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Asian Zika virus strains target CD14+ blood monocytes and induce M2-skewed immunosuppression during pregnancy

Nature Microbiology volume 2, pages 1558–1570 (2017)Cite this article

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Abstract

Blood CD14+ monocytes are frontline immunomodulators categorized into classical, intermediate or non-classical subsets, and subsequently differentiated into M1 pro- or M2 anti-inflammatory macrophages on stimulation. Although the Zika virus (ZIKV) rapidly establishes viraemia, the target cells and immune responses, particularly during pregnancy, remain elusive. Furthermore, it is unknown whether African- and Asian-lineage ZIKV have different phenotypic impacts on host immune responses. Using human blood infection, we identified CD14+ monocytes as the primary target for African- or Asian-lineage ZIKV infection. When immunoprofiles of human blood infected with ZIKV were compared, a classical/intermediate monocyte-mediated M1-skewed inflammation by the African-lineage ZIKV infection was observed, in contrast to a non-classical monocyte-mediated M2-skewed immunosuppression by the Asian-lineage ZIKV infection. Importantly, infection of the blood of pregnant women revealed an enhanced susceptibility to ZIKV infection. Specifically, Asian-lineage ZIKV infection of pregnant women’s blood led to an exacerbated M2-skewed immunosuppression of non-classical monocytes in conjunction with a global suppression of type I interferon-signalling pathway and an aberrant expression of host genes associated with pregnancy complications. Also, 30 ZIKV+ sera from symptomatic pregnant patients showed elevated levels of M2-skewed immunosuppressive cytokines and pregnancy-complication-associated fibronectin-1. This study demonstrates the differential immunomodulatory responses of blood monocytes, particularly during pregnancy, on infection with different lineages of ZIKV.

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Fig. 1: ZIKV infects CD14+ monocytes and drives the monocyte subset shift to the CD16+ non-classical subset during whole-blood infection.
Fig. 2: Different lineages of ZIKV infection of whole blood elicit differential immunomodulatory responses.
Fig. 3: Asian ZIKV preferentially targets non-classical monocytes, driving specific IL-10 expression.
Fig. 4: Pregnancy is associated with enhanced ZIKV infection and a profound monocyte-subset shift.
Fig. 5: Pregnancy exacerbates Asian-ZIKV-induced M2-skewed immunosuppression.
Fig. 6: Transcriptome analysis of blood monocytes following African or Asian ZIKV infection.

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References

  1. Benitez, M. A. Climate change could affect mosquito-borne diseases in Asia. Lancet 373, 1070 (2009).

    Article  PubMed  Google Scholar 

  2. Chouin-Carneiro, T. et al. Differential susceptibilities of Aedes aegypti and Aedes albopictus from the Americas to Zika virus. PLoS Negl. Trop. Dis. 10, e0004543 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  3. Zika Situation Report: 20 January 2017 (World Health Organization, 2017).

  4. Enfissi, A., Codrington, J., Roosblad, J., Kazanji, M. & Rousset, D. Zika virus genome from the Americas. Lancet 387, 227–228 (2016).

    Article  PubMed  Google Scholar 

  5. Wang, L. et al. From mosquitos to humans: genetic evolution of Zika virus. Cell Host Microbe 19, 561–565 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Simonin, Y. et al. Zika virus strains potentially display different infectious profiles in human neural cells. EBioMedicine 12, 161–169 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  7. Jurado, K. A. et al. Zika virus productively infects primary human placenta-specific macrophages. JCI Insight 1, e88461 (2016).

  8. Noronha, L., Zanluca, C., Azevedo, M. L., Luz, K. G. & Santos, C. N. Zika virus damages the human placental barrier and presents marked fetal neurotropism. Mem. Inst. Oswaldo Cruz 111, 287–293 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  9. Racicot, K., Kwon, J. Y., Aldo, P., Silasi, M. & Mor, G. Understanding the complexity of the immune system during pregnancy. Am. J. Reprod. Immunol. 72, 107–116 (2014).

    Article  PubMed  Google Scholar 

  10. Faas, M. M., Spaans, F. & De Vos, P. Monocytes and macrophages in pregnancy and pre-eclampsia. Front. Immunol. 5, 298 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  11. Brown, M. B., von Chamier, M., Allam, A. B. & Reyes, L. M1/M2 macrophage polarity in normal and complicated pregnancy. Front. Immunol. 5, 606 (2014).

    PubMed  PubMed Central  Google Scholar 

  12. Wong, K. L. et al. The three human monocyte subsets: implications for health and disease. Immunol. Res. 53, 41–57 (2012).

    Article  CAS  PubMed  Google Scholar 

  13. Shechter, R., London, A. & Schwartz, M. Orchestrated leukocyte recruitment to immune-privileged sites: absolute barriers versus educational gates. Nat. Rev. Immunol. 13, 206–218 (2013).

    Article  CAS  PubMed  Google Scholar 

  14. Audoy-Rémus, J. et al. Rod-shaped monocytes patrol the brain vasculature and give rise to perivascular macrophages under the influence of proinflammatory cytokines and angiopoietin-2. J. Neurosci. 28, 10187–10199 (2008).

    Article  PubMed  Google Scholar 

  15. Kourtis, A. P., Read, J. S. & Jamieson, D. J. Pregnancy and infection. N. Engl. J. Med. 370, 2211–2218 (2014).

    Article  Google Scholar 

  16. Mantovani, A. et al. The chemokine system in diverse forms of macrophage activation and polarization. Trends Immunol. 25, 677–686 (2004).

    Article  CAS  PubMed  Google Scholar 

  17. Martinez, F. O. & Gordon, S. The M1 and M2 paradigm of macrophage activation: time for reassessment. F1000Prime Rep. 6, 13 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  18. Murray, P. J. & Wynn, T. A. Protective and pathogenic functions of macrophage subsets. Nat. Rev. Immunol. 11, 723–737 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Jaguin, M., Houlbert, N., Fardel, O. & Lecureur, V. Polarization profiles of human M-CSF-generated macrophages and comparison of M1-markers in classically activated macrophages from GM-CSF and M-CSF origin. Cell Immunol. 281, 51–61 (2013).

    Article  CAS  PubMed  Google Scholar 

  20. Magatti, M. et al. Human amnion favours tissue repair by inducing the M1-to-M2 switch and enhancing M2 macrophage features. J. Tissue Eng. Regen. Med. 10, 2193 (2016).

    Google Scholar 

  21. Mack, I. et al. The role of chitin, chitinases, and chitinase-like proteins in pediatric lung diseases. Mol. Cell Pediatr. 2, 3 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  22. Martines, R. B. Notes from the field: evidence of Zika virus infection in brain and placental tissues from two congenitally infected newborns and two fetal losses—Brazil, 2015. MMWR 65, 159–160 (2016).

    PubMed  Google Scholar 

  23. Sordet, O. et al. Specific involvement of caspases in the differentiation of monocytes into macrophages. Blood 100, 4446–4453 (2002).

    Article  CAS  PubMed  Google Scholar 

  24. Saeed, S. et al. Epigenetic programming of monocyte-to-macrophage differentiation and trained innate immunity. Science 345, 1251086 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  25. Brasil, P. et al. Zika virus infection in pregnant women in Rio de Janeiro—preliminary report. N. Engl. J. Med. 375, 2321–2334 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  26. Brasil, P. et al. Zika virus infection in pregnant women in Rio de Janeiro. N. Engl. J. Med. 375, 2321–2334 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  27. Ishida, J. et al. Pregnancy-associated homeostasis and dysregulation: lessons from genetically modified animal models. J. Biochem. 150, 5–14 (2011).

    Article  CAS  PubMed  Google Scholar 

  28. Bruchova, H. et al. Effect of maternal tobacco smoke exposure on the placental transcriptome. Placenta 31, 186–191 (2010).

    Article  CAS  PubMed  Google Scholar 

  29. Chaemsaithong, P. et al. Characterization of the myometrial transcriptome in women with an arrest of dilatation during labor. J. Perinat. Med. 41, 665–681 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Chen, C. K. et al. Fibronectin levels in normal pregnancy and preeclampsia. J. Formosan Med. Assoc. 93, 921–924 (1994).

    CAS  PubMed  Google Scholar 

  31. Rasanen, J. et al. Maternal serum glycosylated fibronectin as a point-of-care biomarker for assessment of preeclampsia. Am. J. Obstet. Gynecol. 212, 82.e1–82.e9 (2015).

    Article  Google Scholar 

  32. Melo, A. S. et al. Congenital Zika virus infection: beyond neonatal microcephaly. JAMA Neurol. 73, 1407–1416 (2016).

    Article  PubMed  Google Scholar 

  33. Parra, B. et al. Guillain–Barré syndrome associated with Zika virus infection in Colombia. N. Engl. J. Med 375, 1513–1523 (2016).

    Article  PubMed  Google Scholar 

  34. Waggoner, J. J. & Pinsky, B. A. Zika virus: diagnostics for an emerging pandemic threat. J. Clin. Microbiol. 54, 860–867 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Rossi, S. L. et al. Characterization of a novel murine model to study Zika virus. Am. J. Trop. Med. Hyg. 94, 1362–1369 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Delaloye, J. et al. Innate immune sensing of modified vaccinia virus Ankara (MVA) is mediated by TLR2-TLR6, MDA-5 and the NALP3 inflammasome. PLoS Pathog. 5, e1000480 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  37. Her, Z. et al. Active infection of human blood monocytes by Chikungunya virus triggers an innate immune response. J. Immunol. 184, 5903–5913 (2010).

    Article  CAS  PubMed  Google Scholar 

  38. Hou, W. et al. Viral infection triggers rapid differentiation of human blood monocytes into dendritic cells. Blood 119, 3128–3131 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Osuna, C. E. et al. Zika viral dynamics and shedding in rhesus and cynomolgus macaques. Nat. Med. 22, 1448–1455 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Teng, T. S. et al. Viperin restricts chikungunya virus replication and pathology. J. Clin. Invest. 122, 4447–4460 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Robinson, T. O., Zhang, M., Ochsenbauer, C., Smythies, L. E. & Cron, R. Q. CD4 regulatory T cells augment HIV-1 expression of polarized M1 and M2 monocyte derived macrophages. Virology 504, 79–87 (2017).

    Article  CAS  PubMed  Google Scholar 

  42. Fischer-Smith, T., Tedaldi, E. M. & Rappaport, J. CD163/CD16 coexpression by circulating monocytes/macrophages in HIV: potential biomarkers for HIV infection and AIDS progression. AIDS Res. Hum. Retroviruses 24, 417–421 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Palmer, C. et al. HIV elite controllers have lower frequencies of CD14dimCD16+ inflammatory monocytes with greater CX3CR1-dependent tissue homing potential than viremic controllers (VIR9P. 1138). J. Immunol. 194, 215 (2015).

    Google Scholar 

  44. Zonneveld, R. et al. Three atypical lethal cases associated with acute Zika virus infection in Suriname. IDCases 5, 49–53 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  45. Halai, U. A. et al. Maternal Zika virus disease severity, virus load, prior dengue antibodies and their relationship to birth outcomes. Clin. Infect. Dis 2017, 472 (2017).

    Google Scholar 

  46. Suy, A. et al. Prolonged Zika virus viremia during pregnancy. N. Engl. J. Med. 375, 2611–2613 (2016).

    Article  PubMed  Google Scholar 

  47. Driggers, R. W. et al. Zika virus infection with prolonged maternal viremia and fetal brain abnormalities. N. Engl. J. Med. 374, 2142–2151 (2016).

    Article  CAS  PubMed  Google Scholar 

  48. Hamel, R. et al. Biology of Zika virus infection in human skin cells. J. Virol. 89, 8880–8896 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Miner, J. J. et al. Zika virus infection during pregnancy in mice causes placental damage and fetal demise. Cell 165, 1081–1091 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Melgert, B. N. et al. Pregnancy and preeclampsia affect monocyte subsets in humans and rats. PLoS ONE 7, e45229 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Brooks, D. G. et al. Interleukin-10 determines viral clearance or persistence in vivo. Nat. Med. 12, 1301–1309 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Brooks, D. G., Lee, A. M., Elsaesser, H., McGavern, D. B. & Oldstone, M. B. IL-10 blockade facilitates DNA vaccine-induced T cell responses and enhances clearance of persistent virus infection. J. Exp. Med. 205, 533–541 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Redpath, S., Ghazal, P. & Gascoigne, N. R. Hijacking and exploitation of IL-10 by intracellular pathogens. Trends Microbiol. 9, 86–92 (2001).

    Article  CAS  PubMed  Google Scholar 

  54. Ornelas, A. M. et al. Immune activation in amniotic fluid from Zika virus-associated microcephaly. Ann. Neurol. 81, 152–156 (2017).

    Article  CAS  PubMed  Google Scholar 

  55. Zhu, Z. et al. Comparative genomic analysis of pre-epidemic and epidemic Zika virus strains for virological factors potentially associated with the rapidly expanding epidemic. Emerg. Microbes Infect. 5, e22 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  56. Klein, R. S. et al. Neuronal CXCL10 directs CD8+ T-cell recruitment and control of West Nile virus encephalitis. J. Virol. 79, 11457–11466 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Bhowmick, S. et al. Induction of IP-10 (CXCL10) in astrocytes following Japanese encephalitis. Neurosci. Lett. 414, 45–50 (2007).

    Article  CAS  PubMed  Google Scholar 

  58. Challis, J. R. et al. Inflammation and pregnancy. Reprod. Sci. 16, 206–215 (2009).

    Article  CAS  PubMed  Google Scholar 

  59. Lanciotti, R. S. et al. Genetic and serologic properties of Zika virus associated with an epidemic, Yap State, Micronesia, 2007. Emerg Infect Dis. 14, 1232–1239 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

We thank M. Diamond and C. Baronti for providing the ZIKV H/PF/2013 strain, and all the healthy volunteers for blood donations. This work was partly supported by CA200422, CA180779, DE023926, AI073099, AI116585, Hastings Foundation and Fletcher Jones Foundation (J.U.J.), MH106806 (A.B.) and 2T90DE021982-06 (J.W.B.), AI28697 and 1R21AI129534-01 from the National Institute of Allergy and Infectious Diseases/National Institutes of Health (K.N.S.), and CAPES/ 88887.116627/2016-01 from Departamento de Ciência e Tecnologia (DECIT) do Ministério da Saúde do Brasil and Coordenacao de Aperfeicoamento de Pessoal de Nivel Superior (P.B.).

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Authors and Affiliations

  1. Department of Molecular Microbiology and Immunology, University of Southern California, Keck School of Medical, Zilkha Neurogenetic Institute, 1501 San Pablo Street, Los Angeles, CA, 90033, USA

    Suan-Sin Foo, Weiqiang Chen, James W. Bowman, Lin-Chun Chang, Younho Choi, Ji Seung Yoo, Jianning Ge & Jae U. Jung

  2. Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, University of Southern California, Keck School of Medicine, Zilkha Neurogenetic Institute, 1501 San Pablo Street, Los Angeles, CA, 90033, USA

    Yen Chan

  3. Department of Microbiology, Immunology and Molecular Genetics, University of California, Los Angeles, CA, 90095, USA

    Genhong Cheng

  4. Department of Cell and Neurobiology, University of Southern California, Keck School of Medicine, Zilkha Neurogenetic Institute, 1501 San Pablo Street, Los Angeles, CA, 90033, USA

    Alexandre Bonnin

  5. Division of Pediatric Infectious Diseases, David Geffen School of Medicine, University of California, Los Angeles, Marion Davies Children’s Health Center, 10833 LeConte Avenue, Los Angeles, CA, 90095, USA

    Karin Nielsen-Saines

  6. Laboratório de Pesquisa Clínica em Doenças Febris Agudas, Instituto Nacional de Infectologia Evandro Chagas, FIOCRUZ, 4365 Avenida Brasil, Rio de Janeiro, RJ, 21040-360, Brazil

    Patrícia Brasil

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Contributions

S.-S.F. performed and analysed all the experiments, prepared the figures and wrote the first draft of the manuscript. W.C., Y.C., J.W.B., L.-C.C., Y.C., J.S.Y., J.G., G.C., A.B., K.N.S. and P.B. collaborated for the experimental design and interpretation. S.-S.F. and J.U.J. jointly conceived the experimental design, interpreted the results and wrote subsequent drafts of the manuscript.

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Correspondence to Jae U. Jung.

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Supplementary Figures 1–11, Supplementary Tables 3 and 5, Supplementary References.

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Multiplexed NanoString gene profiling (gene expression fold change relative to mock controls).

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Foo, SS., Chen, W., Chan, Y. et al. Asian Zika virus strains target CD14+ blood monocytes and induce M2-skewed immunosuppression during pregnancy. Nat Microbiol 2, 1558–1570 (2017). https://doi.org/10.1038/s41564-017-0016-3

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