A clinical and histopathological study of malformations observed in fetuses infected by the Zika virus

[en] Background: The recent outbreak of Zika virus (ZIKV) infection and the associated increased prevalence of microcephaly in Brazil underline the impact of viral infections on embryo fetal development. The aim of the present study is to provide a detailed clinical and histopathological study of the fetal disruption caused by the ZIKV, with a special focus on the associated neuropathological findings. Methods: A detailed feto-placental examination, as well as neuropathological and neurobiological studies were performed on three fetuses collected after pregnancy termination between 22 and 25 weeks of gestation (WG), because brain malformations associated with a maternal and fetal ZIKV infection was diagnosed. Results: In all three cases, the maternal infection occurred during the first trimester of pregnancy. A small head was observed on the ultrasound examination of the second trimester of pregnancy and led to the diagnosis of ZIKV fetopathy and pregnancy termination. The fetal histopathological examination was unremarkable on the viscera but showed on the testis an interstitial lymphocytic infiltrate. The placenta contained a Hofbauer cells hyperplasia with signs of inflammation. Neuropathological findings included a meningoencephalitis and an ex vacuo hydrocephalus. Immunohistochemical studies showed the presence of T lymphocytic and histiocytic meningitis associated with an abundant cerebral astroglial and macrophagic reaction. In situ hybridization demonstrated, abundant ZIKV particles within the cerebral parenchyma mainly in the ventricular/subventricular zone and in the cortical plate. In addition massive cells death and endoplasmic reticulum damage were present. Conclusion: The present study reports on the clinical and histopathological findings observed in three fetuses infected by the ZIKV. It emphasizes the severity of brain damages and the minimal visceral and placental changes observed upon ZIKV infection. This confirms the selective neurotropism of ZIKV. Finally, it allows us to describe the cascade of multifactorial developmental defects leading to microcephaly. © 2018 International Society of Neuropathology

Disciplines :

Immunology & infectious disease

Author, co-author :

Beaufrère, Aurélie; Service d'Histologie-Embryologie-Cytogénétique, Hôpital Universitaire Necker-Enfants Malades, APHP, Paris, France

Bessières, Bettina; Service d'Histologie-Embryologie-Cytogénétique, Hôpital Universitaire Necker-Enfants Malades, APHP, Paris, France

Bonnière, Maryse; Service d'Histologie-Embryologie-Cytogénétique, Hôpital Universitaire Necker-Enfants Malades, APHP, Paris, France

Driessen, Marine; Service de Gynécologie-Obstétrique, Hôpital Universitaire Necker-Enfants Malades, APHP, Paris, France

Alfano, Christian ; Université de Liège - ULiège > Neurosciences-Molecular Regulation of Neurogenesis

Couderc, Thérèse; Institut Pasteur, Biology of Infection Unit, Paris, France, Inserm U1117, Paris, France

Thiry, Marc ; Université de Liège - ULiège > Département des sciences de la vie > Biologie cellulaire

Thelen, Nicolas ; Université de Liège - ULiège > Département des sciences de la vie > Biologie cellulaire

Lecuit, Marc; Institut Pasteur, Biology of Infection Unit, Paris, France, Inserm U1117, Paris, France, Paris-Descartes University, Sorbonne Paris Cité, Centre d'Infectiologie Necker-Pasteur, Necker-Enfants Malades, Paris, France

Attié-Bitach, Tania; Service d'Histologie-Embryologie-Cytogénétique, Hôpital Universitaire Necker-Enfants Malades, APHP, Paris, France, INSERM U-1163, Institut Imagine, Paris, France, Université Paris Descartes, Paris, France

More authors (5 more)

Language :

English

Title :

A clinical and histopathological study of malformations observed in fetuses infected by the Zika virus

Publication date :

2019

Journal title :

Brain Pathology

ISSN :

1015-6305

Publisher :

Blackwell Publishing Ltd

Volume :

Issue :

Pages :

114-125

Peer reviewed :

Peer Reviewed verified by ORBi

Available on ORBi :

since 09 May 2019

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Bibliography

Aagaard KM, Lahon A, Suter MA, Arya RP, Seferovic MD, Vogt MB et al (2017) Primary human placental trophoblasts are permissive for zika virus (ZIKV) replication. Sci Rep 7:41389.
Benirschke K, Mendoza GR, Bazeley PL (1974) Placental and fetal manifestations of cytomegalovirus infection. Virchows Arch B Cell Pathol 16(2):121.
Besnard M, Eyrolle-Guignot D, Guillemette-Artur P, Lastère S, Bost-Bezeaud F, Marcelis L, et al (2016) Congenital cerebral malformations and dysfunction in fetuses and newborns following the 2013 to 2014 Zika virus epidemic in French Polynesia. Euro Surveill Bull Eur Sur Mal Transom Eur Common Dis Bull 21(13).
Bhatnagar J, Rabeneck DB, Martines RB, Reagan-Steiner S, Ermias Y, Estetter LBC, et al (2017) Zika virus RNA replication and persistence in brain and placental tissue. Emerg Infect Dis 23(3):405.
Blázquez A-B, Saiz J-C (2016) Neurological manifestations of Zika virus infection. World J Virol 5(4):135–143.
Brasil P, Pereira JP, Moreira ME, Ribeiro Nogueira RM, Damasceno L, Wakimoto M, et al (2016) Zika virus infection in pregnant women in Rio de Janeiro. N Engl J Med 375(24):2321–2334.
Carvalho FHC, Cordeiro KM, Peixoto AB, Tonni G, Moron AF, Feitosa FEL, et al (2016) Associated ultrasonographic findings in fetuses with microcephaly because of suspected Zika virus (ZIKV) infection during pregnancy. Prenat Diagn 36(9):882–887.
Cau E, Gradwohl G, Fode C, Guillemot F (1997) Mash1 activates a cascade of bHLH regulators in olfactory neuron progenitors. Dev Camb Engl 124(8):1611–1621.
Cauchemez S, Besnard M, Bompard P, Dub T, Guillemette-Artur P, Eyrolle-Guignot D, et al (2016) Association between Zika virus and microcephaly in French Polynesia, 2013-15: a retrospective study. Lancet Lond Engl 387(10033):2125–2132.
Chavali PL, Stojic L, Meredith LW, Joseph N, Nahorski MS, Sanford TJ, et al (2017) Neurodevelopmental protein Musashi-1 interacts with the Zika genome and promotes viral replication. Science 357(6346):83–88.
Chimelli L, Melo ASO, Avvad-Portari E, Wiley CA, Camacho AHS, Lopes VS, et al (2017) The spectrum of neuropathological changes associated with congenital Zika virus infection. Acta Neuropathol 133(6):983.
Driggers RW, Ho C-Y, Korhonen EM, Kuivanen S, Jääskeläinen AJ, Smura T, et al (2016) Zika virus infection with prolonged maternal viremia and fetal brain abnormalities. N Engl J Med 374(22):2142–2151.
Eppes C, Rac M, Dunn J, Versalovic J, Murray KO, Suter MA, et al (2017) Testing for Zika virus infection in pregnancy: Key concepts to deal with an emerging epidemic. Am J Obstet Gynecol 216(3):209–225.
Garcia AG, Marques RL, Lobato YY, Fonseca ME, Wigg MD (1985) Placental pathology in congenital rubella. Placenta 6(4):281–295.
Gladwyn-Ng I, Cordón-Barris L, Alfano C, Creppe C, Couderc T, Morelli G, et al (2018) Stress-induced unfolded protein response contributes to Zika virus-associated microcephaly. Nat Neurosci 21(1):63–71.
Govero J, Esakky P, Scheaffer SM, Fernandez E, Drury A, Platt DJ, et al (2016) Zika virus infection damages the testes in mice. Nature 540(7633):438–442.
Guihard-Costa AM, Larroche JC, Droullé P, Narcy F (1995) Fetal biometry. Growth charts for practical use in fetopathology and antenatal ultrasonography. Introduction. Fetal Diagn Ther 10(4):211–278.
Honein MA, Dawson AL, Petersen EE, Jones AM, Lee EH, Yazdy MM, et al (2017) Birth defects among fetuses and infants of US women with evidence of possible Zika virus infection during pregnancy. JAMA 317(1):59–68.
Joguet G, Mansuy J-M, Matusali G, Hamdi S, Walschaerts M, Pavili L, et al (2017) Effect of acute Zika virus infection on sperm and virus clearance in body fluids: a prospective observational study. Lancet Infect Dis 17(11):1200–1208.
Laguesse S, Creppe C, Nedialkova DD, Prévot PP, Borgs L, Huysseune S, et al (2015) A dynamic unfolded protein response contributes to the control of cortical neurogenesis. Dev Cell 5:553–567.
Li H, Saucedo-Cuevas L, Regla-Nava JA, Chai G, Sheets N, Tang W, et al (2016) Zika virus infects neural progenitors in the adult mouse brain and alters proliferation. Cell Stem Cell 19(5):593–598.
Melo AS de O, Aguiar RS, Amorim MMR, Arruda MB, Melo F de O, Ribeiro STC, et al (2016) Congenital Zika virus infection: beyond neonatal microcephaly. JAMA Neurol 73(12):1407–1416.
Merfeld E, Ben-Avi L, Kennon M, Cerveny KL (2017) Potential mechanisms of Zika-linked microcephaly. Wiley Interdiscip Rev Dev Biol 6(4)
Mladinich MC, Schwedes J, Mackow ER (2017) Zika virus persistently infects and is basolaterally released from primary human brain microvascular endothelial cells. mBio 8(4).
Mlakar J, Korva M, Tul N, Popović M, Poljšak-Prijatelj M, Mraz J, et al (2016) Zika virus associated with microcephaly. N Engl J Med 374(10):951–958.
Noronha L de, Zanluca C, Azevedo MLV, Luz KG, Santos CNDD (2016) Zika virus damages the human placental barrier and presents marked fetal neurotropism. Mem Inst Oswaldo Cruz 111(5):287–293.
Ogata M, Hino S, Saito A, Morikawa K, Kondo S, Kanemoto S, et al (2006) Autophagy is activated for cell survival after endoplasmic reticulum stress. Mol Cell Biol 26(24):9220–9231.
Pomar L, Malinger G, Benoist G, Carles G, Ville Y, Rousset D, et al Association between Zika virus and fetopathy: A prospective cohort study in French Guiana (2017) Ultrasound Obstet Gynecol Off J Int Soc Ultrasound Obstet Gynecol 49(6):729–736.
Quicke KM, Bowen JR, Johnson EL, McDonald CE, Ma H, O'Neal JT, et al (2016) Zika virus infects human placental macrophages. Cell Host Microbe 20(1):83–90.
Rosenberg AZ, Yu W, Hill DA, Reyes CA, Schwartz DA (2017) Placental pathology of Zika virus: viral infection of the placenta induces villous stromal macrophage (Hofbauer cell) proliferation and hyperplasia. Arch Pathol Lab Med 141(1):43–48.
Sarno M, Aquino M, Pimentel K, Cabral R, Costa G, Bastos F, et al (2016) Progressive lesions of central nervous system in microcephalic fetuses with suspected congenital Zika virus syndrome. Ultrasound Obstet Gynecol Off J Int Soc Ultrasound Obstet Gynecol 50(6):717–722.
Schaub B, Vouga M, Najioullah F, Gueneret M, Monthieux A, Harte C, et al (2017) Analysis of blood from Zika virus-infected fetuses: A prospective case series. Lancet Infect Dis 17(5):520–527.
Schwartz DA (2017) Autopsy and postmortem studies are concordant: pathology of Zika virus infection is neurotropic in fetuses and infants with microcephaly following transplacental transmission. Arch Pathol Lab Med 141(1):68.
Sheng Z-Y, Gao N, Wang Z-Y, Cui X-Y, Zhou D-S, Fan D-Y, et al (2017) Sertoli cells are susceptible to ZIKV infection in mouse testis. Front Cell Infect Microbiol 7:272.
Tang H, Hammack C, Ogden SC, Wen Z, Qian X, Li Y, et al (2016) Zika virus infects human cortical neural progenitors and attenuates their growth. Cell Stem Cell 18(5):587–590.
Teissier N, Fallet-Bianco C, Delezoide A-L, Laquerrière A, Marcorelles P, Khung-Savatovsky S, et al (2014) Cytomegalovirus-induced brain malformations in fetuses. J Neuropathol Exp Neurol 73(2):143–158.
van der Eijk AA, van Genderen PJ, Verdijk RM, Reusken CB, Mögling R, van Kampen JJA, et al (2016) Miscarriage associated with Zika virus infection. N Engl J Med 375(10):1002–1004.
Walter P, Ron D (2011) The unfolded protein response: from stress pathway to homeostatic regulation. Science 334(6059):1081.
WHO. Zika virus and complications: 2016 Public Health Emergency of International Concern WHO. Available at: http://www.who.int/emergencies/zika-virus-tmp/en/