Plasmodium falciparum erythrocyte membrane protein 1 domain cassettes 8 and 13 are associated with severe malaria in children

Thomas Lavstsen; Louise Turner; Fredy Saguti; Pamela Almeida Magistrado; Thomas Salhøj Rask; Jakob Schmidt Jespersen; Christian William Wang; Sanne Schou Berger; Vito Baraka; Andrea Marion Marquard; Andaine Seguin-Orlando; Eske Willerslev; Tom Gilbert; John Peter Andrea Lusingu; Thor Grundtvig Theander

doi:10.1073/pnas.1120455109

Plasmodium falciparum erythrocyte membrane protein 1 domain cassettes 8 and 13 are associated with severe malaria in children

Thomas Lavstsen, Louise Turner, Fredy Saguti, Pamela Almeida Magistrado, Thomas Salhøj Rask, Jakob Schmidt Jespersen, Christian William Wang, Sanne Schou Berger, Vito Baraka, Andrea Marion Marquard, Andaine Seguin-Orlando, Eske Willerslev, Tom Gilbert, John Peter Andrea Lusingu, Thor Grundtvig Theander

173 Citations (Scopus)

Abstract

The clinical outcome of Plasmodium falciparum infections ranges from asymptomatic parasitemia to severe malaria syndromes associated with high mortality. The virulence of P. falciparum infections is associated with the type of P. falciparum erythrocyte membrane protein 1 (PfEMP1) expressed on the surface of infected erythrocytes to anchor these to the vascular lining. Although var2csa, the var gene encoding the PfEMP1 associated with placental malaria, was discovered in 2003, the identification of the var/PfEMP1 variants associated with severe malaria in children has remained elusive. To identify var/PfEMP1 variants associated with severe disease outcome, we compared var transcript levels in parasites from 88 children with severe malaria and 40 children admitted to the hospital with uncomplicated malaria. Transcript analysis was performed by RT-quantitative PCR using a set of 42 primer pairs amplifying var subtype-specific loci covering most var/PfEMP1 subtypes. In addition, we characterized the near-full-length sequence of the most prominently expressed var genes in three patients diagnosed with severe anemia and/or cerebral malaria. The combined analysis showed that severe malaria syndromes, including severe anemia and cerebral malaria, are associated with high transcript levels of PfEMP1 domain cassette 8-encoding var genes. Transcript levels of group A var genes, including genes encoding domain cassette 13, were also significantly higher in patients with severe syndromes compared with those with uncomplicated malaria. This study specifies the var/PfEMP1 types expressed in severe malaria in children, and thereby provides unique targets for future efforts to prevent and treat severe malaria infections.

Original language	English
Journal	Proceedings of the National Academy of Sciences of the United States of America
Volume	109
Issue number	26
Pages (from-to)	E1791-E1800
Number of pages	10
ISSN	0027-8424
DOIs	https://doi.org/10.1073/pnas.1120455109
Publication status	Published - 26 Jun 2012

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Lavstsen, T., Turner, L., Saguti, F., Magistrado, P. A., Rask, T. S., Jespersen, J. S., Wang, C. W., Berger, S. S., Baraka, V., Marquard, A. M., Seguin-Orlando, A., Willerslev, E., Gilbert, T., Lusingu, J. P. A., & Theander, T. G. (2012). Plasmodium falciparum erythrocyte membrane protein 1 domain cassettes 8 and 13 are associated with severe malaria in children. Proceedings of the National Academy of Sciences of the United States of America, 109(26), E1791-E1800. https://doi.org/10.1073/pnas.1120455109

Plasmodium falciparum erythrocyte membrane protein 1 domain cassettes 8 and 13 are associated with severe malaria in children. / Lavstsen, Thomas ; Turner, Louise; Saguti, Fredy et al.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 109, No. 26, 26.06.2012, p. E1791-E1800.

Research output: Contribution to journal › Journal article › Research › peer-review

Lavstsen, T , Turner, L, Saguti, F, Magistrado, PA, Rask, TS, Jespersen, JS , Wang, CW, Berger, SS, Baraka, V, Marquard, AM, Seguin-Orlando, A, Willerslev, E , Gilbert, T, Lusingu, JPA & Theander, TG 2012, 'Plasmodium falciparum erythrocyte membrane protein 1 domain cassettes 8 and 13 are associated with severe malaria in children', Proceedings of the National Academy of Sciences of the United States of America, vol. 109, no. 26, pp. E1791-E1800. https://doi.org/10.1073/pnas.1120455109

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abstract = "The clinical outcome of Plasmodium falciparum infections ranges from asymptomatic parasitemia to severe malaria syndromes associated with high mortality. The virulence of P. falciparum infections is associated with the type of P. falciparum erythrocyte membrane protein 1 (PfEMP1) expressed on the surface of infected erythrocytes to anchor these to the vascular lining. Although var2csa, the var gene encoding the PfEMP1 associated with placental malaria, was discovered in 2003, the identification of the var/PfEMP1 variants associated with severe malaria in children has remained elusive. To identify var/PfEMP1 variants associated with severe disease outcome, we compared var transcript levels in parasites from 88 children with severe malaria and 40 children admitted to the hospital with uncomplicated malaria. Transcript analysis was performed by RT-quantitative PCR using a set of 42 primer pairs amplifying var subtype-specific loci covering most var/PfEMP1 subtypes. In addition, we characterized the near-full-length sequence of the most prominently expressed var genes in three patients diagnosed with severe anemia and/or cerebral malaria. The combined analysis showed that severe malaria syndromes, including severe anemia and cerebral malaria, are associated with high transcript levels of PfEMP1 domain cassette 8-encoding var genes. Transcript levels of group A var genes, including genes encoding domain cassette 13, were also significantly higher in patients with severe syndromes compared with those with uncomplicated malaria. This study specifies the var/PfEMP1 types expressed in severe malaria in children, and thereby provides unique targets for future efforts to prevent and treat severe malaria infections.",

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AU - Rask, Thomas Salhøj

AU - Jespersen, Jakob Schmidt

AU - Wang, Christian William

AU - Berger, Sanne Schou

AU - Baraka, Vito

AU - Marquard, Andrea Marion

AU - Seguin-Orlando, Andaine

AU - Willerslev, Eske

AU - Gilbert, Tom

AU - Lusingu, John Peter Andrea

AU - Theander, Thor Grundtvig

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AB - The clinical outcome of Plasmodium falciparum infections ranges from asymptomatic parasitemia to severe malaria syndromes associated with high mortality. The virulence of P. falciparum infections is associated with the type of P. falciparum erythrocyte membrane protein 1 (PfEMP1) expressed on the surface of infected erythrocytes to anchor these to the vascular lining. Although var2csa, the var gene encoding the PfEMP1 associated with placental malaria, was discovered in 2003, the identification of the var/PfEMP1 variants associated with severe malaria in children has remained elusive. To identify var/PfEMP1 variants associated with severe disease outcome, we compared var transcript levels in parasites from 88 children with severe malaria and 40 children admitted to the hospital with uncomplicated malaria. Transcript analysis was performed by RT-quantitative PCR using a set of 42 primer pairs amplifying var subtype-specific loci covering most var/PfEMP1 subtypes. In addition, we characterized the near-full-length sequence of the most prominently expressed var genes in three patients diagnosed with severe anemia and/or cerebral malaria. The combined analysis showed that severe malaria syndromes, including severe anemia and cerebral malaria, are associated with high transcript levels of PfEMP1 domain cassette 8-encoding var genes. Transcript levels of group A var genes, including genes encoding domain cassette 13, were also significantly higher in patients with severe syndromes compared with those with uncomplicated malaria. This study specifies the var/PfEMP1 types expressed in severe malaria in children, and thereby provides unique targets for future efforts to prevent and treat severe malaria infections.

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SN - 0027-8424

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JF - Proceedings of the National Academy of Sciences of the United States of America

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ER -

Plasmodium falciparum erythrocyte membrane protein 1 domain cassettes 8 and 13 are associated with severe malaria in children

Abstract

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