Zika virus infection in pregnant rhesus macaques causes placental dysfunction and immunopathology

Alec J. Hirsch; Victoria H.J. Roberts; Peta L. Grigsby; Nicole Haese; Matthias C. Schabel; Xiaojie Wang; Jamie O. Lo; Zheng Liu; Christopher D. Kroenke; Jessica L. Smith; Meredith Kelleher; Rebecca Broeckel; Craig N. Kreklywich; Christopher J. Parkins; Michael Denton; Patricia Smith; Victor Defilippis; William Messer; Jay A. Nelson; Jon D. Hennebold; Marjorie Grafe; Lois Colgin; Anne Lewis; Rebecca Ducore; Tonya Swanson; Alfred W. Legasse; Michael K. Axthelm; Rhonda MacAllister; Ashlee V. Moses; Terry K. Morgan; Antonio E. Frias; Daniel N. Streblow

doi:10.1038/s41467-017-02499-9

Zika virus infection in pregnant rhesus macaques causes placental dysfunction and immunopathology

Alec J. Hirsch, Victoria H.J. Roberts, Peta L. Grigsby, Nicole Haese, Matthias C. Schabel, Xiaojie Wang, Jamie O. Lo, Zheng Liu, Christopher D. Kroenke, Jessica L. Smith, Meredith Kelleher, Rebecca Broeckel, Craig N. Kreklywich, Christopher J. Parkins, Michael Denton, Patricia Smith, Victor Defilippis, William Messer, Jay A. Nelson, Jon D. HenneboldMarjorie Grafe, Lois Colgin, Anne Lewis, Rebecca Ducore, Tonya Swanson, Alfred W. Legasse, Michael K. Axthelm, Rhonda MacAllister, Ashlee V. Moses, Terry K. Morgan, Antonio E. Frias, Daniel N. Streblow

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Abstract

Zika virus (ZIKV) infection during pregnancy leads to an increased risk of fetal growth restriction and fetal central nervous system malformations, which are outcomes broadly referred to as the Congenital Zika Syndrome (CZS). Here we infect pregnant rhesus macaques and investigate the impact of persistent ZIKV infection on uteroplacental pathology, blood flow, and fetal growth and development. Despite seemingly normal fetal growth and persistent fetal-placenta-maternal infection, advanced non-invasive in vivo imaging studies reveal dramatic effects on placental oxygen reserve accompanied by significantly decreased oxygen permeability of the placental villi. The observation of abnormal oxygen transport within the placenta appears to be a consequence of uterine vasculitis and placental villous damage in ZIKV cases. In addition, we demonstrate a robust maternal-placental-fetal inflammatory response following ZIKV infection. This animal model reveals a potential relationship between ZIKV infection and uteroplacental pathology that appears to affect oxygen delivery to the fetus during development.

Original language	English (US)
Article number	263
Journal	Nature communications
Volume	9
Issue number	1
DOIs	https://doi.org/10.1038/s41467-017-02499-9
State	Published - Dec 1 2018

ASJC Scopus subject areas

Chemistry(all)
Biochemistry, Genetics and Molecular Biology(all)
Physics and Astronomy(all)

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10.1038/s41467-017-02499-9

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Hirsch, A. J., Roberts, V. H. J., Grigsby, P. L., Haese, N., Schabel, M. C., Wang, X., Lo, J. O., Liu, Z., Kroenke, C. D., Smith, J. L., Kelleher, M., Broeckel, R., Kreklywich, C. N., Parkins, C. J., Denton, M., Smith, P., Defilippis, V., Messer, W., Nelson, J. A., ... Streblow, D. N. (2018). Zika virus infection in pregnant rhesus macaques causes placental dysfunction and immunopathology. Nature communications, 9(1), [263]. https://doi.org/10.1038/s41467-017-02499-9

Zika virus infection in pregnant rhesus macaques causes placental dysfunction and immunopathology. / Hirsch, Alec J.; Roberts, Victoria H.J.; Grigsby, Peta L.; Haese, Nicole; Schabel, Matthias C.; Wang, Xiaojie; Lo, Jamie O.; Liu, Zheng; Kroenke, Christopher D.; Smith, Jessica L.; Kelleher, Meredith; Broeckel, Rebecca; Kreklywich, Craig N.; Parkins, Christopher J.; Denton, Michael; Smith, Patricia; Defilippis, Victor; Messer, William; Nelson, Jay A.; Hennebold, Jon D.; Grafe, Marjorie; Colgin, Lois ; Lewis, Anne; Ducore, Rebecca; Swanson, Tonya; Legasse, Alfred W.; Axthelm, Michael K.; MacAllister, Rhonda ; Moses, Ashlee V.; Morgan, Terry K.; Frias, Antonio E.; Streblow, Daniel N.

In: Nature communications, Vol. 9, No. 1, 263, 01.12.2018.

Research output: Contribution to journal › Article › peer-review

Hirsch, AJ, Roberts, VHJ, Grigsby, PL, Haese, N, Schabel, MC, Wang, X, Lo, JO, Liu, Z, Kroenke, CD , Smith, JL , Kelleher, M, Broeckel, R, Kreklywich, CN, Parkins, CJ, Denton, M, Smith, P, Defilippis, V, Messer, W, Nelson, JA, Hennebold, JD, Grafe, M, Colgin, L , Lewis, A, Ducore, R, Swanson, T, Legasse, AW, Axthelm, MK , MacAllister, R , Moses, AV , Morgan, TK , Frias, AE & Streblow, DN 2018, 'Zika virus infection in pregnant rhesus macaques causes placental dysfunction and immunopathology', Nature communications, vol. 9, no. 1, 263. https://doi.org/10.1038/s41467-017-02499-9

Hirsch, Alec J. ; Roberts, Victoria H.J. ; Grigsby, Peta L. ; Haese, Nicole ; Schabel, Matthias C. ; Wang, Xiaojie ; Lo, Jamie O. ; Liu, Zheng ; Kroenke, Christopher D. ; Smith, Jessica L. ; Kelleher, Meredith ; Broeckel, Rebecca ; Kreklywich, Craig N. ; Parkins, Christopher J. ; Denton, Michael ; Smith, Patricia ; Defilippis, Victor ; Messer, William ; Nelson, Jay A. ; Hennebold, Jon D. ; Grafe, Marjorie ; Colgin, Lois ; Lewis, Anne ; Ducore, Rebecca ; Swanson, Tonya ; Legasse, Alfred W. ; Axthelm, Michael K. ; MacAllister, Rhonda ; Moses, Ashlee V. ; Morgan, Terry K. ; Frias, Antonio E. ; Streblow, Daniel N. / Zika virus infection in pregnant rhesus macaques causes placental dysfunction and immunopathology. In: Nature communications. 2018 ; Vol. 9, No. 1.

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title = "Zika virus infection in pregnant rhesus macaques causes placental dysfunction and immunopathology",

abstract = "Zika virus (ZIKV) infection during pregnancy leads to an increased risk of fetal growth restriction and fetal central nervous system malformations, which are outcomes broadly referred to as the Congenital Zika Syndrome (CZS). Here we infect pregnant rhesus macaques and investigate the impact of persistent ZIKV infection on uteroplacental pathology, blood flow, and fetal growth and development. Despite seemingly normal fetal growth and persistent fetal-placenta-maternal infection, advanced non-invasive in vivo imaging studies reveal dramatic effects on placental oxygen reserve accompanied by significantly decreased oxygen permeability of the placental villi. The observation of abnormal oxygen transport within the placenta appears to be a consequence of uterine vasculitis and placental villous damage in ZIKV cases. In addition, we demonstrate a robust maternal-placental-fetal inflammatory response following ZIKV infection. This animal model reveals a potential relationship between ZIKV infection and uteroplacental pathology that appears to affect oxygen delivery to the fetus during development.",

author = "Hirsch, {Alec J.} and Roberts, {Victoria H.J.} and Grigsby, {Peta L.} and Nicole Haese and Schabel, {Matthias C.} and Xiaojie Wang and Lo, {Jamie O.} and Zheng Liu and Kroenke, {Christopher D.} and Smith, {Jessica L.} and Meredith Kelleher and Rebecca Broeckel and Kreklywich, {Craig N.} and Parkins, {Christopher J.} and Michael Denton and Patricia Smith and Victor Defilippis and William Messer and Nelson, {Jay A.} and Hennebold, {Jon D.} and Marjorie Grafe and Lois Colgin and Anne Lewis and Rebecca Ducore and Tonya Swanson and Legasse, {Alfred W.} and Axthelm, {Michael K.} and Rhonda MacAllister and Moses, {Ashlee V.} and Morgan, {Terry K.} and Frias, {Antonio E.} and Streblow, {Daniel N.}",

note = "Funding Information: The work presented in this manuscript was supported by the Oregon National Primate Research Center (ONPRC) P51 OD011092 NIH Core Grant as well as R21-HD091032 (D.N.S.) and R01-HD086331 (A.E.F.). Veterinarian and husbandry staff at the ONPRC provided excellent care for the animals used in this study. We thank Jessica Gaffney for technical assistance on this project. Publisher Copyright: {\textcopyright} 2018 The Author(s).",

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T1 - Zika virus infection in pregnant rhesus macaques causes placental dysfunction and immunopathology

AU - Hirsch, Alec J.

AU - Roberts, Victoria H.J.

AU - Grigsby, Peta L.

AU - Haese, Nicole

AU - Schabel, Matthias C.

AU - Wang, Xiaojie

AU - Lo, Jamie O.

AU - Liu, Zheng

AU - Kroenke, Christopher D.

AU - Smith, Jessica L.

AU - Kelleher, Meredith

AU - Broeckel, Rebecca

AU - Kreklywich, Craig N.

AU - Parkins, Christopher J.

AU - Denton, Michael

AU - Smith, Patricia

AU - Defilippis, Victor

AU - Messer, William

AU - Nelson, Jay A.

AU - Hennebold, Jon D.

AU - Grafe, Marjorie

AU - Colgin, Lois

AU - Lewis, Anne

AU - Ducore, Rebecca

AU - Swanson, Tonya

AU - Legasse, Alfred W.

AU - Axthelm, Michael K.

AU - MacAllister, Rhonda

AU - Moses, Ashlee V.

AU - Morgan, Terry K.

AU - Frias, Antonio E.

AU - Streblow, Daniel N.

N1 - Funding Information: The work presented in this manuscript was supported by the Oregon National Primate Research Center (ONPRC) P51 OD011092 NIH Core Grant as well as R21-HD091032 (D.N.S.) and R01-HD086331 (A.E.F.). Veterinarian and husbandry staff at the ONPRC provided excellent care for the animals used in this study. We thank Jessica Gaffney for technical assistance on this project. Publisher Copyright: © 2018 The Author(s).

PY - 2018/12/1

Y1 - 2018/12/1

N2 - Zika virus (ZIKV) infection during pregnancy leads to an increased risk of fetal growth restriction and fetal central nervous system malformations, which are outcomes broadly referred to as the Congenital Zika Syndrome (CZS). Here we infect pregnant rhesus macaques and investigate the impact of persistent ZIKV infection on uteroplacental pathology, blood flow, and fetal growth and development. Despite seemingly normal fetal growth and persistent fetal-placenta-maternal infection, advanced non-invasive in vivo imaging studies reveal dramatic effects on placental oxygen reserve accompanied by significantly decreased oxygen permeability of the placental villi. The observation of abnormal oxygen transport within the placenta appears to be a consequence of uterine vasculitis and placental villous damage in ZIKV cases. In addition, we demonstrate a robust maternal-placental-fetal inflammatory response following ZIKV infection. This animal model reveals a potential relationship between ZIKV infection and uteroplacental pathology that appears to affect oxygen delivery to the fetus during development.

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Zika virus infection in pregnant rhesus macaques causes placental dysfunction and immunopathology

Abstract

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