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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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.
Rigau-Perez, J. G. et al. Dengue and dengue haemorrhagic fever. Lancet 352, 971–977 (1998).
Bhatt, S. et al. The global distribution and burden of dengue. Nature 496, 504–507 (2013).
Kraemer, M. U. et al. The global distribution of the arbovirus vectors Aedes aegypti and Ae. albopictus. eLife 4, e08347 (2015).
Franz, A. W., Kantor, A. M., Passarelli, A. L. & Clem, R. J. Tissue barriers to arbovirus infection in mosquitoes. Viruses 7, 3741–3767 (2015).
Cheng, G., Liu, Y., Wang, P. & Xiao, X. Mosquito defense strategies against viral infection. Trends Parasitol. 32, 177–186 (2016).
Nguyet, M. N. et al. Host and viral features of human dengue cases shape the population of infected and infectious Aedes aegypti mosquitoes. Proc. Natl Acad. Sci. USA 110, 9072–9077 (2013).
Wagar, Z. L., Tree, M. O., Mpoy, M. C. & Conway, M. J. Low density lipopolyprotein inhibits flavivirus acquisition in Aedes aegypti. Insect Mol. Biol. 26, 734–742 (2017).
Zhu, Y. et al. Blood meal acquisition enhances arbovirus replication in mosquitoes through activation of the GABAergic system. Nat. Commun. 8, 1262 (2017).
Bennink, S., Kiesow, M. J. & Pradel, G. The development of malaria parasites in the mosquito midgut. Cell. Microbiol. 18, 905–918 (2016).
Simon, N. et al. Malaria parasites co-opt human factor H to prevent complement-mediated lysis in the mosquito midgut. Cell Host Microbe 13, 29–41 (2013).
Drexler, A. L. et al. Human IGF1 regulates midgut oxidative stress and epithelial homeostasis to balance lifespan and Plasmodium falciparum resistance in Anopheles stephensi. PLoS Pathog. 10, e1004231 (2014).
Liu, Y. et al. Evolutionary enhancement of Zika virus infectivity in Aedes aegypti mosquitoes. Nature 545, 482–486 (2017).
Liu, J. et al. Flavivirus NS1 protein in infected host sera enhances viral acquisition by mosquitoes. Nat. Microbiol. 1, 16087 (2016).
Gibson, S. Micronutrient intakes, micronutrient status and lipid profiles among young people consuming different amounts of breakfast cereals: further analysis of data from the National Diet and Nutrition Survey of Young People aged 4 to 18 years. Public Health Nutr. 6, 815–820 (2003).
Gibson, S. & Boyd, A. Associations between added sugars and micronutrient intakes and status: further analysis of data from the National Diet and Nutrition Survey of Young People aged 4 to 18 years. Br. J. Nutr. 101, 100–107 (2009).
Rivera-Perez, C., Clifton, M. E. & Noriega, F. G. How micronutrients influence the physiology of mosquitoes. Curr. Opin. Insect Sci. 23, 112–117 (2017).
Keberle, H. The biochemistry of desferrioxamine and its relation to iron metabolism. Ann. NY Acad. Sci. 119, 758–768 (1964).
Guo, X. et al. Nasal delivery of nanoliposome-encapsulated ferric ammonium citrate can increase the iron content of rat brain. J. Nanobiotechnology 15, 42 (2017).
Andrews, N. C. & Schmidt, P. J. Iron homeostasis. Annu. Rev. Physiol. 69, 69–85 (2007).
Elsayed, M. E., Sharif, M. U. & Stack, A. G. Transferrin saturation: a body iron biomarker. Adv. Clin. Chem. 75, 71–97 (2016).
Sugimura, R. et al. Haematopoietic stem and progenitor cells from human pluripotent stem cells. Nature 545, 432–438 (2017).
Tang, X. & Zhou, B. Iron homeostasis in insects: insights from Drosophila studies. IUBMB life 65, 863–872 (2013).
Nichol, H., Law, J. H. & Winzerling, J. J. Iron metabolism in insects. Annu. Rev. Entomol. 47, 535–559 (2002).
Walter-Nuno, A. B., Taracena, M. L., Mesquita, R. D., Oliveira, P. L. & Paiva-Silva, G. O. Silencing of iron and heme-related genes revealed a paramount role of iron in the physiology of the hematophagous vector Rhodnius prolixus. Front. Genet. 9, 19 (2018).
Whiten, S. R., Eggleston, H. & Adelman, Z. N. Ironing out the details: exploring the role of iron and heme in blood-sucking arthropods. Front. Physiol. 8, 1134 (2017).
Zhou, G. et al. Fate of blood meal iron in mosquitoes. J. Insect Physiol. 53, 1169–1178 (2007).
Latunde-Dada, G. O., Takeuchi, K., Simpson, R. J. & McKie, A. T. Haem carrier protein 1 (HCP1): expression and functional studies in cultured cells. FEBS Lett. 580, 6865–6870 (2006).
Andrews, N. C. Understanding heme transport. New Engl. J. Med. 353, 2508–2509 (2005).
Altruda, F., Poli, V., Restagno, G. & Silengo, L. Structure of the human hemopexin gene and evidence for intron-mediated evolution. J. Mol. Evol. 27, 102–108 (1988).
Wassell, J. Haptoglobin: function and polymorphism. Clin. Lab. 46, 547–552 (2000).
Sim, S., Jupatanakul, N. & Dimopoulos, G. Mosquito immunity against arboviruses. Viruses 6, 4479–4504 (2014).
Pan, X. et al. Wolbachia induces reactive oxygen species (ROS)-dependent activation of the Toll pathway to control dengue virus in the mosquito Aedes aegypti. Proc. Natl Acad. Sci. USA 109, E23–E31 (2012).
Oliveira, J. H. M. et al. Catalase protects Aedes aegypti from oxidative stress and increases midgut infection prevalence of Dengue but not Zika. PLoS Negl. Trop. Dis. 11, e0005525 (2017).
Wen, D. et al. N-glycosylation of viral E protein is the determinant for vector midgut invasion by flaviviruses. mBio 9, e00046-18 (2018).
Halasi, M. et al. ROS inhibitor N-acetyl-l-cysteine antagonizes the activity of proteasome inhibitors. Biochem. J. 454, 201–208 (2013).
Denic, S. & Agarwal, M. M. Nutritional iron deficiency: an evolutionary perspective. Nutrition 23, 603–614 (2007).
Carr, W. R. & Gelfand, M. Serum iron and iron binding capacity of the African in Southern Rhodesia. Trans. R. Soc. Trop. Med. Hyg. 55, 452–458 (1961).
Yanoff, L. B. et al. Inflammation and iron deficiency in the hypoferremia of obesity. Int. J. Obes. 31, 1412–1419 (2007).
Cassat, J. E. & Skaar, E. P. Iron in infection and immunity. Cell Host Microbe 13, 509–519 (2013).
Drakesmith, H. & Prentice, A. Viral infection and iron metabolism. Nat. Rev. Microbiol. 6, 541–552 (2008).
Drakesmith, H. & Prentice, A. M. Hepcidin and the iron-infection axis. Science 338, 768–772 (2012).
Oliveira Gde, A., Lieberman, J. & Barillas-Mury, C. Epithelial nitration by a peroxidase/NOX5 system mediates mosquito antiplasmodial immunity. Science 335, 856–859 (2012).
Sadrzadeh, S. M., Graf, E., Panter, S. S., Hallaway, P. E. & Eaton, J. W. Hemoglobin. A biologic fenton reagent. J. Biol. Chem. 259, 14354–14356 (1984).
Champion, C. J. & Xu, J. The impact of metagenomic interplay on the mosquito redox homeostasis. Free Radic. Biol. Med. 105, 79–85 (2017).
Geiser, D. L. & Winzerling, J. J. Insect transferrins: multifunctional proteins. Biochim. Biophys. Acta 1820, 437–451 (2012).
Gonzales, K. K., Tsujimoto, H. & Hansen, I. A. Blood serum and BSA, but neither red blood cells nor hemoglobin can support vitellogenesis and egg production in the dengue vector Aedes aegypti. PeerJ 3, e938 (2015).
Fillebeen, C. & Pantopoulos, K. Iron inhibits replication of infectious hepatitis C virus in permissive Huh7.5.1 cells. J. Hepatol. 53, 995–999 (2010).
Fillebeen, C. et al. Iron inactivates the RNA polymerase NS5B and suppresses subgenomic replication of hepatitis C Virus. J. Biol. Chem. 280, 9049–9057 (2005).
Wang, H. et al. Antiviral effects of ferric ammonium citrate. Cell Discov. 4, 14 (2018).
Rose, P. P. et al. Natural resistance-associated macrophage protein is a cellular receptor for sindbis virus in both insect and mammalian hosts. Cell Host Microbe 10, 97–104 (2011).
Tsujimoto, H., Anderson, M. A. E., Myles, K. M. & Adelman, Z. N. Identification of candidate iron transporters from the ZIP/ZnT gene families in the mosquito Aedes aegypti. Front. Physiol. 9, 380 (2018).
Salam, N. et al. Global prevalence and distribution of coinfection of malaria, dengue and chikungunya: a systematic review. BMC Public Health 18, 710 (2018).
Gwamaka, M. et al. Iron deficiency protects against severe Plasmodium falciparum malaria and death in young children. Clin. Infect. Dis. 54, 1137–1144 (2012).
Clark, M. A. et al. Host iron status and iron supplementation mediate susceptibility to erythrocytic stage Plasmodium falciparum. Nat. Commun. 5, 4446 (2014).
Sazawal, S. et al. Effects of routine prophylactic supplementation with iron and folic acid on admission to hospital and mortality in preschool children in a high malaria transmission setting: community-based, randomised, placebo-controlled trial. Lancet 367, 133–143 (2006).
Gangaidzo, I. T. et al. Association of pulmonary tuberculosis with increased dietary iron. J. Infect. Dis. 184, 936–939 (2001).
Sanchez, K. K. et al. Cooperative metabolic adaptations in the host can favor asymptomatic infection and select for attenuated virulence in an enteric pathogen. Cell 175, 146–158 (2018).
Doherty, C. P. Host-pathogen interactions: the role of iron. J. Nutr. 137, 1341–1344 (2007).
Lachowicz, J. I. et al. Nutritional iron deficiency: the role of oral iron supplementation. Curr. Med. Chem. 21, 3775–3784 (2014).
Oppenheimer, S. J. Iron and its relation to immunity and infectious disease. J. Nutr 131, 616S–633S (2001).
Oppenheimer, S. J. et al. Iron supplementation increases prevalence and effects of malaria: report on clinical studies in Papua New Guinea. Trans. R. Soc. Trop. Med. Hyg. 80, 603–612 (1986).
Agarwal, A., Panda, M. & Dash, P. K. Impact of transmission cycles and vector competence on global expansion and emergence of arboviruses. Rev. Med. Virol. 27, e1941 (2017).
Jupatanakul, N., Sim, S. & Dimopoulos, G. The insect microbiome modulates vector competence for arboviruses. Viruses 6, 4294–4313 (2014).
Lambrechts, L. & Failloux, A. B. Vector biology prospects in dengue research. Mem. Inst. Oswaldo Cruz 107, 1080–1082 (2012).
Angeles, I. T., Schultink, W. J., Matulessi, P., Gross, R. & Sastroamidjojo, S. Decreased rate of stunting among anemic Indonesian preschool children through iron supplementation. Am. J. Clin. Nutr. 58, 339–342 (1993).
Xiao, X. et al. Complement-related proteins control the flavivirus infection of Aedes aegypti by inducing antimicrobial peptides. PLoS Pathog. 10, e1004027 (2014).
Wu, P. et al. A gut commensal bacterium promotes mosquito permissiveness to arboviruses. Cell Host Microbe 25, 101–112 (2019).
Ciota, A. T. & Kramer, L. D. Vector–virus interactions and transmission dynamics of West Nile virus. Viruses 5, 3021–3047 (2013).
Bandyopadhyay, S. et al. Iron-deficient erythropoiesis in blood donors and red blood cell recovery after transfusion: initial studies with a mouse model. Blood Transfus. 15, 158–164 (2017).
Cheng, G. et al. A C-type lectin collaborates with a CD45 phosphatase homolog to facilitate West Nile virus infection of mosquitoes. Cell 142, 714–725 (2010).
Sanchez-Varga, I., Harrington, L. C., Black, W. C. T. & Olson, K. E. Analysis of salivary glands and saliva from Aedes albopictus and Aedes aegypti infected with chikungunya viruses. Insects 10, 39 (2019).
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.
The authors declare no competing interests.
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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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