The Brazilian Zika virus strain causes birth defects in experimental models.
Zika virus (ZIKV) is an arbovirus belonging to the genus Flavivirus (family Flaviviridae) and was first described in 1947 in Uganda following blood analyses of sentinel Rhesus monkeys. Until the twentieth century, the African and Asian lineages of the virus did not cause meaningful infections in humans. However, in 2007, vectored by Aedes aegypti mosquitoes, ZIKV caused the first noteworthy epidemic on the Yap Island in Micronesia. Patients experienced fever, skin rash, arthralgia and conjunctivitis. From 2013 to 2015, the Asian lineage of the virus caused further massive outbreaks in New Caledonia and French Polynesia. In 2013, ZIKV reached Brazil, later spreading to other countries in South and Central America. In Brazil, the virus has been linked to congenital malformations, including microcephaly and other severe neurological diseases, such as Guillain-Barré syndrome. Despite clinical evidence, direct experimental proof showing that the Brazilian ZIKV (ZIKV(BR)) strain causes birth defects remains absent. Here we demonstrate that ZIKV(BR) infects fetuses, causing intrauterine growth restriction, including signs of microcephaly, in mice. Moreover, the virus infects human cortical progenitor cells, leading to an increase in cell death. We also report that the infection of human brain organoids results in a reduction of proliferative zones and disrupted cortical layers. These results indicate that ZIKV(BR) crosses the placenta and causes microcephaly by targeting cortical progenitor cells, inducing cell death by apoptosis and autophagy, and impairing neurodevelopment. Our data reinforce the growing body of evidence linking the ZIKV(BR) outbreak to the alarming number of cases of congenital brain malformations. Our model can be used to determine the efficiency of therapeutic approaches to counteracting the harmful impact of ZIKV(BR) in human neurodevelopment.
University of São Paulo, Department of Surgery, Stem Cell Laboratory, São Paulo, São Paulo 05508-270, Brazil.
Fernanda R
FR
Cugola
University of São Paulo, Department of Surgery, Stem Cell Laboratory, São Paulo, São Paulo 05508-270, Brazil.|University of California San Diego, School of Medicine, Department of Pediatrics/Rady Children's Hospital San Diego, Department of Cellular &Molecular Medicine, Stem Cell Program, La Jolla, California 92037-0695, USA.
Isabella R
IR
Fernandes
University of São Paulo, Department of Surgery, Stem Cell Laboratory, São Paulo, São Paulo 05508-270, Brazil.|Tismoo, The Biotech Company, São Paulo, São Paulo 01401-000, Brazil.
Fabiele B
FB
Russo
University of California San Diego, School of Medicine, Department of Pediatrics/Rady Children's Hospital San Diego, Department of Cellular &Molecular Medicine, Stem Cell Program, La Jolla, California 92037-0695, USA.
Beatriz C
BC
Freitas
University of São Paulo, Department of Surgery, Stem Cell Laboratory, São Paulo, São Paulo 05508-270, Brazil.
João L M
JL
Dias
University of São Paulo, Department of Surgery, Stem Cell Laboratory, São Paulo, São Paulo 05508-270, Brazil.
Katia P
KP
Guimarães
University of São Paulo, Department of Surgery, Stem Cell Laboratory, São Paulo, São Paulo 05508-270, Brazil.
Cecília
C
Benazzato
University of São Paulo, Department of Surgery, Stem Cell Laboratory, São Paulo, São Paulo 05508-270, Brazil.
Nathalia
N
Almeida
University of São Paulo, Department of Surgery, Stem Cell Laboratory, São Paulo, São Paulo 05508-270, Brazil.|Tismoo, The Biotech Company, São Paulo, São Paulo 01401-000, Brazil.
Graciela C
GC
Pignatari
University of California San Diego, School of Medicine, Department of Pediatrics/Rady Children's Hospital San Diego, Department of Cellular &Molecular Medicine, Stem Cell Program, La Jolla, California 92037-0695, USA.
Sarah
S
Romero
University of São Paulo, Department of Immunology, Neuroimmune Interactions Laboratory, São Paulo, São Paulo 05508-000, Brazil.
Carolina M
CM
Polonio
University of São Paulo, Department of Immunology, Neuroimmune Interactions Laboratory, São Paulo, São Paulo 05508-000, Brazil.
Isabela
I
Cunha
University of São Paulo, Department of Immunology, Neuroimmune Interactions Laboratory, São Paulo, São Paulo 05508-000, Brazil.
Carla L
CL
Freitas
University of São Paulo, Department of Immunology, Neuroimmune Interactions Laboratory, São Paulo, São Paulo 05508-000, Brazil.
Wesley N
WN
Brandão
University of São Paulo, Department of Immunology, Neuroimmune Interactions Laboratory, São Paulo, São Paulo 05508-000, Brazil.
Cristiano
C
Rossato
University of São Paulo, Department of Immunology, Neuroimmune Interactions Laboratory, São Paulo, São Paulo 05508-000, Brazil.
David G
DG
Andrade
University of São Paulo, Department of Radiology and Oncology, USP School of Medicine, São Paulo, São Paulo 05403-010, Brazil.
Daniele de P
Dde P
Faria
University of São Paulo, Department of Radiology and Oncology, USP School of Medicine, São Paulo, São Paulo 05403-010, Brazil.
Alexandre T
AT
Garcez
University of São Paulo, Department of Radiology and Oncology, USP School of Medicine, São Paulo, São Paulo 05403-010, Brazil.
Carlos A
CA
Buchpigel
University of São Paulo, Department of Microbiology, Institute of Microbiology Sciences, Laboratory of Molecular Evolution and Bioinformatics, São Paulo, São Paulo 05508-000, Brazil.
Carla T
CT
Braconi
University of São Paulo, Department of Microbiology, Institute of Microbiology Sciences, Laboratory of Molecular Evolution and Bioinformatics, São Paulo, São Paulo 05508-000, Brazil.
Erica
E
Mendes
Institute Pasteur in Dakar, Dakar 220, Sénégal.
Amadou A
AA
Sall
University of São Paulo, Department of Microbiology, Institute of Microbiology Sciences, Laboratory of Molecular Evolution and Bioinformatics, São Paulo, São Paulo 05508-000, Brazil.
Paolo M de A
PM
Zanotto
University of São Paulo, Department of Immunology, Neuroimmune Interactions Laboratory, São Paulo, São Paulo 05508-000, Brazil.
Jean Pierre S
JP
Peron
University of California San Diego, School of Medicine, Department of Pediatrics/Rady Children's Hospital San Diego, Department of Cellular &Molecular Medicine, Stem Cell Program, La Jolla, California 92037-0695, USA.
Alysson R
AR
Muotri
University of São Paulo, Department of Surgery, Stem Cell Laboratory, São Paulo, São Paulo 05508-270, Brazil.|University of São Paulo, School of Arts, Sciences and Humanities, Department of Obstetrics, São Paulo, São Paulo 03828-000, Brazil.
Patricia C B
PC
Beltrão-Braga
D000818:Animals; D017209:Apoptosis; D001343:Autophagy; D001921:Brain / Q000473:pathology / Q000821:virology; D001938:Brazil / Q000453:epidemiology; D049109:Cell Proliferation; D004195:Disease Models, Animal; D005260:Female; D005317:Fetal Growth Retardation / Q000473:pathology / Q000821:virology; D005333:Fetus / Q000821:virology; D051379:Mice; D008831:Microcephaly / Q000453:epidemiology / Q000209:etiology / Q000473:pathology / Q000821:virology*; D058953:Neural Stem Cells / Q000473:pathology / Q000821:virology; D009940:Organoids / Q000473:pathology / Q000821:virology; D010920:Placenta / Q000821:virology; D011247:Pregnancy; D000071244:Zika Virus / Q000472:pathogenicity*; D000071243:Zika Virus Infection / Q000150:complications / Q000453:epidemiology / Q000473:pathology / Q000821:virology