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Transgenic Anopheles stephensi coexpressing single-chain antibodies resist Plasmodium falciparum development

Alison T. Isaacs, Nijole Jasinskiene, Mikhail Tretiakov, Isabelle Thiery, Agnès Zettor, Catherine Bourgouin, and Anthony A. James
PNAS published ahead of print June 11, 2012 https://doi.org/10.1073/pnas.1207738109
Alison T. Isaacs
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Mikhail Tretiakov
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Isabelle Thiery
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Agnès Zettor
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Catherine Bourgouin
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  1. Contributed by Anthony A. James, May 7, 2012 (sent for review January 28, 2012)

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Abstract

Anopheles stephensi mosquitoes expressing m1C3, m4B7, or m2A10 single-chain antibodies (scFvs) have significantly lower levels of infection compared to controls when challenged with Plasmodium falciparum, a human malaria pathogen. These scFvs are derived from antibodies specific to a parasite chitinase, the 25 kDa protein and the circumsporozoite protein, respectively. Transgenes comprising m2A10 in combination with either m1C3 or m4B7 were inserted into previously-characterized mosquito chromosomal “docking” sites using site-specific recombination. Transgene expression was evaluated at four different genomic locations and a docking site that permitted tissue- and sex-specific expression was researched further. Fitness studies of docking site and dual scFv transgene strains detected only one significant fitness cost: adult docking-site males displayed a late-onset reduction in survival. The m4B7/m2A10 mosquitoes challenged with P. falciparum had few or no sporozoites, the parasite stage infective to humans, in three of four experiments. No sporozoites were detected in m1C3/m2A10 mosquitoes in challenge experiments when both genes were induced at developmentally relevant times. These studies support the conclusion that expression of a single copy of a dual scFv transgene can completely inhibit parasite development without imposing a fitness cost on the mosquito.

  • mosquito vector
  • population replacement
  • genetic engineering

Footnotes

  • ↵1To whom correspondence should be addressed. E-mail: aajames{at}uci.edu.
  • Author contributions: A.T.I., N.J., I.T., A.Z., C.B., and A.A.J. designed research; A.T.I., N.J., M.T., I.T., A.Z., and C.B. performed research; A.T.I. contributed new reagents/analytic tools; A.T.I. and A.A.J. analyzed data; and A.T.I., C.B., and A.A.J. wrote the paper.

  • The authors declare no conflict of interest.

  • This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1207738109/-/DCSupplemental.

Freely available online through the PNAS open access option.

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Transgene elimination of malaria parasites
Alison T. Isaacs, Nijole Jasinskiene, Mikhail Tretiakov, Isabelle Thiery, Agnès Zettor, Catherine Bourgouin, Anthony A. James
Proceedings of the National Academy of Sciences Jun 2012, DOI: 10.1073/pnas.1207738109

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Transgene elimination of malaria parasites
Alison T. Isaacs, Nijole Jasinskiene, Mikhail Tretiakov, Isabelle Thiery, Agnès Zettor, Catherine Bourgouin, Anthony A. James
Proceedings of the National Academy of Sciences Jun 2012, DOI: 10.1073/pnas.1207738109
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