Dietary alterations modulate susceptibility to Plasmodium infection

  • Nature Microbiologyvolume 2pages16001607 (2017)
  • doi:10.1038/s41564-017-0025-2
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The relevance of genetic factors in conferring protection to severe malaria has been demonstrated, as in the case of sickle cell trait and G6PD deficiency1. However, it remains unknown whether environmental components, such as dietary or metabolic variations, can contribute to the outcome of infection2. Here, we show that administration of a high-fat diet to mice for a period as short as 4 days impairs Plasmodium liver infection by over 90%. Plasmodium sporozoites can successfully invade and initiate replication but die inside hepatocytes, thereby are unable to cause severe disease. Transcriptional analyses combined with genetic and chemical approaches reveal that this impairment of infection is mediated by oxidative stress. We show that reactive oxygen species, probably spawned from fatty acid β-oxidation, directly impact Plasmodium survival inside hepatocytes, and parasite load can be rescued by exogenous administration of the antioxidant N-acetylcysteine or the β-oxidation inhibitor etomoxir. Together, these data reveal that acute and transient dietary alterations markedly impact the establishment of a Plasmodium infection and disease outcome.

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  1. 1.

    Karlsson, E. K., Kwiatkowski, D. P. & Sabeti, P. C. Natural selection and infectious disease in human populations. Nat. Rev. Genet. 15, 379–393 (2014).

  2. 2.

    Traoré, K., Arama, C., Médebielle, M., Doumbo, O. & Picot, S. Do advanced glycation end-products play a role in malaria susceptibility? Parasite 23, 15 (2016).

  3. 3.

    Wymann, M. P. & Schneiter, R. Lipid signalling in disease. Nat. Rev. Mol. Cell Biol. 9, 162–176 (2008).

  4. 4.

    Medzhitov, R. Toll-like receptors and innate immunity. Nat. Rev. Immunol. 1, 135–145 (2001).

  5. 5.

    Matsuzawa-Nagata, N. et al. Increased oxidative stress precedes the onset of high-fat diet-induced insulin resistance and obesity. Metabolism 57, 1071–1077 (2008).

  6. 6.

    Wenk, M. R. Lipidomics of host–pathogen interactions. FEBS Lett. 580, 5541–5551 (2006).

  7. 7.

    Prudêncio, M., Rodriguez, A. & Mota, M. M. The silent path to thousands of merozoites: the Plasmodium liver stage. Nat. Rev. Microbiol. 4, 849–856 (2006).

  8. 8.

    Deschermeier, C. et al. Mitochondrial lipoic acid scavenging is essential for Plasmodium berghei liver stage development. Cell. Microbiol. 14, 416–430 (2012).

  9. 9.

    Itoe, M. A. et al. Host cell phosphatidylcholine is a key mediator of malaria parasite survival during liver stage infection. Cell Host Microbe 16, 778–786 (2014).

  10. 10.

    Wiedemann, M. S. et al. Short-term HFD does not alter lipolytic function of adipocytes. Adipocyte 3, 115–120 (2014).

  11. 11.

    Sinnis, P., Willnow, T. E., Briones, M. R. S. & Herzfl, J. Remnant lipoproteins inhibit malaria sporozoite invasion of hepatocytes. J. Exp. Med. 184, 945–954 (1996).

  12. 12.

    Liehl, P. & Mota, M. M. Innate recognition of malarial parasites by mammalian hosts. Int. J. Parasitol. 42, 557–566 (2012).

  13. 13.

    Mota, M. M. & Rodriguez, A. (eds) Malaria: Immune Response to Infection and Vaccination (Springer, Cham, 2017).

  14. 14.

    Lyons, C. L., Kennedy, E. B. & Roche, H. M. Metabolic inflammation-differential modulation by dietary constituents. Nutrients 8, E247 (2016).

  15. 15.

    Deng, Z. et al. Immature myeloid cells induced by a high-fat diet contribute to liver inflammation. Hepatology 50, 1412–1420 (2009).

  16. 16.

    Fritsche, K. L. The science of fatty acids and inflammation. Adv. Nutr. 6, 293S–301S (2015).

  17. 17.

    Hanson, K. K. et al. Torins are potent antimalarials that block replenishment of Plasmodium liver stage parasitophorous vacuole membrane proteins. Proc. Natl. Acad. Sci. USA 110, E2838–E2847 (2013).

  18. 18.

    Raj, L. et al. Selective killing of cancer cells by a small molecule targeting the stress response to ROS. Nature 475, 231–234 (2011).

  19. 19.

    Cardoso, A. R., Kakimoto, P. A. H. B. & Kowaltowski, A. J. Diet-sensitive sources of reactive oxygen species in liver mitochondria: role of very long chain acyl-CoA dehydrogenases. PLoS ONE http://doi.org/10.1371/journal.pone.0077088 (2013).

  20. 20.

    Luiken, J. J. F. P. et al. Etomoxir-induced partial carnitine palmitoyltransferase-I (CPT-I) inhibition in vivo does not alter cardiac long-chain fatty acid uptake and oxidation rates. Biochem. J. 419, 447–455 (2009).

  21. 21.

    Kwiatkowski, D. P. P. How malaria has affected the human genome and what human genetics can teach us about malaria. Am. J. Hum. Genet. 77, 171–190 (2005).

  22. 22.

    Mejia, P. et al. Dietary restriction protects against experimental cerebral malaria via leptin modulation and T-cell mTORC1 suppression. Nat. Commun. 6, 6050 (2015).

  23. 23.

    Mancio-Silva, L. et al. Nutrient sensing modulates malaria parasite virulence. Nature 547, 213–216 (2017).

  24. 24.

    Miller, J. L., Harupa, A., Kappe, S. H. I. & Mikolajczak, S. A. Plasmodium yoelii macrophage migration inhibitory factor is necessary for efficient liver-stage development. Infect. Immun. 80, 1399–1407 (2012).

  25. 25.

    Ng, S. et al. Hypoxia promotes liver-stage malaria infection in primary human hepatocytes in vitro. Dis. Model. Mech. 7, 215–224 (2014).

  26. 26.

    Cappellini, M. & Fiorelli, G. Glucose-6-phosphate dehydrogenase deficiency. Lancet 371, 64–74 (2008).

  27. 27.

    Voskou, S., Aslan, M., Fanis, P., Phylactides, M. & Kleanthous, M. Oxidative stress in beta-thalassaemia and sickle cell disease. Redox Biol. 6, 226–239 (2015).

  28. 28.

    NCD Risk Factor Collaboration (NCD-RisC). et al. Trends in adult body-mass index in 200 countries from 1975 to 2014: a pooled analysis of 1698 population-based measurement studies with 19·2 million participants. Lancet 387, 1377–1396 (2016).

  29. 29.

    Arama, C. et al. Ethnic differences in susceptibility to malaria: what have we learned from immuno-epidemiological studies in West Africa? Acta Tropica  146, 152–156 (2015).

  30. 30.

    Glew, R. H. et al. Lipid profiles and trans fatty acids in serum phospholipids of semi-nomadic fulani in Northern Nigeria. J. Heal. Popul. Nutr. 28, 159–166 (2010).

  31. 31.

    Zuzarte-Luis, V., Sales-Dias, J. & Mota, M. M. Simple, sensitive and quantitative bioluminescence assay for determination of malaria pre-patent period. Malar. J. 13, 15 (2014).

  32. 32.

    Thoolen, B. et al. Proliferative and nonproliferative lesions of the rat and mouse hepatobiliary system. Toxicol. Pathol. 38, 5S–81S (2010).

  33. 33.

    van Goor, H., Gerrits, P. O. & Grond, J. The application of lipid-soluble stains in plastic-embedded sections. Histochemistry 85, 251–253 (1986).

  34. 34.

    Umemura, A. et al. Liver damage, inflammation, and enhanced tumorigenesis after persistent mTORC1 inhibition. Cell Metab. 20, 133–144 (2014).

  35. 35.

    Zhang, W. et al. PCB 126 and other dioxin-like PCBs specifically suppress hepatic PEPCK expression via the aryl hydrocarbon receptor. PLoS ONE 7, e37103 (2012).

  36. 36.

    Gonçalves, L. A., Vigário, A. M. & Penha-Gonçalves, C. Improved isolation of murine hepatocytes for in vitro malaria liver stage studies. Malar. J. 6, 169 (2007).

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The authors would like to thank A. Parreira for mosquito and sporozoite production; iMM’s rodent facility and histology unit; A.M. Vigário, A. Pamplona and S. Portugal for discussion; A.M. Vigário, I. Bento and I. Vera for critical reading of the manuscript. This work was supported by Fundação para a Ciência e Tecnologia (Portugal) through grant EXCL/IMI-MIC/0056/2012 and the ERC (agreement No. 311502) to M.M.M. V.Z.-L. was sponsored by EMBO (ALTF 357-2009) and FCT (BPD-81953-2011).

Author information

Author notes

    • Céline K. Carret

    Present address: EMBO, Meyerhofstrasse 1, 69117, Heidelberg, Germany

  1. João Mello-Vieira and Inês M. Marreiros contributed equally to this work.


  1. Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, 1649-028, Lisboa, Portugal

    • Vanessa Zuzarte-Luís
    • , João Mello-Vieira
    • , Inês M. Marreiros
    • , Peter Liehl
    • , Ângelo F. Chora
    • , Céline K. Carret
    • , Tânia Carvalho
    •  & Maria M. Mota


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V.Z.-L. and M.M.M. conceived and designed the study and wrote the manuscript. V.Z.-L., J.M.-V., I.M.M., P.L. and A.F.C. performed the experiments, acquired the data, performed data analysis and interpreted results. V.Z.-L. and C.K.C. performed transcriptome data analysis. T.C. performed histology data analysis. All authors read, edited and approved the final manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Vanessa Zuzarte-Luís or Maria M. Mota.

Electronic supplementary material

  1. Supplementary Information

    Supplementary Figures 1–7, Supplementary Table 1.

  2. Life Sciences Reporting Summary

  3. Supplementary Table 2

    Differentially expressed genes.

  4. Supplementary Table 3

    Complete statistical analysis.