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Host serum iron modulates dengue virus acquisition by mosquitoes

Nature Microbiology volume 4, pages 2405–2415 (2019)Cite this article

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Abstract

A blood meal is the primary route through which mosquitoes acquire an arbovirus infection. Blood components or their metabolites may regulate the susceptibility of mosquitoes to arboviruses. Here we report that serum iron in human blood influences dengue virus acquisition by mosquitoes. Dengue virus acquisition by Aedes aegypti was inversely correlated with the iron concentration in serum from human donors. In a mouse–mosquito acquisition model, iron supplementation reduced dengue virus prevalence and viral load, whereas neutralization of serum iron facilitated dengue virus infection in A. aegypti mosquitoes. Of note, mosquitoes feeding on iron-deficient (sideropenic) mice exhibited a higher prevalence of dengue virus. Reversal of the sideropenic status of hosts largely reduced dengue virus acquisition and infection by mosquitoes. Serum iron, rather than haem-bound iron, was utilized by the mosquito iron metabolism pathway to boost the activity of reactive oxygen species in the gut epithelium, subsequently inhibiting infection by dengue virus. On the basis of these results, a status of iron deficiency in the human population might contribute to the vectorial permissiveness to dengue virus, thereby facilitating its spread by mosquitoes.

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Fig. 1: Correlations between basic blood constituents and DENV infectivity in A. aegypti.
Fig. 2: Iron supplementation suppresses DENV acquisition by mosquitoes.
Fig. 3: Mosquito iron metabolism resists DENV infection via ROS activation.
Fig. 4: Iron-deficiency status in the host facilitates DENV acquisition by mosquitoes.
Fig. 5: Reversal of the sideropenic status in hosts reduces DENV acquisition by the mosquitoes.

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Data availability

The sequencing data were deposited in the Short Read Archive (NCBI) under accession number GSE119036. The data that support the findings of this study are available from the corresponding author upon request.

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Acknowledgements

This work was funded by grants from the National Key Research and Development Plan of China (2017YFC1201004, 2018YFA0507202, 2018ZX09711003-004-003, 2016ZX10004001-008 and 2016YFD0500400), the National Natural Science Foundation of China (31825001, 81730063 and 81571975) and Shenzhen San-Ming Project for prevention and research on vector-borne diseases (SZSM201611064). G.C. is a Newton Advanced Fellow awarded by the Academy of Medical Sciences and the Newton Fund. We thank the core facilities of the Center for Life Sciences and Center of Biomedical Analysis (Tsinghua University) for technical assistance.

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Authors and Affiliations

  1. Tsinghua-Peking Center for Life Sciences, School of Medicine, Tsinghua University, Beijing, China

    Yibin Zhu, Liangqin Tong, Kaixiao Nie, Peng Sun, Qingqing Li, Xi Yu, Pa Wu, Chen Yu & Gong Cheng

  2. Institute of Pathogenic Organisms, Shenzhen Center for Disease Control and Prevention, Shenzhen, China

    Yibin Zhu, Liangqin Tong, Kaixiao Nie, Peng Sun, Xi Yu, Pa Wu, Chen Yu & Gong Cheng

  3. School of Life Sciences, Tsinghua University, Beijing, China

    Yibin Zhu & Xi Yu

  4. Center of Excellence in Applied Biosciences, King Mongkut’s Institute of Technology Ladkrabang, Bangkok, Thailand

    Itsanun Wiwatanaratanabutr

  5. Department of Plant Production Technology, Faculty of Agricultural Technology, King Mongkut’s Institute of Technology, Ladkrabang, Bangkok, Thailand

    Itsanun Wiwatanaratanabutr

  6. Clinical Laboratory Department, Tsinghua University Hospital Beijing, Beijing, China

    Tianshi Wu

  7. State Key Laboratory of Infectious Disease Prevention and Control, CCID, ICDC, China CDC, Beijing, China

    Qiyong Liu

  8. 920 Hospital, Joint Logistics Support Force, PLA, Kunming, China

    Zhongqi Bian

  9. Department of Immunology, School of Medicine, University of Connecticut Health Center, Farmington, CT, USA

    Penghua Wang

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Contributions

G.C. designed the experiments and wrote the manuscript; Y.Z. performed the majority of the experiments and analysed data; L.T., Q.Li., K.N., P.S., C.Y., X.Y. and P.Wu. helped with the RNA isolation and qPCR detection. T.W. provided the human blood samples. Q.Liu. provided the field-derived mosquitoes. I.W., Z.B. and P.Wang. contributed experimental suggestions and contributed to the writing of the manuscript. All authors reviewed, critiqued and provided comments on the text.

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Correspondence to Gong Cheng.

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Supplementary Figs. 1–18 and Supplementary Tables 1–5.

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Supplementary Dataset 1

Datasets for Figs. 1a–17b.

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Zhu, Y., Tong, L., Nie, K. et al. Host serum iron modulates dengue virus acquisition by mosquitoes. Nat Microbiol 4, 2405–2415 (2019). https://doi.org/10.1038/s41564-019-0555-x

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