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Developmental Biology - Zika Birth Defects
Zika's Effects Vary Depending on Mom's Antibodies
Birth defects associated with Zika virus may depend on the mother's own immunity...
New research led by scientists at The Rockefeller University in New York helps explain why infection by the Zika virus causes birth defects in some children but not others. The study, published August 14 in the Journal of Experimental Medicine, suggests the risk of developing an abnormally small head (microcephaly) depends on the antibodies produced by pregnant mothers in response to a Zika infection.
Zika is spread by mosquitoes in tropical and subtropical climates, and symptoms of infection are fairly mild. But, the widespread Zika outbreak in Brazil in 2015-2016 revealed that being infected during pregnancy causes a wide range of fetal abnormalities. Microcephaly occurring in about 5% of live births by Zika-infected moms.
"Why some Zika infected pregnant women deliver apparently healthy newborns while others' babies were born with microcephaly is unknown."
Davide F. Robbiani, Research Associate, Professor, Rockefeller University, study co-leader along with Professor Michel C. Nussenzweig.
Various factors have been proposed that might increase the risk of microcephaly, including previous exposure to viruses similar to Zika — such as dengue and West Nile viruses. Antibodies generated by mom's immune system to combat Zika may recognize the virus and instead of neutralizing it, help it enter mom's cells where it crosses the placenta to infect the unborn fetus.
With the help of researchers and physicians in Brazil, Robbiani and colleagues analyzed blood samples collected during the 2015-2016 outbreak from Zika-infected mothers who gave birth to both healthy and microcephalic children.
Through a series of laboratory tests, researchers saw no significant differences in the activity of dengue, Zika or related virus antibodies, which suggests prior exposure to such viruses doesn't increase risk of Zika-associated birth defects.
However, after taking blood samples and determining which antibodies are produced against Zika virus, Robbiani and colleagues identified several differences in moms of babies with microcephaly. These moms' antibodies were more effective at neutralizing Zika than antibodies produced by mothers of healthy newborns. These antibodies also boosted entry of Zika in laboratory grown human cells.
Researchers confirmed these findings with pregnant macaque monkeys infected by Zika. Pregnant monkeys producing antibodies capable of acelerating Zika's entry into cells, also had higher risk of giving birth to babies with Zika-induced brain damage.
"Though our results only show a correlation at this point, they suggest antibodies may be implicated in Zika acting as a fetal disease.
Antibodies may exist that do not protect against, but enhance the risk of Zika microcephaly. The next step is to find which antibodies:
(1) are responsible for protection - and/or
(2) how these antibodies promote fetal damage.
This has significant implications for vaccine development. A safe Zika vaccine must elicit protective antibodies, and avoid those that might enhance risk for microcephaly."
Davide F. Robbiani, MD PhD,
Research and Associate Professor, Rockefeller University, New York, NY, USA.
Abstract
Zika virus (ZIKV) infection during pregnancy causes congenital abnormalities, including microcephaly. However, rates vary widely, and the contributing risk factors remain unclear. We examined the serum antibody response to ZIKV and other flaviviruses in Brazilian women giving birth during the 2015–2016 outbreak. Infected pregnancies with intermediate or higher ZIKV antibody enhancement titers were at increased risk to give birth to microcephalic infants compared with those with lower titers (P < 0.0001). Similarly, analysis of ZIKV-infected pregnant macaques revealed that fetal brain damage was more frequent in mothers with higher enhancement titers. Thus, features of the maternal antibodies are associated with and may contribute to the genesis of ZIKV-associated microcephaly.
Authors
Davide F. Robbiani, Priscilla C. Olsen, Federico Costa, View ORCID ProfileQiao Wang, Thiago Y. Oliveira, Nivison Nery, Adeolu Aromolaran, Mateus S. do Rosário, Gielson A. Sacramento, Jaqueline S. Cruz, Ricardo Khouri, View ORCID ProfileElsio A. Wunder, Adriana Mattos, Bruno de Paula Freitas, Manoel Sarno, Gracinda Archanjo, Dina Daltro, Gustavo B.S. Carvalho, Kleber Pimentel, View ORCID ProfileIsadora C. de Siqueira, View ORCID ProfileJoão R.M. de Almeida, Daniele F. Henriques, Juliana A. Lima, Pedro F.C. Vasconcelos, Dennis Schaefer-Babajew, Stephanie A. Azzopardi, Leonia Bozzacco, Anna Gazumyan, View ORCID ProfileRubens Belfort, Ana P. Alcântara, Gustavo Carvalho, View ORCID ProfileLicia Moreira, Katiaci Araujo, Mitermayer G. Reis, Rebekah I. Keesler, Lark L. Coffey, Jennifer Tisoncik-Go, View ORCID ProfileMichael Gale, Lakshmi Rajagopal, Kristina M. Adams Waldorf, View ORCID ProfileDawn M. Dudley, Heather A. Simmons, View ORCID ProfileAndres Mejia, David H. O’Connor, Rosemary J. Steinbach, View ORCID ProfileNicole Haese, Jessica Smith, View ORCID ProfileAnne Lewis, Lois Colgin, Victoria Roberts, Antonio Frias, View ORCID ProfileMeredith Kelleher, Alec Hirsch, Daniel N. Streblow, Charles M. Rice, View ORCID ProfileMargaret R. MacDonald, Antonio R.P. de Almeida, View ORCID ProfileKoen K.A. Van Rompay, View ORCID ProfileAlbert I. Ko, View ORCID Profile Michel C. Nussenzweig.
Acknowledgments
We would like to first thank the pregnant women and their families who agreed to participate in this study, as well as the staff of the Oswaldo Cruz Foundation, Hospital Geral Roberto Santos, Hospital Aliança, and Hospital Santo Amaro for their assistance with the clinical protocols. Moreover, we are thankful to Pamela Bjorkman, Jennifer Keeffe, Yu Lee, and Alisa Voll from the Bjorkman Lab at Caltech for providing purified EDIII proteins and Arlene Hurley, Roshni Patel, and Irina Shimeliovich at Rockefeller for assistance with work with human samples. We thank Jason Ogle, Wonsok Lee, and Jason Thiel for technical assistance with monitoring the pigtail macaques, Keisuke Yamamoto for collating the WNPRC pathology data, and Raj Kapur (University of Washington, Seattle) for pathology evaluation.
This work was supported by National Institutes of Health grants 5R01AI121207, R01TW009504, and R25TW009338 to A.I. Ko; National Institutes of Health pilot awards U19AI111825 and UL1TR001866 to D.F. Robbiani; National Institutes of Health grants R01AI037526, UM1AI100663, U19AI111825, UL1TR001866, and P01AI138938 to M.C. Nussenzweig; National Institutes of Health grants R01AI124690 and U19AI057229 (Cooperative Center for Human Immunology pilot project); The Rockefeller University Development Office and anonymous donors (to C.M. Rice); Fundação de Amparo à Pesquisa do Estado da Bahia grant PET0021/2016 (to M.G. Reis); National Institutes of Health grant R21AI129479-Supplement (to K.K.A. Van Rompay) and the National Institutes of Health Office of Research Infrastructure Programs/OD (P51OD011107 to the CNPRC); the United States Food and Drug Administration contract HHSF223201610542P (to L.L. Coffey); National Institutes of Health grants R01AI100989 and R01AI133976 (to L. Rajagopal and K.M. Adams Waldorf); and National Institutes of Health grants AI083019 and AI104002 (to M. Gale Jr.) and grant P51OD010425 to the WaNPRC (to K.M. Adams Waldorf, J. Tisoncik-Go, and M. Gale Jr.). Studies at WNPRC were supported by DHHS/PHS/National Institutes of Health grant R01Al116382-01A1 (to D.H. O’Connor), in part by the National Institutes of Health Office of Research Infrastructure Programs/OD (grant P51OD011106) awarded to WNPRC, at a facility constructed in part with support from Research Facilities Improvement Program grants RR15459-01 and RR020141-01; and National Institutes of Health core and pilot grant P51 OD011092 and grants R21-HD091032 and R01-HD08633 (to ONPRC). P.F.C. Vasconcelos was supported by Conselho Nacional de Desenvolvimento Cientifico e Tecnológico (projects 303999/2016-0, 439971/20016-0, and 440405/2016-5) and Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (Zika fast-track). P.C. Olsen is supported by the Pew Latin American Fellows Program in the Biomedical Sciences. D. Schaefer-Babajew is supported by Studienstiftung des Deutschen Volkes. F. Costa is a Wellcome Trust Fellow in Public Health and Tropical Medicine, and M.C. Nussenzweig is a Howard Hughes Medical Institute Investigator.
Grant numbers
5R01AI121207, R01TW009504, R25TW009338, U19AI111825, UL1TR001866, R01AI037526, UM1AI100663, U19AI111825, UL1TR001866, P01AI138938, R01AI124690, U19AI057229, PET0021/2016, R21AI129479-Supplement, P51OD011107, HHSF223201610542P, R01AI100989, R01AI133976, AI083019, AI104002, P51OD010425, R01Al116382-01A1, P51OD011106, RR15459-01, RR020141-01, P51 OD011092, R21-HD091032, R01-HD08633, 303999/2016-0, 439971/20016-0, 440405/2016-5
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Oct 25 2019 Fetal Timeline Maternal Timeline News
Analysis of ZIKV-infected pregnant macaque monkeys reveals that fetal brain damage was more frequent in mothers with higher antibody titers. So, maternal antibodies are now associated with and may contribute to ZIKV associated microcephaly. CREDIT Center for Disease Control/CDC.
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