {F}.{G}. and {A}chache, {S}. and {P}radines, {B}. and {C}ottrell, {G}illes and {A}riey, {F}. and {K}him, {N}. and {P}opovici, {J}. and {M}ita, {T}. and {G}roger, {M}. and {R}amharter, {M}. and {E}gbo, {T}. and {J}uma, {D}.{W}. and {A}kala, {H}. and {H}ouz{\'e}, {S}. and {C}lain, {J}. and {A}bou-{B}acar, {A}. and {A}gnamey, {P}. and {A}it-{A}mmar, {N}. and {A}ngoulvant, {A}. and {A}rgy, {N}. and {A}zjenberg, {D}. and {B}asmaciyan, {L}. and {B}astien, {P}. and {B}elaz, {S}. and {B}elkadi, {G}. and {B}ellanger, {A}.{P}. and {B}emba, {D}. and {B}erry, {A}. and {B}otterel, {F}. and {B}ouden, {F}. and {B}ougnoux, {M}.{E}. and {B}ouzayene, {A}. and {B}ret, {L}. and {B}retagne, {S}. and {B}rumpt, {C}. and {B}uret, {B}. and {C}araux-{P}az, {P}. and {C}heruiyot, {A}. and {C}hlilek, {A}. and {C}lauser, {S}. and {C}ojean, {S}. and {C}uisenier, {B}. and {D}ahane, {N}. and {D}annaoui, {E}. and {D}ard, {C}. and {D}ard{\'e}, {M}.{L}. and {D}e {G}entile, {L}. and {D}ebourgogne, {A}. and {D}echavanne, {C}{\'e}lia and et al.},
  editor = {},
  language = {{ENG}},
  abstract = {{B}ackground {M}utations in the {P}lasmodium falciparum dhfr gene confer resistance to pyrimethamine, which is widely used for malaria chemoprevention in {A}frica. {W}e aimed to evaluate the frequency and evolution of dhfr mutations {P}lasmodium ovale spp in {A}frica and their functional consequences, which are incompletely characterised. {M}ethods {W}e analysed dhfr mutations and their frequencies in {P} ovale spp isolates collected between {F}eb 1, 2004, {A}ug 31, 2023, from the {F}rench {N}ational {M}alaria {R}eference {C}entre collection and from fi eld studies in {B}enin, {G}abon, {K}enya. {G}enetic patterns of positive selection were investigated. {F}ull-length recombinant wild-type and mutant {DHFR} enzymes from both {P} ovale curtisi and {P} ovale wallikeri were expressed in bacteria to test whether the most common mutations reduced pyrimethamine susceptibility. {F}indings {W}e included 518 {P} ovale spp samples (314 {P} ovale curtisi and 204 {P} ovale wallikeri ). {I}n {P} ovale curtisi {A}la15{S}er-{S}er58{A}rg was the most common dhfr mutation (39%; 124 of 314 samples). {I}n {P} ovale wallikeri , mutations were less frequent, with {P}he57{L}eu-{S}er58{A}rg reaching 17% (34 of 204 samples). {T}hese two mutants were the most prevalent in central and east {A}frica and were fi xed in {K}enyan isolates. {W}e detected six and four other non-synonymous mutations, representing 8% (24 isolates) and 2% ( fi ve isolates) of the {P} ovale curtisi {P} ovale wallikeri isolates, respectively. {W}hole-genome sequencing and microsatellite analyses revealed reduced genetic diversity around the mutant pocdhfr and powdhfr genes. {T}he mutant {DHFR} proteins showed structural changes at the pyrimethamine binding site in-silico, con fi rmed by a 4-times increase in pyrimethamine half-maximal inhibitory concentration in an {E}scherichia coli growth assay for the {P}he57{L}eu-{S}er58{A}rg mutant 50-times increase for the {A}la15{S}er-{S}er58{A}rg mutant, compared with the wild-type counterparts. {I}nterpretation {T}he widespread use of sulfadoxine - pyrimethamine for malaria chemoprevention might have exerted fortuitous selection pressure for dhfr mutations in {P} ovale spp. {T}his calls for closer monitoring of dhfr and dhps mutations in {P} ovale spp.},
  keywords = {{AFRIQUE} {SUBSAHARIENNE} ; {BENIN} ; {GABON} ; {KENYA}},
  booktitle = {},
  journal = {{T}he {L}ancet {M}icrobe},
  volume = {5},
  numero = {7},
  pages = {669--678},
  ISSN = {2666-5247},
  year = {2024},
  DOI = {10.1016/s2666-5247(24)00054-5},
  URL = {https://www.documentation.ird.fr/hor/fdi:010091513},
}