Subclinical in utero Zika virus infection is associated with interferon alpha sequelae and sex-specific molecular brain pathology in asymptomatic porcine offspring

English version

Autoři: Ivan Trus ^aff001; Daniel Udenze ^aff001; Brian Cox ^aff003; Nathalie Berube ^aff001; Rebecca E. Nordquist ^aff004; Franz Josef van der Staay ^aff004; Yanyun Huang ^aff006; Gary Kobinger ^aff007; David Safronetz ^aff008; Volker Gerdts ^aff001; Uladzimir Karniychuk ^aff001
Působiště autorů: Vaccine and Infectious Disease Organization-International Vaccine Centre (VIDO-InterVac), University of Saskatchewan, Saskatoon, Canada ^aff001; School of Public Health, University of Saskatchewan, Saskatoon, Canada ^aff002; Department of Physiology, Department of Obstetrics and Gynaecology, University of Toronto, Toronto, ON, Canada ^aff003; Behavior and Welfare Group, Department of Farm Animal Health, Faculty of Veterinary Medicine, Utrecht University, Utrecht, CL, Netherlands ^aff004; Brain Center Rudolf Magnus, Utrecht University, Utrecht, Netherlands ^aff005; Prairie Diagnostic Services, Saskatoon, Canada ^aff006; CHUL and Laval University, Québec City, QC, Canada ^aff007; Canada National Microbiology Laboratory, Public Health Agency of Canada, Winnipeg, MB, Canada ^aff008; Department of Veterinary Microbiology, Western College of Veterinary Medicine, University of Saskatchewan, Saskatoon, Canada ^aff009
Vyšlo v časopise: Subclinical in utero Zika virus infection is associated with interferon alpha sequelae and sex-specific molecular brain pathology in asymptomatic porcine offspring. PLoS Pathog 15(11): e32767. doi:10.1371/journal.ppat.1008038
Kategorie: Research Article
doi: https://doi.org/10.1371/journal.ppat.1008038

Souhrn

Zika virus (ZIKV) infection during human pregnancy may lead to severe fetal pathology and debilitating impairments in offspring. However, the majority of infections are subclinical and not associated with evident birth defects. Potentially detrimental life-long health outcomes in asymptomatic offspring evoke high concerns. Thus, animal models addressing sequelae in offspring may provide valuable information. To induce subclinical infection, we inoculated selected porcine fetuses at the mid-stage of development. Inoculation resulted in trans-fetal virus spread and persistent infection in the placenta and fetal membranes for two months. Offspring did not show congenital Zika syndrome (e.g., microcephaly, brain calcifications, congenital clubfoot, arthrogryposis, seizures) or other visible birth defects. However, a month after birth, a portion of offspring exhibited excessive interferon alpha (IFN-α) levels in blood plasma in a regular environment. Most affected offspring also showed dramatic IFN-α shutdown during social stress providing the first evidence for the cumulative impact of prenatal ZIKV exposure and postnatal environmental insult. Other eleven cytokines tested before and after stress were not altered suggesting the specific IFN-α pathology. While brains from offspring did not have histopathology, lesions, and ZIKV, the whole genome expression analysis of the prefrontal cortex revealed profound sex-specific transcriptional changes that most probably was the result of subclinical in utero infection. RNA-seq analysis in the placenta persistently infected with ZIKV provided independent support for the sex-specific pattern of in utero-acquired transcriptional responses. Collectively, our results provide strong evidence that two hallmarks of fetal ZIKV infection, altered type I IFN response and molecular brain pathology can persist after birth in offspring in the absence of congenital Zika syndrome.

Klíčová slova:

Birth – Blood plasma – Fetuses – Pig models – placenta – Swine – Zika virus – Molecular pathology

Zdroje

1. Wheeler AC, Ventura CV, Ridenour T, Toth D, Nobrega LL, Silva de Souza Dantas LC, et al. Skills attained by infants with congenital Zika syndrome: Pilot data from Brazil. Gopichandran V, editor. PLoS One. 2018;13: e0201495. doi: 10.1371/journal.pone.0201495 30048541

2. Brasil P, Pereira JP, Moreira ME, Ribeiro Nogueira RM, Damasceno L, Wakimoto M, et al. Zika Virus Infection in Pregnant Women in Rio de Janeiro. N Engl J Med. 2016;375: 2321–2334. doi: 10.1056/NEJMoa1602412 26943629

3. de Araújo TVB, Rodrigues LC, de Alencar Ximenes RA, de Barros Miranda-Filho D, Montarroyos UR, de Melo APL, et al. Association between Zika virus infection and microcephaly in Brazil, January to May, 2016: preliminary report of a case-control study. The Lancet Infectious Diseases. 2016. doi: 10.1016/S1473-3099(16)30318-8

4. Silva AAM, Ganz JSS, Sousa PS, Doriqui MJR, Ribeiro MRC, Branco MRFC, et al. Early growth and neurologic outcomes of infants with probable congenital Zika virus syndrome. Emerg Infect Dis. 2016;22: 1953–1956. doi: 10.3201/eid2211.160956 27767931

5. Nogueira ML, Nery Júnior NRR, Estofolete CF, Bernardes Terzian AC, Guimarães GF, Zini N, et al. Adverse birth outcomes associated with Zika virus exposure during pregnancy in São José do Rio Preto, Brazil. Clin Microbiol Infect. 2018;24: 646–652. doi: 10.1016/j.cmi.2017.11.004 29133154

6. Vianna RAO, Lovero KL, Oliveira SA, Fernandes AR, Santos TCS, Lima LCSS, et al. Children Born to Mothers with Rash During Zika Virus Epidemic in Brazil: First 18 Months of Life. J Trop Pediatr. 2019; doi: 10.1093/tropej/fmz019 31006031

7. Nielsen-Saines K, Brasil P, Kerin T, Vasconcelos Z, Gabaglia CR, Damasceno L, et al. Delayed childhood neurodevelopment and neurosensory alterations in the second year of life in a prospective cohort of ZIKV-exposed children. Nat Med. 2019; doi: 10.1038/s41591-019-0496-1 31285631

8. Adams Waldorf KM, Olson EM, Nelson BR, Little MTE, Rajagopal L. The Aftermath of Zika: Need for Long-Term Monitoring of Exposed Children. Trends Microbiol. 2018; doi: 10.1016/j.tim.2018.05.011 29960747

9. Subissi L, Dub T, Besnard M, Mariteragi-Helle T, Nhan T, Lutringer-Magnin D, et al. Zika virus infection during pregnancy and effects on early childhood development, French Polynesia, 2013–2016. Emerg Infect Dis. 2018;24: 1850–1858. doi: 10.3201/eid2410.172079 30226164

10. Adams Waldorf KM, Nelson BR, Stencel-Baerenwald JE, Studholme C, Kapur RP, Armistead B, et al. Congenital Zika virus infection as a silent pathology with loss of neurogenic output in the fetal brain. Nat Med. 2018;24: 368–374. doi: 10.1038/nm.4485 29400709

11. Adams Waldorf KM, Stencel-Baerenwald JE, Kapur RP, Studholme C, Boldenow E, Vornhagen J, et al. Fetal brain lesions after subcutaneous inoculation of Zika virus in a pregnant nonhuman primate. Nat Med. 2016;22: 1256–1259. doi: 10.1038/nm.4193 27618651

12. Stanelle-Bertram S, Walendy-Gnirß K, Speiseder T, Thiele S, Asante IA, Dreier C, et al. Male offspring born to mildly ZIKV-infected mice are at risk of developing neurocognitive disorders in adulthood. Nat Microbiol. 2018; doi: 10.1038/s41564-018-0236-1 30202017

13. Paul AM, Acharya D, Neupane B, Thompson EA, Gonzalez-Fernandez G, Copeland KM, et al. Congenital Zika Virus Infection in Immunocompetent Mice Causes Postnatal Growth Impediment and Neurobehavioral Deficits. Front Microbiol. 2018;9: 2028. doi: 10.3389/fmicb.2018.02028 30210488

14. Mavigner M, Raper J, Kovacs-Balint Z, Gumber S, O’Neal JT, Bhaumik SK, et al. Postnatal Zika virus infection is associated with persistent abnormalities in brain structure, function, and behavior in infant macaques. Sci Transl Med. 2018;10: eaao6975. doi: 10.1126/scitranslmed.aao6975 29618564

15. Giovanoli S, Engler H, Engler A, Richetto J, Voget M, Willi R, et al. Stress in Puberty Unmasks Latent Neuropathological Consequences of Prenatal Immune Activation in Mice. Science. 2013;339: 1095–1099. doi: 10.1126/science.1228261 23449593

16. Straley ME, Van Oeffelen W, Theze S, Sullivan AM, O’Mahony SM, Cryan JF, et al. Distinct alterations in motor & reward seeking behavior are dependent on the gestational age of exposure to LPS-induced maternal immune activation. Brain Behav Immun. 2017;63: 21–34. doi: 10.1016/j.bbi.2016.06.002 27266391

17. Wichgers Schreur PJ, Van Keulen L, Anjema D, Kant J, Kortekaas J. Microencephaly in fetal piglets following in utero inoculation of Zika virus. Emerg Microbes Infect. 2018;7: 42. doi: 10.1038/s41426-018-0044-y 29593256

18. Darbellay J, Cox B, Lai K, Delgado-Ortega M, Wheler C, Wilson D, et al. Zika Virus Causes Persistent Infection in Porcine Conceptuses and may Impair Health in Offspring. EBioMedicine. 2017;25: 73–86. doi: 10.1016/j.ebiom.2017.09.021 29097124

19. Trus I, Darbellay J, Huang Y, Gilmour M, Safronetz D, Gerdts V, et al. Persistent Zika virus infection in porcine conceptuses is associated with elevated in utero cortisol levels. Virulence. 2018;9: 1338–1343. doi: 10.1080/21505594.2018.1504558 30058440

20. Ibrahim Z, Busch J, Awwad M, Wagner R, Wells K, Cooper DKC. Selected physiologic compatibilities and incompatibilities between human and porcine organ systems. Xenotransplantation. 2006;13: 488–499. doi: 10.1111/j.1399-3089.2006.00346.x 17059572

21. Goco RV, Kress MB, Brantigan OC. Comparison of Mucus Glands in the Tracheobronchial Tree of Man and Animals. Ann N Y Acad Sci. 1963;106: 555–571. doi: 10.1111/j.1749-6632.1963.tb16665.x 13963227

22. Pabst R, Binns RM. The immune system of the respiratory tract in pigs. Vet Immunol Immunopathol. 1994;43: 151–156. doi: 10.1016/0165-2427(94)90131-7 7856047

23. Dawson HD, Loveland JE, Pascal G, Gilbert JGR, Uenishi H, Mann KM, et al. Structural and functional annotation of the porcine immunome. BMC Genomics. 2013;14: 332. doi: 10.1186/1471-2164-14-332 23676093

24. Dawson HD, Smith AD, Chen C, Urban JF. An in-depth comparison of the porcine, murine and human inflammasomes; lessons from the porcine genome and transcriptome. Vet Microbiol. 2017;202: 2–15. doi: 10.1016/j.vetmic.2016.05.013 27321134

25. Bendixen E, Danielsen M, Larsen K, Bendixen C. Advances in porcine genomics and proteomics-a toolbox for developing the pig as a model organism for molecular biomedical research. Briefings Funct Genomics Proteomics. 2010;9: 208–219. doi: 10.1093/bfgp/elq004 20495211

26. Lunney JK. Advances in swine biomedical model genomics. Int J Biol Sci. 2007;3: 179–184. doi: 10.7150/ijbs.3.179 17384736

27. Meurens F, Summerfield A, Nauwynck H, Saif L, Gerdts V. The pig: A model for human infectious diseases. Trends Microbiol. 2012;20: 50–57. doi: 10.1016/j.tim.2011.11.002 22153753

28. Dickerson JW, Dobbing J. Prenatal and postnatal growth and development of the central nervous system of the pig. Proc R Soc London Ser B, Biol Sci. 1967;166: 384–395. doi: 10.1098/rspb.1967.0002 24796035

29. Rothkötter HJ, Sowa E, Pabst R. The pig as a model of developmental immunology. Hum Exp Toxicol. 2002;21: 533–536. doi: 10.1191/0960327102ht293oa 12458912

30. Dobbing J, Sands J. Comparative aspects of the brain growth spurt. Early Hum Dev. 1979;3: 79–83. doi: 10.1016/0378-3782(79)90022-7 118862

31. Pond WG, Boleman SL, Fiorotto ML, Ho H, Knabe DA, Mersmann HJ, et al. Perinatal ontogeny of brain growth in the domestic pig. Proc Soc Exp Biol Med. 2000;223: 102–108. doi: 10.1046/j.1525-1373.2000.22314.x 10632968

32. Honein MA, Dawson AL, Petersen EE, Jones AM, Lee EH, Yazdy MM, et al. Birth defects among fetuses and infants of US women with evidence of possible Zika virus infection during pregnancy. JAMA—J Am Med Assoc. 2017;317: 59–68. doi: 10.1001/jama.2016.19006 27960197

33. Jagger BW, Miner JJ, Cao B, Arora N, Smith AM, Kovacs A, et al. Gestational Stage and IFN-λ Signaling Regulate ZIKV Infection In Utero. Cell Host Microbe. 2017;22: 366–376.e3. doi: 10.1016/j.chom.2017.08.012 28910635

34. Yockey LJ, Jurado KA, Arora N, Millet A, Rakib T, Milano KM, et al. Type I interferons instigate fetal demise after Zika virus infection. Sci Immunol. 2018;3: eaao1680. doi: 10.1126/sciimmunol.aao1680 29305462

35. Vermillion MS, Lei J, Shabi Y, Baxter VK, Crilly NP, McLane M, et al. Intrauterine Zika virus infection of pregnant immunocompetent mice models transplacental transmission and adverse perinatal outcomes. Nat Commun. 2017;8: 14575. doi: 10.1038/ncomms14575 28220786

36. Antonson AM, Radlowski EC, Lawson MA, Rytych JL, Johnson RW. Maternal viral infection during pregnancy elicits anti-social behavior in neonatal piglet offspring independent of postnatal microglial cell activation. Brain Behav Immun. 2017;59: 300–312. doi: 10.1016/j.bbi.2016.09.019 27650113

37. Udenze D, Trus I, Berube N, Gerdts V, Karniychuk U. The African strain of Zika virus causes more severe in utero infection than Asian strain in a porcine fetal transmission model. Emerg Microbes Infect. 2019;8: 1098–1107. doi: 10.1080/22221751.2019.1644967 31340725

38. Tayade C, Black GP, Fang Y, Croy BA. Differential Gene Expression in Endometrium, Endometrial Lymphocytes, and Trophoblasts during Successful and Abortive Embryo Implantation. J Immunol. 2006;176: 148–156. doi: 10.4049/jimmunol.176.1.148 16365405

39. Vanderhaeghe C, Dewulf J, De Vliegher S, Papadopoulos GA, de Kruif A, Maes D. Longitudinal field study to assess sow level risk factors associated with stillborn piglets. Anim Reprod Sci. 2010;120: 78–83. doi: 10.1016/j.anireprosci.2010.02.010 20346603

40. Šterzl J, Rejnek J, Trávníček J. Impermeability of pig placenta for antibodies. Folia Microbiol (Praha). 1966;11: 7–10. doi: 10.1007/BF02877148 4957967

41. Waysbort A, Giroux M, Mansat V, Teixeira M, Dumas JC, Puel J. Experimental study of transplacental passage of alpha interferon by two assay techniques. Antimicrob Agents Chemother. 1993;37: 1232–1237. doi: 10.1128/aac.37.6.1232 8328774

42. Šplíchal I, Řeháková Z, Šinkora M, Šinkora J, Trebichavský I, Laude H, et al. In vivo study of interferon-alpha-secreting cells in pig foetal lymphohaematopoietic organs following in utero TGEV coronavirus injection. Res Immunol. 1997;148: 247–256. doi: 10.1016/s0923-2494(97)80866-8 9300531

43. Li J, Mirnics K, Garbett K, Patterson PH, Smith SEP. Maternal Immune Activation Alters Fetal Brain Development through Interleukin-6. J Neurosci. 2007;27: 10695–10702. doi: 10.1523/JNEUROSCI.2178-07.2007 17913903

44. Choi GB, Yim YS, Wong H, Kim S, Kim H, Kim S V., et al. The maternal interleukin-17a pathway in mice promotes autism-like phenotypes in offspring. Science. 2016;351: 933–939. doi: 10.1126/science.aad0314 26822608

45. Brasil P, Nielsen-Saines K, Jung JU, Chan Y, Chen W, Cheng G, et al. Biomarkers and immunoprofiles associated with fetal abnormalities of ZIKV-positive pregnancies. JCI Insight. 2018;3. doi: 10.1172/jci.insight.124152 30385728

46. Russell E, Koren G, Rieder M, Van Uum S. Hair cortisol as a biological marker of chronic stress: Current status, future directions and unanswered questions. Psychoneuroendocrinology. 2012;37: 589–601. doi: 10.1016/j.psyneuen.2011.09.009 21974976

47. Davenport MD, Tiefenbacher S, Lutz CK, Novak MA, Meyer JS. Analysis of endogenous cortisol concentrations in the hair of rhesus macaques. Gen Comp Endocrinol. 2006;147: 255–61. doi: 10.1016/j.ygcen.2006.01.005 16483573

48. Karniychuk UU, Nauwynck HJ. Quantitative Changes of Sialoadhesin and CD163 Positive Macrophages in the Implantation Sites and Organs of Porcine Embryos/Fetuses During Gestation. Placenta. 2009;30: 497–500. doi: 10.1016/j.placenta.2009.03.016 19410291

49. Karniychuk UU, Saha D, Geldhof M, Vanhee M, Cornillie P, Van den Broeck W, et al. Porcine reproductive and respiratory syndrome virus (PRRSV) causes apoptosis during its replication in fetal implantation sites. Microb Pathog. 2011;51: 194–202. doi: 10.1016/j.micpath.2011.04.001 21511026

50. Novakovic P, Harding JCS, Ladinig A, Al-Dissi AN, MacPhee DJ, Detmer SE. Relationships of CD163 and CD169 positive cell numbers in the endometrium and fetal placenta with type 2 PRRSV RNA concentration in fetal thymus. Vet Res. 2016;47: 76. doi: 10.1186/s13567-016-0364-7 27494990

51. Rosenberg AZ, Yu W, Hill DA, Reyes CA, Schwartz DA. Placental Pathology of Zika Virus: Viral Infection of the Placenta Induces Villous Stromal Macrophage (Hofbauer Cell) Proliferation and Hyperplasia. Arch Pathol Lab Med. 2017;141: 43–48. doi: 10.5858/arpa.2016-0401-OA 27681334

52. Caires-Júnior LC, Goulart E, Melo US, Araujo BSH, Alvizi L, Soares-Schanoski A, et al. Discordant congenital Zika syndrome twins show differential in vitro viral susceptibility of neural progenitor cells. Nat Commun. 2018;9: 475. doi: 10.1038/s41467-017-02790-9 29396410

53. Linden V, Linden H Jr, Leal MC, Rolim Filho EL, Linden A, Aragão MFVV, et al. Discordant clinical outcomes of congenital Zika virus infection in twin pregnancies. Arq Neuropsiquiatr. 2017;75: 381–386. doi: 10.1590/0004-282X20170066 28658408

54. Corry J, Arora N, Good CA, Sadovsky Y, Coyne CB. Organotypic models of type III interferon-mediated protection from Zika virus infections at the maternal–fetal interface. Proc Natl Acad Sci. 2017;114: 9433–9438. doi: 10.1073/pnas.1707513114 28784796

55. Sun X, Hua S, Chen H-R, Ouyang Z, Einkauf K, Tse S, et al. Transcriptional Changes during Naturally Acquired Zika Virus Infection Render Dendritic Cells Highly Conducive to Viral Replication. Cell Rep. 2017;21: 3471–3482. doi: 10.1016/j.celrep.2017.11.087 29262327

56. Szaba FM, Tighe M, Kummer LW, Lanzer KG, Ward JM, Lanthier P, et al. Zika virus infection in immunocompetent pregnant mice causes fetal damage and placental pathology in the absence of fetal infection. PLoS Pathog. 2018;14: e1006994. doi: 10.1371/journal.ppat.1006994 29634758

57. Hirsch AJ, Roberts VHJ, Grigsby PL, Haese N, Schabel MC, Wang X, et al. Zika virus infection in pregnant rhesus macaques causes placental dysfunction and immunopathology. Nat Commun. 2018;9: 263. doi: 10.1038/s41467-017-02499-9 29343712

58. Meese GB, Ewbank R. The establishment and nature of the dominance hierarchy in the domesticated pig. Anim Behav. 1973;21: 326–334. doi: 10.1016/S0003-3472(73)80074-0

59. Shao Q, Herrlinger S, Zhu Y-N, Yang M, Goodfellow F, Stice SL, et al. The African Zika virus MR-766 is more virulent and causes more severe brain damage than current Asian lineage and dengue virus. Development. 2017;144: 4114–4124. doi: 10.1242/dev.156752 28993398

60. Coffey LL, Keesler RI, Pesavento PA, Woolard K, Singapuri A, Watanabe J, et al. Intraamniotic Zika virus inoculation of pregnant rhesus macaques produces fetal neurologic disease. Nat Commun. 2018;9: 2414. doi: 10.1038/s41467-018-04777-6 29925843

61. Boulanger-Bertolus J, Pancaro C, Mashour GA. Increasing Role of Maternal Immune Activation in Neurodevelopmental Disorders. Front Behav Neurosci. 2018;12: 230. doi: 10.3389/fnbeh.2018.00230 30344483

62. Barker DJP. The fetal and infant origins of disease. Eur J Clin Invest. 1995;25: 457–463. doi: 10.1111/j.1365-2362.1995.tb01730.x 7556362

63. Blomström Å, Karlsson H, Gardner R, Jörgensen L, Magnusson C, Dalman C. Associations between Maternal Infection during Pregnancy, Childhood Infections, and the Risk of Subsequent Psychotic Disorder—A Swedish Cohort Study of Nearly 2 Million Individuals. Schizophr Bull. 2016;42: 125–133. doi: 10.1093/schbul/sbv112 26303935

64. Spann MN, Monk C, Scheinost D, Peterson BS. Maternal Immune Activation During the Third Trimester Is Associated with Neonatal Functional Connectivity of the Salience Network and Fetal to Toddler Behavior. J Neurosci. 2018;38: 2877–2886. doi: 10.1523/JNEUROSCI.2272-17.2018 29487127

65. da Paz VRF, Sequeira D, Pyrrho A. Infection by Schistosoma mansoni during pregnancy: Effects on offspring immunity. Life Sci. 2017;185: 46–52. doi: 10.1016/j.lfs.2017.07.021 28754617

66. Cheong JN, Wlodek ME, Moritz KM, Cuffe JSM. Programming of maternal and offspring disease: impact of growth restriction, fetal sex and transmission across generations. J Physiol. 2016;594: 4727–4740. doi: 10.1113/JP271745 26970222

67. Garay PA, Hsiao EY, Patterson PH, McAllister AK. Maternal immune activation causes age- and region-specific changes in brain cytokines in offspring throughout development. Brain Behav Immun. 2013;31: 54–68. doi: 10.1016/j.bbi.2012.07.008 22841693

68. Brenhouse HC, Schwarz JM. Immunoadolescence: Neuroimmune development and adolescent behavior. Neurosci Biobehav Rev. 2016;70: 288–299. doi: 10.1016/j.neubiorev.2016.05.035 27260127

69. Györffy BA, Gulyássy P, Gellén B, Völgyi K, Madarasi D, Kis V, et al. Widespread alterations in the synaptic proteome of the adolescent cerebral cortex following prenatal immune activation in rats. Brain Behav Immun. 2016;56: 289–309. doi: 10.1016/j.bbi.2016.04.002 27058163

70. Giovanoli S, Weber-Stadlbauer U, Schedlowski M, Meyer U, Engler H. Prenatal immune activation causes hippocampal synaptic deficits in the absence of overt microglia anomalies. Brain Behav Immun. 2016;55: 25–38. doi: 10.1016/j.bbi.2015.09.015 26408796

71. Meyer U, Feldon J, Fatemi SH. In-vivo rodent models for the experimental investigation of prenatal immune activation effects in neurodevelopmental brain disorders. Neurosci Biobehav Rev. 2009;33: 1061–1079. doi: 10.1016/j.neubiorev.2009.05.001 19442688

72. Lupien SJ, McEwen BS, Gunnar MR, Heim C. Effects of stress throughout the lifespan on the brain, behaviour and cognition. Nat Rev Neurosci. 2009;10: 434–445. doi: 10.1038/nrn2639 19401723

73. Le Pen G, Gourevitch R, Hazane F, Hoareau C, Jay TM, Krebs M-O. Peri-pubertal maturation after developmental disturbance: A model for psychosis onset in the rat. Neuroscience. 2006;143: 395–405. doi: 10.1016/j.neuroscience.2006.08.004 16973297

74. McCormick CM, Mathews IZ. Adolescent development, hypothalamic-pituitary-adrenal function, and programming of adult learning and memory. Prog Neuro-Psychopharmacology Biol Psychiatry. 2010;34: 756–765. doi: 10.1016/j.pnpbp.2009.09.019 19782715

75. Darbellay J, Lai K, Babiuk S, Berhane Y, Ambagala A, Wheler C, et al. Neonatal pigs are susceptible to experimental Zika virus infection. Emerg Microbes Infect. 2017;6: e6. doi: 10.1038/emi.2016.133 28196970

76. Bolhuis JE, Schouten WGP, Schrama JW, Wiegant VM. Individual coping characteristics, aggressiveness and fighting strategies in pigs. Anim Behav. 2005;69: 1085–1091. doi: 10.1016/j.anbehav.2004.09.013

77. van der Staay FJ, De Groot J, Van Reenen CG, Hoving-Bolink AH, Schuurman T, Schmidt BH. Effects of Butafosfan on salivary cortisol and behavioral response to social stress in piglets. J Vet Pharmacol Ther. 2007;30: 410–416. doi: 10.1111/j.1365-2885.2007.00884.x 17803732

78. van der Staay FJ, de Groot J, Schuurman T, Korte SM. Repeated social defeat in female pigs does not induce neuroendocrine symptoms of depression, but behavioral adaptation. Physiol Behav. 2008;93: 453–460. doi: 10.1016/j.physbeh.2007.10.002 17991496

79. Kranendonk G, Hopster H, Fillerup M, Ekkel ED, Mulder EJH, Taverne MAM. Cortisol administration to pregnant sows affects novelty-induced locomotion, aggressive behaviour, and blunts gender differences in their offspring. Horm Behav. 2006;49: 663–672. doi: 10.1016/j.yhbeh.2005.12.008 16488416

80. Hansmann L, Groeger S, von Wulffen W, Bein G, Hackstein H. Human monocytes represent a competitive source of interferon-α in peripheral blood. Clin Immunol. 2008;127: 252–264. doi: 10.1016/j.clim.2008.01.014 18342575

81. Siegal FP, Kadowaki N, Shodell M, Fitzgerald-Bocarsly PA, Shah K, Ho S, et al. The nature of the principal type 1 interferon-producing cells in human blood. Science. 1999;284: 1835–7. doi: 10.1126/science.284.5421.1835 10364556

82. Summerfield A, Guzylack-Piriou L, Schaub A, Carrasco CP, Tâche V, Charley B, et al. Porcine peripheral blood dendritic cells and natural interferon-producing cells. Immunology. 2003;110: 440–9. doi: 10.1111/j.1365-2567.2003.01755.x 14632641

83. Kasper C, Lübking A, Beelen DW, Dührsen U. Interferon alpha (IFN) treatment of bone marrow stroma inhibits haematopoesis. Leuk Res. 2004;28: 1217–1220. doi: 10.1016/j.leukres.2004.03.012 15380348

84. Essers MAG, Offner S, Blanco-Bose WE, Waibler Z, Kalinke U, Duchosal MA, et al. IFNα activates dormant haematopoietic stem cells in vivo. Nature. 2009;458: 904–908. doi: 10.1038/nature07815 19212321

85. Prendergast ÁM, Kuck A, van Essen M, Haas S, Blaszkiewicz S, Essers MAG. IFNα-mediated remodeling of endothelial cells in the bone marrow niche. Haematologica. 2017;102: 445–453. doi: 10.3324/haematol.2016.151209 27742772

86. Tobler LH, Cameron MJ, Lanteri MC, Prince HE, Danesh A, Persad D, et al. Interferon and Interferon‐Induced Chemokine Expression Is Associated with Control of Acute Viremia in West Nile Virus–Infected Blood Donors. J Infect Dis. 2008;198: 979–983. doi: 10.1086/591466 18729779

87. Kurane I, Innis BL, Nimmannitya S, Nisalak A, Ennis FA, Meager A. High Levels of Interferon Alpha in the Sera of Children with Dengue Virus Infection. Am J Trop Med Hyg. 1993;48: 222–229. doi: 10.4269/ajtmh.1993.48.222 8447527

88. Davidson S, Crotta S, McCabe TM, Wack A. Pathogenic potential of interferon αβ in acute influenza infection. Nat Commun. 2014;5: 3864. doi: 10.1038/ncomms4864 24844667

89. Cha L, Berry CM, Nolan D, Castley A, Fernandez S, French MA. Interferon-alpha, immune activation and immune dysfunction in treated HIV infection. Clin Transl Immunol. 2014;3: e10. doi: 10.1038/cti.2014.1 25505958

90. Mostafavi S, Battle A, Zhu X, Potash JB, Weissman MM, Shi J, et al. Type I interferon signaling genes in recurrent major depression: Increased expression detected by whole-blood RNA sequencing. Mol Psychiatry. 2014;19: 1267–1274. doi: 10.1038/mp.2013.161 24296977

91. Huckans M, Fuller B, Wheaton V, Jaehnert S, Ellis C, Kolessar M, et al. A longitudinal study evaluating the effects of interferon-alpha therapy on cognitive and psychiatric function in adults with chronic hepatitis C. J Psychosom Res. 2015;78: 184–192. doi: 10.1016/j.jpsychores.2014.07.020 25219976

92. Rho MB, Wesselingh S, Glass JD, McArthur JC, Choi S, Griffin J, et al. A potential role for interferon-α in the pathogenesis of HIV-associated dementia. Brain Behav Immun. 1995;9: 366–377. doi: 10.1006/brbi.1995.1034 8903853

93. Shakil AO, Di Bisceglie AM, Hoofnagle JH. Seizures during alpha interferon therapy. J Hepatol. 1996;24: 48–51. doi: 10.1016/s0168-8278(96)80185-1 8834024

94. Lieb K, Engelbrecht MA, Gut O, Fiebich BL, Bauer J, Janssen G, et al. Cognitive impairment in patients with chronic hepatitis treated with interferon alpha (IFNα): results from a prospective study. Eur Psychiatry. 2006;21: 204–210. doi: 10.1016/j.eurpsy.2004.09.030 16632167

95. Murray DM, Hensey OJ, O’Dwyer TP, King MD. Letter to the editor: Further evidence of neurological sequelae associated with interferon therapy in the pediatric population. Eur J Paediatr Neurol. 2000;4: 295–296. doi: 10.1053/ejpn.2000.0388 11277372

96. Schaefer M, Engelbrechta MA, Gut O, Fiebich BL, Bauer J, Schmidt F, et al. Interferon alpha (IFNα) and psychiatric syndromes: A review. Prog Neuro-Psychopharmacology Biol Psychiatry. 2002;26: 731–746. doi: 10.1016/S0278-5846(01)00324-4

97. Juengling FD, Ebert D, Gut O, Engelbrecht MA, Rasenack J, Nitzsche EU, et al. Prefrontal cortical hypometabolism during low-dose interferon alpha treatment. Psychopharmacology (Berl). 2000;152: 383–389. doi: 10.1007/s002130000549 11140330

98. Raison CL, Demetrashvili M, Capuron L, Miller AH. Neuropsychiatric adverse effects of interferon-alpha: recognition and management. CNS Drugs. 2005;19: 105–23. doi: 10.2165/00023210-200519020-00002 15697325

99. Kieffer F, Thulliez P, Brézin A, Nobre R, Romand S, Yi-Gallimard E, et al. [Treatment of subclinical congenital toxoplasmosis by sulfadiazine and pyrimethamine continuously during 1 year: apropos of 46 cases]. Arch Pediatr. 2002;9: 7–13. French. doi: 10.1016/s0929-693x(01)00687-x 11865553

100. Stagno S, Reynolds DW, Amos CS, Dahle AJ, McCollister FP, Mohindra I, et al. Auditory and visual defects resulting from symptomatic and subclinical congenital cytomegaloviral and toxoplasma infections. Pediatrics. 1977;59: 669–78. 193086

101. Diez B, Galdeano A, Nicolas R, Cisterna R. Relationship between the production of interferon-alpha/beta and interferon-gamma during acute toxoplasmosis. Parasitology. 1989;99 Pt 1: 11–5.

102. DeFilippis VR, Alvarado D, Sali T, Rothenburg S, Früh K. Human Cytomegalovirus Induces the Interferon Response via the DNA Sensor ZBP1. J Virol. 2010;84: 585–598. doi: 10.1128/JVI.01748-09 19846511

103. Hoarau C, Ranivoharimina V, Chavet-Quéru MS, Rason I, Rasatemalala H, Rakotonirina G, et al. [Congenital syphilis: update and perspectives]. Sante. 9: 38–45. French. 10210801

104. Smoleniec JS, Pillai M, Caul EO, Usher J. Subclinical transplacental parvovirus B19 infection: an increased fetal risk? Lancet. 1994;343: 1100–1101. doi: 10.1016/S0140-6736(94)90212-7

105. Hayden GF, Herrmann KL, Buimovici-Klein E, Weiss KE, Nieburg PI, Mitchell JE. Subclinical congenital rubella infection associated with maternal rubella vaccination in early pregnancy. J Pediatr. 1980;96: 869–72. doi: 10.1016/s0022-3476(80)80562-2 7365590

106. Duran N, Yarkin F, Evruke C, Koksal F. Asymptomatic herpes simplex virus type 2 (HSV-2) infection among pregnant women in Turkey. Indian J Med Res. 2004;120: 106–10. 15347860

107. Abbink P, Larocca RA, De La Barrera RA, Bricault CA, Moseley ET, Boyd M, et al. Protective efficacy of multiple vaccine platforms against Zika virus challenge in rhesus monkeys. Science. 2016;353: 1129–1132. doi: 10.1126/science.aah6157 27492477

108. Rasmussen SB, Sørensen LN, Malmgaard L, Ank N, Baines JD, Chen ZJ, et al. Type I interferon production during herpes simplex virus infection is controlled by cell-type-specific viral recognition through Toll-like receptor 9, the mitochondrial antiviral signaling protein pathway, and novel recognition systems. J Virol. 2007;81: 13315–24. doi: 10.1128/JVI.01167-07 17913820

109. Martinot AJ, Abbink P, Afacan O, Prohl AK, Bronson R, Hecht JL, et al. Fetal Neuropathology in Zika Virus-Infected Pregnant Female Rhesus Monkeys. Cell. 2018;173: 1111–1122.e10. doi: 10.1016/j.cell.2018.03.019 29606355

110. Cardenas I, Means RE, Aldo P, Koga K, Lang SM, Booth CJ, et al. Viral infection of the placenta leads to fetal inflammation and sensitization to bacterial products predisposing to preterm labor. J Immunol. 2010;185: 1248–57. doi: 10.4049/jimmunol.1000289 20554966

111. Desai M, ter Kuile FO, Nosten F, McGready R, Asamoa K, Brabin B, et al. Epidemiology and burden of malaria in pregnancy. Lancet Infect Dis. 2007;7: 93–104. doi: 10.1016/S1473-3099(07)70021-X 17251080

112. Mor G. Placental Inflammatory Response to Zika Virus may Affect Fetal Brain Development. Am J Reprod Immunol. 2016;75: 421–422. doi: 10.1111/aji.12505 26892436

113. Eriksson JG, Kajantie E, Osmond C, Thornburg K, Barker DJP. Boys live dangerously in the womb. Am J Hum Biol. 2010;22: 330–335. doi: 10.1002/ajhb.20995 19844898

114. Andersen AD, Sangild PT, Munch SL, van der Beek EM, Renes IB, Ginneken C van, et al. Delayed growth, motor function and learning in preterm pigs during early postnatal life. Am J Physiol Integr Comp Physiol. 2016;310: R481–R492. doi: 10.1152/ajpregu.00349.2015 26764054

115. Gieling ET, Schuurman T, Nordquist RE, van der Staay FJ. The pig as a model animal for studying cognition and neurobehavioral disorders. Current Topics in Behavioral Neurosciences. 2011. pp. 359–383. doi: 10.1007/7854_2010_112 21287323

116. Kanitz E, Hameister T, Tuchscherer A, Tuchscherer M, Puppe B. Social Support Modulates Stress-Related Gene Expression in Various Brain Regions of Piglets. Front Behav Neurosci. 2016;10: 227. doi: 10.3389/fnbeh.2016.00227 27965550

117. Lind NM, Olsen AK, Moustgaard A, Jensen SB, Jakobsen S, Hansen AK, et al. Mapping the amphetamine-evoked dopamine release in the brain of the Göttingen minipig. Brain Res Bull. 2005;65: 1–9. doi: 10.1016/j.brainresbull.2004.08.007 15680539

118. Lind NM, Arnfred SM, Hemmingsen RP, Hansen AK. Prepulse inhibition of the acoustic startle reflex in pigs and its disruption by D-amphetamine. Behav Brain Res. 2004;155: 217–222. doi: 10.1016/j.bbr.2004.04.014 15364480

119. van der Staay FJ, Pouzet B, Mahieu M, Nordquist RE, Schuurman T. The d-amphetamine-treated Göttingen miniature pig: An animal model for assessing behavioral effects of antipsychotics. Psychopharmacology (Berl). 2009;206: 715–729. doi: 10.1007/s00213-009-1599-z 19626314

120. Lanciotti RS, Lambert AJ, Holodniy M, Saavedra S, del Carmen Castillo Signor L. Phylogeny of Zika virus in western Hemisphere, 2015. Emerg Infect Dis. 2016;22: 933–935. doi: 10.3201/eid2205.160065 27088323

121. Saha D, Karniychuk UU, Huang L, Geldhof M, Vanhee M, Lefebvre DJ, et al. Unusual outcome of in utero infection and subsequent postnatal super-infection with different PCV2b strains. Virol Sin. 2014;29. doi: 10.1007/s12250-014-3431-0 24950783

122. McGlone JJ. Influence of resources on pig aggression and dominance. Behav Processes. 1986;12: 135–144. doi: 10.1016/0376-6357(86)90052-5 24897348

123. Arey DS, Franklin MF. Effects of straw and unfamiliarity on fighting between newly mixed growing pigs. Appl Anim Behav Sci. 1995;45: 23–30. doi: 10.1016/0168-1591(95)00600-W

124. Fleiss JL. Measuring nominal scale agreement among many raters. Psychol Bull. 1971;76: 378–382. doi: 10.1037/h0031619

125. Xu MY, Liu SQ, Deng CL, Zhang QY, Zhang B. Detection of Zika virus by SYBR green one-step real-time RT-PCR. J Virol Methods. 2016;236: 93–97. doi: 10.1016/j.jviromet.2016.07.014 27444120

126. Faye O, Faye O, Dupressoir A, Weidmann M, Ndiaye M, Alpha Sall A. One-step RT-PCR for detection of Zika virus. J Clin Virol. 2008;43: 96–101. doi: 10.1016/j.jcv.2008.05.005 18674965

127. Nem de Oliveira Souza I, Frost PS, França J V., Nascimento-Viana JB, Neris RLS, Freitas L, et al. Acute and chronic neurological consequences of early-life zika virus infection in mice. Sci Transl Med. 2018;10: eaar2749. doi: 10.1126/scitranslmed.aar2749 29875203

128. Zupan M, Zanella AJ. Peripheral regulation of stress and fear responses in pigs from tail-biting pens. Rev Bras Zootec. 2017;46: 33–38. doi: 10.1590/S1806-92902017000100006

129. Turpin DL, Langendijk P, Chen TY, Lines D, Pluske JR. Intermittent suckling causes a transient increase in cortisol that does not appear to compromise selected measures of pigletwelfare and stress. Animals. 2016;6: 24. doi: 10.3390/ani6030024 26999224

130. Rault JL, Dunshea FR, Pluske JR. Effects of oxytocin administration on the response of piglets to weaning. Animals. 2015;5: 545–560. doi: 10.3390/ani5030371 26479373

131. Macbeth BJ, Cattet MRL, Stenhouse GB, Gibeau ML, Janz DM. Hair cortisol concentration as a noninvasive measure of long-term stress in free-ranging grizzly bears (Ursus arctos): considerations with implications for other wildlife. Can J Zool. 2010;88: 935–949. doi: 10.1139/z10-057

132. Bray NL, Pimentel H, Melsted P, Pachter L. Near-optimal probabilistic RNA-seq quantification. Nat Biotechnol. 2016;34: 525–527. doi: 10.1038/nbt.3519 27043002