Pairwise growth competitions identify relative fitness relationships among artemisinin resistant Plasmodium falciparum field isolates
Identifieur interne : 000973 ( Ncbi/Merge ); précédent : 000972; suivant : 000974Pairwise growth competitions identify relative fitness relationships among artemisinin resistant Plasmodium falciparum field isolates
Auteurs : Abigail R. Tirrell [États-Unis] ; Katelyn M. Vendrely [États-Unis] ; Lisa A. Checkley [États-Unis] ; Sage Z. Davis [États-Unis] ; Marina Mcdew-White [États-Unis] ; Ian H. Cheeseman [États-Unis] ; Ashley M. Vaughan [États-Unis] ; François H. Nosten [Thaïlande, Royaume-Uni] ; Timothy J. C. Anderson [États-Unis] ; Michael T. Ferdig [États-Unis]Source :
- Malaria Journal [ 1475-2875 ] ; 2019.
Abstract
Competitive outcomes between co-infecting malaria parasite lines can reveal fitness disparities in blood stage growth. Blood stage fitness costs often accompany the evolution of drug resistance, with the expectation that relatively fitter parasites will be more likely to spread in populations. With the recent emergence of artemisinin resistance, it is important to understand the relative competitive fitness of the metabolically active asexual blood stage parasites. Genetically distinct drug resistant parasite clones with independently evolved sets of mutations are likely to vary in asexual proliferation rate, contributing to their chance of transmission to the mosquito vector.
An optimized in vitro 96-well plate-based protocol was used to quantitatively measure-head-to-head competitive fitness during blood stage development between seven genetically distinct field isolates from a hotspot of emerging artemisinin resistance and the laboratory strain, NF54. These field isolates were isolated from patients in Southeast Asia carrying different alleles of
Twenty-eight pairwise competitive growth outcomes allowed for an unambiguous ranking among a set of seven genetically distinct parasite lines isolated from patients in Southeast Asia displaying a range of both
This optimized competitive growth assay can be employed for assessment of relative growth as an index of fitness during the asexual blood stage growth between natural lines carrying different genetic variants associated with artemisinin resistance. Improved understanding of the fitness costs of different parasites proliferating in human blood and the role different resistance mutations play in the context of specific genetic backgrounds will contribute to an understanding of the potential for specific mutations to spread in populations, with the potential to inform targeted strategies for malaria therapy.
Url:
DOI: 10.1186/s12936-019-2934-4
PubMed: 31462253
PubMed Central: 6714446
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<sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Pairwise growth competitions identify relative fitness relationships among artemisinin resistant <italic>Plasmodium falciparum</italic>
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<author><name sortKey="Ferdig, Michael T" sort="Ferdig, Michael T" uniqKey="Ferdig M" first="Michael T." last="Ferdig">Michael T. Ferdig</name>
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<imprint><date when="2019">2019</date>
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<front><div type="abstract" xml:lang="en"><sec><title>Background</title>
<p id="Par1">Competitive outcomes between co-infecting malaria parasite lines can reveal fitness disparities in blood stage growth. Blood stage fitness costs often accompany the evolution of drug resistance, with the expectation that relatively fitter parasites will be more likely to spread in populations. With the recent emergence of artemisinin resistance, it is important to understand the relative competitive fitness of the metabolically active asexual blood stage parasites. Genetically distinct drug resistant parasite clones with independently evolved sets of mutations are likely to vary in asexual proliferation rate, contributing to their chance of transmission to the mosquito vector.</p>
</sec>
<sec><title>Methods</title>
<p id="Par2">An optimized in vitro 96-well plate-based protocol was used to quantitatively measure-head-to-head competitive fitness during blood stage development between seven genetically distinct field isolates from a hotspot of emerging artemisinin resistance and the laboratory strain, NF54. These field isolates were isolated from patients in Southeast Asia carrying different alleles of <italic>kelch13</italic>
and included both artemisinin-sensitive and artemisinin-resistant isolates. Fluorescent labeled microsatellite markers were used to track the relative densities of each parasite throughout the co-growth period of 14–60 days. All-on-all competitions were conducted for the panel of eight parasite lines (28 pairwise competitions) to determine their quantitative competitive fitness relationships.</p>
</sec>
<sec><title>Results</title>
<p id="Par3">Twenty-eight pairwise competitive growth outcomes allowed for an unambiguous ranking among a set of seven genetically distinct parasite lines isolated from patients in Southeast Asia displaying a range of both <italic>kelch13</italic>
alleles and clinical clearance times and a laboratory strain, NF54. This comprehensive series of assays established the growth relationships among the eight parasite lines. Interestingly, a clinically artemisinin resistant parasite line that carries the wild-type form of <italic>kelch13</italic>
outcompeted all other parasites in this study. Furthermore, a <italic>kelch13</italic>
mutant line (E252Q) was competitively more fit without drug than lines with other resistance-associated <italic>kelch13</italic>
alleles, including the C580Y allele that has expanded to high frequencies under drug pressure in Southeast Asian resistant populations.</p>
</sec>
<sec><title>Conclusions</title>
<p id="Par4">This optimized competitive growth assay can be employed for assessment of relative growth as an index of fitness during the asexual blood stage growth between natural lines carrying different genetic variants associated with artemisinin resistance. Improved understanding of the fitness costs of different parasites proliferating in human blood and the role different resistance mutations play in the context of specific genetic backgrounds will contribute to an understanding of the potential for specific mutations to spread in populations, with the potential to inform targeted strategies for malaria therapy.</p>
</sec>
</div>
</front>
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<pmc article-type="research-article"><pmc-dir>properties open_access</pmc-dir>
<front><journal-meta><journal-id journal-id-type="nlm-ta">Malar J</journal-id>
<journal-id journal-id-type="iso-abbrev">Malar. J</journal-id>
<journal-title-group><journal-title>Malaria Journal</journal-title>
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<issn pub-type="epub">1475-2875</issn>
<publisher><publisher-name>BioMed Central</publisher-name>
<publisher-loc>London</publisher-loc>
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<article-meta><article-id pub-id-type="pmid">31462253</article-id>
<article-id pub-id-type="pmc">6714446</article-id>
<article-id pub-id-type="publisher-id">2934</article-id>
<article-id pub-id-type="doi">10.1186/s12936-019-2934-4</article-id>
<article-categories><subj-group subj-group-type="heading"><subject>Research</subject>
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<title-group><article-title>Pairwise growth competitions identify relative fitness relationships among artemisinin resistant <italic>Plasmodium falciparum</italic>
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</contrib>
<contrib contrib-type="author"><name><surname>Vaughan</surname>
<given-names>Ashley M.</given-names>
</name>
<xref ref-type="aff" rid="Aff3">3</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Nosten</surname>
<given-names>François H.</given-names>
</name>
<xref ref-type="aff" rid="Aff4">4</xref>
<xref ref-type="aff" rid="Aff5">5</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Anderson</surname>
<given-names>Timothy J. C.</given-names>
</name>
<xref ref-type="aff" rid="Aff2">2</xref>
</contrib>
<contrib contrib-type="author" corresp="yes"><name><surname>Ferdig</surname>
<given-names>Michael T.</given-names>
</name>
<address><email>ferdig.1@nd.edu</email>
</address>
<xref ref-type="aff" rid="Aff1">1</xref>
</contrib>
<aff id="Aff1"><label>1</label>
<institution-wrap><institution-id institution-id-type="ISNI">0000 0001 2168 0066</institution-id>
<institution-id institution-id-type="GRID">grid.131063.6</institution-id>
<institution>Eck Institute for Global Health, Dept. of Biological Sciences,</institution>
<institution>University of Notre Dame,</institution>
</institution-wrap>
Notre Dame, IN USA</aff>
<aff id="Aff2"><label>2</label>
<institution-wrap><institution-id institution-id-type="ISNI">0000 0001 2215 0219</institution-id>
<institution-id institution-id-type="GRID">grid.250889.e</institution-id>
<institution>Texas Biomedical Research Institute,</institution>
</institution-wrap>
San Antonio, TX USA</aff>
<aff id="Aff3"><label>3</label>
<institution-wrap><institution-id institution-id-type="ISNI">0000 0000 9026 4165</institution-id>
<institution-id institution-id-type="GRID">grid.240741.4</institution-id>
<institution>Seattle Children’s Research Institute,</institution>
</institution-wrap>
Seattle, WA USA</aff>
<aff id="Aff4"><label>4</label>
<institution-wrap><institution-id institution-id-type="ISNI">0000 0004 1937 0490</institution-id>
<institution-id institution-id-type="GRID">grid.10223.32</institution-id>
<institution>Shoklo Malaria Research Unit, Mahidol-Oxford Tropical Medicine Research Unit,</institution>
<institution>Mahidol University,</institution>
</institution-wrap>
Mae Sot, Thailand</aff>
<aff id="Aff5"><label>5</label>
<institution-wrap><institution-id institution-id-type="ISNI">0000 0004 1936 8948</institution-id>
<institution-id institution-id-type="GRID">grid.4991.5</institution-id>
<institution>Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine Research Building,</institution>
<institution>University of Oxford Old Road Campus,</institution>
</institution-wrap>
Oxford, UK</aff>
</contrib-group>
<pub-date pub-type="epub"><day>28</day>
<month>8</month>
<year>2019</year>
</pub-date>
<pub-date pub-type="pmc-release"><day>28</day>
<month>8</month>
<year>2019</year>
</pub-date>
<pub-date pub-type="collection"><year>2019</year>
</pub-date>
<volume>18</volume>
<elocation-id>295</elocation-id>
<history><date date-type="received"><day>25</day>
<month>6</month>
<year>2019</year>
</date>
<date date-type="accepted"><day>23</day>
<month>8</month>
<year>2019</year>
</date>
</history>
<permissions><copyright-statement>© The Author(s) 2019</copyright-statement>
<license license-type="OpenAccess"><license-p><bold>Open Access</bold>
This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (<ext-link ext-link-type="uri" xlink:href="http://creativecommons.org/licenses/by/4.0/">http://creativecommons.org/licenses/by/4.0/</ext-link>
), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (<ext-link ext-link-type="uri" xlink:href="http://creativecommons.org/publicdomain/zero/1.0/">http://creativecommons.org/publicdomain/zero/1.0/</ext-link>
) applies to the data made available in this article, unless otherwise stated.</license-p>
</license>
</permissions>
<abstract id="Abs1"><sec><title>Background</title>
<p id="Par1">Competitive outcomes between co-infecting malaria parasite lines can reveal fitness disparities in blood stage growth. Blood stage fitness costs often accompany the evolution of drug resistance, with the expectation that relatively fitter parasites will be more likely to spread in populations. With the recent emergence of artemisinin resistance, it is important to understand the relative competitive fitness of the metabolically active asexual blood stage parasites. Genetically distinct drug resistant parasite clones with independently evolved sets of mutations are likely to vary in asexual proliferation rate, contributing to their chance of transmission to the mosquito vector.</p>
</sec>
<sec><title>Methods</title>
<p id="Par2">An optimized in vitro 96-well plate-based protocol was used to quantitatively measure-head-to-head competitive fitness during blood stage development between seven genetically distinct field isolates from a hotspot of emerging artemisinin resistance and the laboratory strain, NF54. These field isolates were isolated from patients in Southeast Asia carrying different alleles of <italic>kelch13</italic>
and included both artemisinin-sensitive and artemisinin-resistant isolates. Fluorescent labeled microsatellite markers were used to track the relative densities of each parasite throughout the co-growth period of 14–60 days. All-on-all competitions were conducted for the panel of eight parasite lines (28 pairwise competitions) to determine their quantitative competitive fitness relationships.</p>
</sec>
<sec><title>Results</title>
<p id="Par3">Twenty-eight pairwise competitive growth outcomes allowed for an unambiguous ranking among a set of seven genetically distinct parasite lines isolated from patients in Southeast Asia displaying a range of both <italic>kelch13</italic>
alleles and clinical clearance times and a laboratory strain, NF54. This comprehensive series of assays established the growth relationships among the eight parasite lines. Interestingly, a clinically artemisinin resistant parasite line that carries the wild-type form of <italic>kelch13</italic>
outcompeted all other parasites in this study. Furthermore, a <italic>kelch13</italic>
mutant line (E252Q) was competitively more fit without drug than lines with other resistance-associated <italic>kelch13</italic>
alleles, including the C580Y allele that has expanded to high frequencies under drug pressure in Southeast Asian resistant populations.</p>
</sec>
<sec><title>Conclusions</title>
<p id="Par4">This optimized competitive growth assay can be employed for assessment of relative growth as an index of fitness during the asexual blood stage growth between natural lines carrying different genetic variants associated with artemisinin resistance. Improved understanding of the fitness costs of different parasites proliferating in human blood and the role different resistance mutations play in the context of specific genetic backgrounds will contribute to an understanding of the potential for specific mutations to spread in populations, with the potential to inform targeted strategies for malaria therapy.</p>
</sec>
</abstract>
<kwd-group xml:lang="en"><title>Keywords</title>
<kwd>Competitive growth</kwd>
<kwd>Fitness</kwd>
<kwd>Artemisinin resistance</kwd>
<kwd><italic>kelch13</italic>
</kwd>
<kwd>Population genetics</kwd>
</kwd-group>
<funding-group><award-group><funding-source><institution-wrap><institution-id institution-id-type="FundRef">http://dx.doi.org/10.13039/100000060</institution-id>
<institution>National Institute of Allergy and Infectious Diseases</institution>
</institution-wrap>
</funding-source>
<award-id>P01 AI127338</award-id>
<award-id>R37 A1048071</award-id>
<principal-award-recipient><name><surname>Anderson</surname>
<given-names>Timothy J. C.</given-names>
</name>
<name><surname>Ferdig</surname>
<given-names>Michael T.</given-names>
</name>
</principal-award-recipient>
</award-group>
</funding-group>
<custom-meta-group><custom-meta><meta-name>issue-copyright-statement</meta-name>
<meta-value>© The Author(s) 2019</meta-value>
</custom-meta>
</custom-meta-group>
</article-meta>
</front>
</pmc>
<affiliations><list><country><li>Royaume-Uni</li>
<li>Thaïlande</li>
<li>États-Unis</li>
</country>
<region><li>Indiana</li>
<li>Texas</li>
<li>Washington (État)</li>
</region>
</list>
<tree><country name="États-Unis"><region name="Indiana"><name sortKey="Tirrell, Abigail R" sort="Tirrell, Abigail R" uniqKey="Tirrell A" first="Abigail R." last="Tirrell">Abigail R. Tirrell</name>
</region>
<name sortKey="Anderson, Timothy J C" sort="Anderson, Timothy J C" uniqKey="Anderson T" first="Timothy J. C." last="Anderson">Timothy J. C. Anderson</name>
<name sortKey="Checkley, Lisa A" sort="Checkley, Lisa A" uniqKey="Checkley L" first="Lisa A." last="Checkley">Lisa A. Checkley</name>
<name sortKey="Cheeseman, Ian H" sort="Cheeseman, Ian H" uniqKey="Cheeseman I" first="Ian H." last="Cheeseman">Ian H. Cheeseman</name>
<name sortKey="Davis, Sage Z" sort="Davis, Sage Z" uniqKey="Davis S" first="Sage Z." last="Davis">Sage Z. Davis</name>
<name sortKey="Ferdig, Michael T" sort="Ferdig, Michael T" uniqKey="Ferdig M" first="Michael T." last="Ferdig">Michael T. Ferdig</name>
<name sortKey="Mcdew White, Marina" sort="Mcdew White, Marina" uniqKey="Mcdew White M" first="Marina" last="Mcdew-White">Marina Mcdew-White</name>
<name sortKey="Vaughan, Ashley M" sort="Vaughan, Ashley M" uniqKey="Vaughan A" first="Ashley M." last="Vaughan">Ashley M. Vaughan</name>
<name sortKey="Vendrely, Katelyn M" sort="Vendrely, Katelyn M" uniqKey="Vendrely K" first="Katelyn M." last="Vendrely">Katelyn M. Vendrely</name>
</country>
<country name="Thaïlande"><noRegion><name sortKey="Nosten, Francois H" sort="Nosten, Francois H" uniqKey="Nosten F" first="François H." last="Nosten">François H. Nosten</name>
</noRegion>
</country>
<country name="Royaume-Uni"><noRegion><name sortKey="Nosten, Francois H" sort="Nosten, Francois H" uniqKey="Nosten F" first="François H." last="Nosten">François H. Nosten</name>
</noRegion>
</country>
</tree>
</affiliations>
</record>
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