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Translational Utility of the Nonhuman Primate Model

  • Alice F. Tarantal
    Correspondence
    Address correspondence to Alice F. Tarantal, Ph.D.
    Affiliations
    Department of Pediatrics, School of Medicine, University of California Davis, Davis, California

    Department of Cell Biology and Human Anatomy, School of Medicine, University of California Davis, Davis, California

    California National Primate Research Center, University of California Davis, Davis, California
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  • Dennis J. Hartigan-O’Connor
    Affiliations
    Department of Medical Microbiology and Immunology, School of Medicine, University of California Davis, Davis, California

    California National Primate Research Center, University of California Davis, Davis, California
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  • Stephen C. Noctor
    Affiliations
    Department of Psychiatry and Behavioral Sciences, School of Medicine, University of California Davis, Davis, California

    Medical Investigation of Neurodevelopmental Disorders Institute, University of California Davis, Davis, California
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Open AccessPublished:March 09, 2022DOI:https://doi.org/10.1016/j.bpsc.2022.03.001

      Abstract

      Nonhuman primates are essential for the study of human disease and to explore the safety of new diagnostics and therapies proposed for human use. They share similar genetic, physiologic, immunologic, reproductive, and developmental features with humans and thus have proven crucial for the study of embryonic/fetal development, organ system ontogeny, and the role of the maternal-placental-fetal interface in health and disease. The fetus may be exposed to a variety of inflammatory stimuli including infectious microbes as well as maternal inflammation, which can result from infections, obesity, or environmental exposures. Growing evidence supports that inflammation is a mediator of fetal programming and that the maternal immune system is tightly integrated with fetal-placental immune responses that may set a postnatal path for future health or disease. This review addresses some of the unique features of the nonhuman primate model system, specifically the rhesus monkey (Macaca mulatta), and importance of the species for studies focused on organ system ontogeny and the impact of viral teratogens in relation to development and congenital disorders.

      Keywords

      Nonhuman primates, such as the rhesus monkey (Macaca mulatta), are an important animal model for the study of human development and disease. Humans and rhesus monkeys share many characteristic features because of their close phylogenetic relationship, which includes similarities in genetic, physiologic, immunologic, reproductive, and developmental features (
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      Characterization of growth, glomerular number, and tubular proteins in the developing rhesus monkey kidney.
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      Ontogeny of the kidney and renal developmental markers in the rhesus monkey (Macaca mulatta).
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      ). For example, the rhesus monkey placenta is discoid and hemochorial, similar to the human placenta (
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      • Harris J.W.
      Interactions of the trophoblast and maternal tissues in three closely related primate species.
      ). In humans and rhesus monkeys, trophoblasts erode through the maternal endothelium and are in direct contact with maternal blood, which results in the hemochorial categorization. In humans, the embryo is completely embedded within the uterine stroma, whereas in the rhesus monkey, the blastocyst remains superficially attached and adheres to the side opposite the initial attachment, forming the location of the future secondary placental disk (approximately 80% with bidiscoid placenta). Trimesters in rhesus monkeys encompass 55 days with the first trimester representing 0 to 55 days of gestation; the second trimester, 56 to 110 days of gestation; and the third trimester, 111 to 165 days of gestation (term 165±10 days in this species) (
      • Tarantal A.F.
      Ultrasound imaging in rhesus and long-tailed macaques: Reproductive and research applications.
      ). Developmental similarities include the period of organogenesis (
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      Morphogenesis of the brain in staged rhesus monkey embryos.
      ,
      • Heuser C.H.
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      Development of the macaque embryo.
      ), growth trajectory, and organ ontogeny, including the hematopoietic and immune systems (
      • Batchelder C.A.
      • Keyser J.L.
      • Lee C.C.I.
      • Tarantal A.F.
      Characterization of growth, glomerular number, and tubular proteins in the developing rhesus monkey kidney.
      ,
      • Batchelder C.A.
      • Lee C.C.I.
      • Duru N.
      • Baker C.
      • Swainson L.
      • McCune J.M.
      • et al.
      Myeloid-lymphoid ontogeny in the rhesus monkey (Macaca mulatta).
      ,
      • Batchelder C.A.
      • Lee C.C.I.
      • Martinez M.L.
      • Tarantal A.F.
      Ontogeny of the kidney and renal developmental markers in the rhesus monkey (Macaca mulatta).
      ,
      • Lee C.I.
      • Fletcher M.D.
      • Tarantal A.F.
      Effects of age on the frequency, cell cycle, and lineage maturation of rhesus monkey (Macaca mulatta) CD34+ and hematopoietic progenitor cells.
      ).
      Comparable to humans, the fetal rhesus monkey liver is the primary site of hematopoiesis in the first trimester (human fetus approximately 5–6 weeks), with a peak in hematopoiesis thereafter (early second trimester; 3–4 months in the human fetus) until bone marrow hematopoiesis is established in the mid-second trimester. Early signs of bone marrow hematopoiesis begin in the fetal monkey in the early second trimester, with a significant decrease in blood islands in fetal liver. This decline continues into the early third trimester when bone marrow takes on the primary hematopoietic role (approximately 7 months in the human fetus) (
      • Lee C.I.
      • Fletcher M.D.
      • Tarantal A.F.
      Effects of age on the frequency, cell cycle, and lineage maturation of rhesus monkey (Macaca mulatta) CD34+ and hematopoietic progenitor cells.
      ,
      • Cowan M.J.
      • Chou S.H.
      • Tarantal A.F.
      Tolerance induction post in utero stem cell transplantation.
      ).
      Given the importance of the human immune system in health and disease, studies that focus on the immune system of nonhuman primates further advance translational research. Immune ontogeny in the rhesus monkey is similar in temporal and anatomical sequence to human development (
      • Batchelder C.A.
      • Lee C.C.I.
      • Duru N.
      • Baker C.
      • Swainson L.
      • McCune J.M.
      • et al.
      Myeloid-lymphoid ontogeny in the rhesus monkey (Macaca mulatta).
      ) and shows significant differences compared to rodents (
      • Mestas J.
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      Of mice and not men: Differences between mouse and human immunology.
      ). These differences are well documented and highlight crucial disparities that may influence outcomes, particularly for the developing fetus and infant, and in relation to, for example, the trafficking of cells between the mother and fetus (
      • Bakkour S.
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      • Wen L.
      • Busch M.P.
      • Lee T.H.
      • et al.
      Analysis of maternal microchimerism in rhesus monkeys (Macaca mulatta) using real-time quantitative PCR amplification of MHC polymorphisms.
      ,
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      • Way S.S.
      • MacKenzie T.C.
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      Forever connected: The lifelong biological consequences of fetomaternal and maternofetal microchimerism.
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      • Jimenez D.F.
      • Leapley A.C.
      • Lee C.I.
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      Fetal CD34+ cells in the maternal circulation and long-term microchimerism in rhesus macaques.
      ,
      • Jimenez D.F.
      • Tarantal A.F.
      Quantitative analysis of male fetal DNA in maternal serum of gravid rhesus monkeys (Macaca mulatta).
      ,
      • Mold J.E.
      • McCune J.M.
      Immunological tolerance during fetal development: From mouse to man.
      ). Similar trafficking in rhesus monkeys and humans is related to the comparable placental structure. The fetus may be exposed to a variety of potential inflammatory stimuli including infectious microbes and allergenic proteins, as well as maternal inflammation that may result from infections, obesity, or environmental influences (
      • Apostol A.C.
      • Jensen K.D.C.
      • Beaudin A.E.
      Training the fetal immune system through maternal inflammation—a layered hygiene hypothesis.
      ,
      • Arora N.
      • Sadovsky Y.
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      • Coyne C.B.
      Microbial vertical transmission during human pregnancy.
      ,
      • Duan Y.
      • Zeng L.
      • Zheng C.
      • Song B.
      • Li F.
      • Kong X.
      • et al.
      Inflammatory links between high fat diets and diseases.
      ,
      • Sureshchandra S.
      • Marshall N.E.
      • Messaoudi I.
      Impact of pregravid obesity on maternal and fetal immunity: Fertile grounds for reprogramming.
      ,
      • Tarantal A.F.
      • Berglund L.
      Obesity and lifespan health—importance of the fetal environment.
      ). Growing evidence supports that inflammation is a mediator of fetal programming and that the maternal immune system is tightly integrated with fetal-placental immune responses that can shape postnatal immunity and set a path for future health or disease (
      • Apostol A.C.
      • Jensen K.D.C.
      • Beaudin A.E.
      Training the fetal immune system through maternal inflammation—a layered hygiene hypothesis.
      ,
      • Tarantal A.F.
      • Berglund L.
      Obesity and lifespan health—importance of the fetal environment.
      ,
      • Chen Q.
      • Gouilly J.
      • Ferrat Y.J.
      • Espino A.
      • Glaziou Q.
      • Cartron G.
      • et al.
      Metabolic reprogramming by Zika virus provokes inflammation in human placenta.
      ,
      • Crooks C.M.
      • Weiler A.M.
      • Rybarczyk S.L.
      • Bliss M.
      • Jaeger A.S.
      • Murphy M.E.
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      African-lineage Zika virus replication dynamics and maternal-fetal interface infection in pregnant rhesus macaques.
      ,
      • Heerema-McKinney A.
      Defense and infection of the human placenta.
      ,
      • Jennewein M.F.
      • Abu-Raya B.
      • Jiang Y.
      • Alter G.
      • Marchant A.
      Transfer of maternal immunity and programming of the newborn immune system.
      ,
      • Kim C.J.
      • Romero R.
      • Chaemsaithong P.
      • Kim J.S.
      Chronic inflammation of the placenta: Definition, classification, pathogenesis, and clinical significance.
      ,
      • Kreis N.N.
      • Ritter A.
      • Louwen F.
      • Yuan J.
      A message from the human placenta: Structural and immunomodulatory defense against SARS-CoV-2.
      ,
      • Ozen M.
      • Novak C.
      • Burd I.
      Placenta immune infiltrates and perinatal outcomes.
      ). Development of the immune system begins early in gestation and continues through the postnatal period, similar to the developing brain (
      • Lu-Culligan A.
      • Iwasaki A.
      The role of immune factors in shaping fetal neurodevelopment.
      ). It is during this time that the fetus, neonate, and infant are most susceptible to pathogenic agents and rely primarily on innate immune responses for protection (
      • Basha S.
      • Surendran N.
      • Pichichero M.
      Immune responses in neonates.
      ,
      • Levy O.
      Innate immunity of the newborn: Basic mechanisms and clinical correlates.
      ).
      It has been shown that by the second trimester, the lymphoid tissues of the fetal rhesus monkey have a reasonably complete repertoire of appropriately organized B cells, T cells, and antigen-presenting cells, which are at least partly functional (
      • Batchelder C.A.
      • Lee C.C.I.
      • Duru N.
      • Baker C.
      • Swainson L.
      • McCune J.M.
      • et al.
      Myeloid-lymphoid ontogeny in the rhesus monkey (Macaca mulatta).
      ). These and other similarities in immune ontogeny when compared to humans have been leveraged to provide key insights into fetal-maternal infectious diseases and the role of the placenta. The placenta can serve as a modulator with postnatal consequences (
      • Kreis N.N.
      • Ritter A.
      • Louwen F.
      • Yuan J.
      A message from the human placenta: Structural and immunomodulatory defense against SARS-CoV-2.
      ). A wide variety of cytokines are synthesized and released by cytotrophoblasts, syncytiotrophoblasts, and resident placental macrophages (
      • Kim C.J.
      • Romero R.
      • Chaemsaithong P.
      • Kim J.S.
      Chronic inflammation of the placenta: Definition, classification, pathogenesis, and clinical significance.
      ,
      • Bayer A.
      • Lennemann N.J.
      • Puyang Y.
      • Bramley J.C.
      • Morpsky S.
      • De Azeved Marques E.T.
      • et al.
      Type III interferons produced by human placental trophoblasts confer protection against Zika virus infection.
      ,
      • Silasi M.
      • Cardenas I.
      • Kwon J.Y.
      • Racicot K.
      • Aldo P.
      • Mor G.
      Viral infections during pregnancy.
      ). Immune cells in the decidua (e.g., uterine natural killer [NK] cells) and toll-like receptors expressed by syncytiotrophoblasts can stimulate production of interferons in response to viruses and maintain placental function (
      • Koga K.
      • Mor G.
      Toll-like receptors at the maternal-fetal interface in normal pregnancy and pregnancy disorders.
      ,
      • Mor G.
      Placental inflammatory response to Zika virus may affect fetal brain development.
      ). It has been proposed that the interleukin 10 and uterine NK cell balance controls excessive inflammation (
      • Racicot K.
      • Kwon J.Y.
      • Aldo P.
      • Silasi M.
      • Mor G.
      Understanding the complexity of the immune system during pregnancy.
      ). A placental viral infection may activate both the maternal and the fetal immune systems and could promote a fetal inflammatory response resulting in high concentrations of inflammatory cytokines that can have a significant effect on the developing central nervous system (CNS).

      Neurodevelopment

      Nonhuman primates have proven essential to address the development and function of the CNS and have led to important insights into the formation of the human cerebral cortex. Production of cortical neurons in fetal rhesus monkeys follows an “inside out” sequence, and the proliferative zones of the fetal monkey cerebral cortex possess the same classes of neural precursor cells (NPCs) that exhibit similar distribution, morphology, protein, and transcription factor expression as shown in small animal models (
      • Clowry G.
      • Molnar Z.
      • Rakic P.
      Renewed focus on the developing human neocortex.
      ,
      • Englund C.
      • Fink A.
      • Lau C.
      • Pham D.
      • Daza R.A.
      • Bulfone A.
      • et al.
      Pax6, Tbr2, and Tbr1 are expressed sequentially by radial glia, intermediate progenitor cells, and postmitotic neurons in developing neocortex.
      ). However, in the brain of both fetal rhesus monkeys and humans, the distribution of the NPC pool is more complex, and the number of NPCs is greatly expanded compared to commonly used small animal species (
      • Hansen D.V.
      • Lui J.H.
      • Parker P.R.
      • Kriegstein A.R.
      Neurogenic radial glia in the outer subventricular zone of human neocortex.
      ). Furthermore, the elaborate folding of sulci and gyri in the mature human cerebral cortex is modeled by findings in the rhesus monkey. Consequently, studies with fetal rhesus monkeys have been instrumental for developing models that explain how cortical lamination and areal differences in the human brain may arise, for example, from a proto-map of localized clusters of NPCs in cortical proliferative zones (
      • Rakic P.
      Specification of cerebral cortical areas.
      ).
      Recent work has provided evidence of the interplay between key components of the developing CNS and immune system during gestation. The foundation for this insight was first established through decades of painstaking work that identified and characterized the form and function of NPCs in the fetal cerebral cortex. Development of the cerebral cortex begins early in gestation with proliferation of NPCs lining the ventricular lumen at the anterior end of the neural tube. Two main classes of NPCs, primary and secondary, have been identified based on expression of cell-specific molecular markers. Primary NPCs express the nuclear transcription factor Pax6 (
      • Englund C.
      • Fink A.
      • Lau C.
      • Pham D.
      • Daza R.A.
      • Bulfone A.
      • et al.
      Pax6, Tbr2, and Tbr1 are expressed sequentially by radial glia, intermediate progenitor cells, and postmitotic neurons in developing neocortex.
      ,
      • Gotz M.
      • Stoykova A.
      • Gruss P.
      Pax6 controls radial glia differentiation in the cerebral cortex.
      ) and initially undergo self-replicating divisions. At the onset of neurogenesis, the Pax6+ primary NPCs undergo asymmetric divisions that generate the secondary population of NPCs (
      • Englund C.
      • Fink A.
      • Lau C.
      • Pham D.
      • Daza R.A.
      • Bulfone A.
      • et al.
      Pax6, Tbr2, and Tbr1 are expressed sequentially by radial glia, intermediate progenitor cells, and postmitotic neurons in developing neocortex.
      ,
      • Cai L.
      • Hayes N.L.
      • Takahashi T.
      • Caviness Jr., V.S.
      • Nowakowski R.S.
      Size distribution of retrovirally marked lineages matches prediction from population measurements of cell cycle behavior.
      ,
      • Noctor S.C.
      • Martínez-Cerdeño V.
      • Ivic L.
      • Kriegstein A.R.
      Cortical neurons arise in symmetric and asymmetric division zones and migrate through specific phases.
      ,
      • Takahashi T.
      • Nowakowski R.S.
      • Caviness Jr., V.
      Early ontogeny of the secondary proliferative population of the embryonic murine cerebral wall.
      ). The secondary NPCs establish a proliferative zone that is called the subventricular zone (
      • Angevine J.B.
      • Bodian D.
      • Coulombre A.J.
      • Edds M.V.
      • Hamburger V.
      • Jacobson M.
      • et al.
      Embryonic vertebrate central nervous system: Revised terminology.
      ), express the cell-specific nuclear transcription factor Tbr2 (
      • Englund C.
      • Fink A.
      • Lau C.
      • Pham D.
      • Daza R.A.
      • Bulfone A.
      • et al.
      Pax6, Tbr2, and Tbr1 are expressed sequentially by radial glia, intermediate progenitor cells, and postmitotic neurons in developing neocortex.
      ), and play a key role in generating telencephalic neurons (
      • Noctor S.C.
      • Martínez-Cerdeño V.
      • Ivic L.
      • Kriegstein A.R.
      Cortical neurons arise in symmetric and asymmetric division zones and migrate through specific phases.
      ,
      • Haubensak W.
      • Attardo A.
      • Denk W.
      • Huttner W.B.
      Neurons arise in the basal neuroepithelium of the early mammalian telencephalon: A major site of neurogenesis.
      ,
      • Kowalczyk T.
      • Pontious A.
      • Englund C.
      • Daza R.A.
      • Bedogni F.
      • Hodge R.
      • et al.
      Intermediate neuronal progenitors (basal progenitors) produce pyramidal-projection neurons for all layers of cerebral cortex.
      ,
      • Miyata T.
      • Kawaguchi A.
      • Saito K.
      • Kawano M.
      • Muto T.
      • Ogawa M.
      Asymmetric production of surface-dividing and non-surface-dividing cortical progenitor cells.
      ,
      • Sessa A.
      • Mao C.A.
      • Colasante G.
      • Nini A.
      • Klein W.H.
      • Broccoli V.
      Tbr2-positive intermediate (basal) neuronal progenitors safeguard cerebral cortex expansion by controlling amplification of pallial glutamatergic neurons and attraction of subpallial GABAergic interneurons.
      ,
      • Sessa A.
      • Mao C.A.
      • Hadjantonakis A.K.
      • Klein W.H.
      • Broccoli V.
      Tbr2 directs conversion of radial glia into basal precursors and guides neuronal amplification by indirect neurogenesis in the developing neocortex.
      ). Studies in nonhuman primates leveraged previous work in small animal models to better predict human CNS development. Proliferative zones in the fetal rhesus monkey cerebral cortex are larger and more complex when compared to small animal species (
      • Smart I.H.
      • Dehay C.
      • Giroud P.
      • Berland M.
      • Kennedy H.
      Unique morphological features of the proliferative zones and postmitotic compartments of the neural epithelium giving rise to striate and extrastriate cortex in the monkey.
      ), but the timing and spatial distribution of the Pax6- and Tbr2-expressing NPCs are maintained in the rhesus monkey (
      • Martinez-Cerdeño V.
      • Cunningham C.L.
      • Camacho J.
      • Antczak J.L.
      • Prakash A.N.
      • Cziep M.E.
      • et al.
      Comparative analysis of the subventricular zone in rat, ferret and macaque: Evidence for an outer subventricular zone in rodents.
      ) and, importantly, model the pattern that has been described in the human fetal brain (
      • Clowry G.
      • Molnar Z.
      • Rakic P.
      Renewed focus on the developing human neocortex.
      ,
      • Hansen D.V.
      • Lui J.H.
      • Parker P.R.
      • Kriegstein A.R.
      Neurogenic radial glia in the outer subventricular zone of human neocortex.
      ).
      Primary NPCs in both fetal human and rhesus monkey cortex are distinguished from NPCs in smaller animal models by precocious expression of the cytostructural intermediate filament glial fibrillary acidic protein (GFAP) (
      • Levitt P.
      • Rakic P.
      Immunoperoxidase localization of glial fibrillary acidic protein in radial glial cells and astrocytes of the developing rhesus monkey brain.
      ), which is maintained throughout the entire neurogenic period (
      • Levitt P.
      • Rakic P.
      Immunoperoxidase localization of glial fibrillary acidic protein in radial glial cells and astrocytes of the developing rhesus monkey brain.
      ,
      • Cunningham C.L.
      • Martinez-Cerdeno V.
      • Noctor S.C.
      Diversity of neural precursor cell types in the prenatal macaque cerebral cortex exists largely within the astroglial cell lineage.
      ,
      • de Azevedo L.C.
      • Fallet C.
      • Moura-Neto V.
      • Daumas-Duport C.
      • Hedin-Pereira C.
      • Lent R.
      Cortical radial glial cells in human fetuses: Depth-correlated transformation into astrocytes.
      ). Studies performed in fetal rhesus monkeys were instrumental in the discovery that newborn cortical neurons migrate from the proliferative zones to the developing cortical gray matter by attaching to GFAP+ pial processes and using the pial process as a migratory guide during the journey (
      • Rakic P.
      Mode of cell migration to the superficial layers of fetal monkey neocortex.
      ), which also occurs in the human fetus (
      • de Azevedo L.C.
      • Fallet C.
      • Moura-Neto V.
      • Daumas-Duport C.
      • Hedin-Pereira C.
      • Lent R.
      Cortical radial glial cells in human fetuses: Depth-correlated transformation into astrocytes.
      ,
      • Sidman R.L.
      • Rakic P.
      Neuronal migration, with special reference to developing human brain: A review.
      ). More recent studies have shown that intercellular communications between migrating neurons, the pial process of primary NPCs, and secondary NPCs are crucial for regulating the proper functions of these cells (
      • Rash B.G.
      • Ackman J.B.
      • Rakic P.
      Bidirectional radial Ca(2+) activity regulates neurogenesis and migration during early cortical column formation.
      ,
      • Yoon K.J.
      • Koo B.K.
      • Im S.K.
      • Jeong H.W.
      • Ghim J.
      • Kwon M.C.
      • et al.
      Mind bomb 1-expressing intermediate progenitors generate notch signaling to maintain radial glial cells.
      )—further highlighting the importance of intercellular relationships in the fetal brain that were revealed in nonhuman primate studies.
      Cortical neurons are generated in a temporal sequence during gestation, with these neurons destined for deep cortical layers generated earliest, followed by neurons destined for more superficial cortical layers, as demonstrated nearly 50 years ago in the fetal rhesus monkey (
      • Rakic P.
      Neurons in rhesus monkey visual cortex: Systematic relation between time of origin and eventual disposition.
      ). Experimental studies have not yet determined the precise timing of cortical neurogenesis in the human cerebral cortex, but examination of fetal tissue supports that development in the rhesus monkey closely models the timing of developmental sequences in the fetal human brain (
      • de Azevedo L.C.
      • Fallet C.
      • Moura-Neto V.
      • Daumas-Duport C.
      • Hedin-Pereira C.
      • Lent R.
      Cortical radial glial cells in human fetuses: Depth-correlated transformation into astrocytes.
      ,
      • Sidman R.L.
      • Rakic P.
      Neuronal migration, with special reference to developing human brain: A review.
      ,
      • Kostovic I.
      • Rakic P.
      Cytology and time of origin of interstitial neurons in the white matter in infant and adult human and monkey telencephalon.
      ). The neurogenic period in rhesus monkey cortex is approximately 2 months long, with neurons destined for each layer of the cerebral cortex generated over a period of at least a week (
      • Rakic P.
      Neurons in rhesus monkey visual cortex: Systematic relation between time of origin and eventual disposition.
      ). Similarly, in the human fetus, cortical neurogenesis occurs over a protracted period of time (
      • Arshad A.
      • Vose L.R.
      • Vinukonda G.
      • Hu F.
      • Yoshikawa K.
      • Csiszar A.
      • et al.
      Extended production of cortical interneurons into the third trimester of human gestation.
      ,
      • Malik S.
      • Vinukonda G.
      • Vose L.R.
      • Diamond D.
      • Bhimavarapu B.B.
      • Hu F.
      • et al.
      Neurogenesis continues in the third trimester of pregnancy and is suppressed by premature birth.
      ). The length of neurogenesis in the human and nonhuman primate contrasts significantly with the shorter 1-week-long neurogenic period in the mouse or rat (
      • Bayer S.A.
      • Altman J.
      Neocortical Development.
      ). Critically, the months-long stages of cortical cell production in nonhuman primates allow for a thorough, temporal study of brain structural development (
      • Smart I.H.
      • Dehay C.
      • Giroud P.
      • Berland M.
      • Kennedy H.
      Unique morphological features of the proliferative zones and postmitotic compartments of the neural epithelium giving rise to striate and extrastriate cortex in the monkey.
      ), molecular mechanisms regulating growth (
      • Rakic P.
      Mode of cell migration to the superficial layers of fetal monkey neocortex.
      ,
      • Dominguez M.H.
      • Ayoub A.E.
      • Rakic P.
      POU-III transcription factors (Brn1, Brn2, and Oct6) influence neurogenesis, molecular identity, and migratory destination of upper-layer cells of the cerebral cortex.
      ,
      • Meinecke D.L.
      • Rakic P.
      Expression of GABA and GABAA receptors by neurons of the subplate zone in developing primate occipital cortex: Evidence for transient local circuits.
      ), and the intersection of critical windows during development of CNS structures with exposure to pathogens.
      The neurogenesis of deep brain structures in nonhuman primates has not been as thoroughly studied as in rodents. However, available data show that the neurogenic phase of these structures extends far longer in nonhuman primates such as the rhesus monkey than in small rodent models. For example, neurons destined for the rhesus monkey neostriatum are generated over a period of 45 days (
      • Brand S.
      • Rakic P.
      Genesis of the primate neostriatum: [3H]thymidine autoradiographic analysis of the time of neuron origin in the rhesus monkey.
      ), which is double the entire length of gestation for the rat and mouse. As with the longer period of cortical formation, the extended production of striatal neurons in human and nonhuman primates may provide greater opportunity for interference through pathogen exposure.

      Microglia: Immune Cells of the CNS

      It has become increasingly clear that the immune system plays a key functional role in development of the brain (
      • Salter M.W.
      • Stevens B.
      Microglia emerge as central players in brain disease.
      ). The innate immune cells of the CNS, microglial cells, contribute to an array of developmental programs, including axon pathfinding, synapse development and maintenance, and cortical layer formation (
      • Salter M.W.
      • Stevens B.
      Microglia emerge as central players in brain disease.
      ,
      • Cunningham C.L.
      • Martinez-Cerdeno V.
      • Noctor S.C.
      Microglia regulate the number of neural precursor cells in the developing cerebral cortex.
      ,
      • Paolicelli R.C.
      • Bolasco G.
      • Pagani F.
      • Maggi L.
      • Scianni M.
      • Panzanelli P.
      • et al.
      Synaptic pruning by microglia is necessary for normal brain development.
      ,
      • Schafer D.P.
      • Lehrman E.K.
      • Kautzman A.G.
      • Koyama R.
      • Mardinly A.R.
      • Yamasaki R.
      • et al.
      Microglia sculpt postnatal neural circuits in an activity and complement-dependent manner.
      ,
      • Squarzoni P.
      • Oller G.
      • Hoeffel G.
      • Pont-Lezica L.
      • Rostaing P.
      • Low D.
      • et al.
      Microglia modulate wiring of the embryonic forebrain.
      ). Microglia in the fetal human and rhesus monkey brain begin to colonize the cerebral cortex at the onset of cortical neurogenesis and initially populate the neural proliferative zones (
      • Cunningham C.L.
      • Martinez-Cerdeno V.
      • Noctor S.C.
      Microglia regulate the number of neural precursor cells in the developing cerebral cortex.
      ,
      • Andjelkovic A.V.
      • Nikolic B.
      • Pachter J.S.
      • Zecevic N.
      Macrophages/microglial cells in human central nervous system during development: An immunohistochemical study.
      ,
      • Arno B.
      • Grassivaro F.
      • Rossi C.
      • Bergamaschi A.
      • Castiglioni V.
      • Furlan R.
      • et al.
      Neural progenitor cells orchestrate microglia migration and positioning into the developing cortex.
      ,
      • Monier A.
      • Evrard P.
      • Gressens P.
      • Verney C.
      Distribution and differentiation of microglia in the human telencephalon during the first two trimesters of gestation.
      ,
      • Rezaie P.
      • Male D.
      Colonisation of the developing human brain and spinal cord by microglia: A review.
      ,
      • Verney C.
      • Monier A.
      • Fallet-Bianco C.
      • Gressens P.
      Early microglial colonization of the human forebrain and possible involvement in periventricular white-matter injury of preterm infants.
      ). On arriving in the fetal cortex, microglia establish connections with NPCs and developing vasculature (
      • Cunningham C.L.
      • Martinez-Cerdeno V.
      • Noctor S.C.
      Microglia regulate the number of neural precursor cells in the developing cerebral cortex.
      ,
      • Barger N.
      • Keiter J.
      • Kreutz A.
      • Krishnamurthy A.
      • Weidenthaler C.
      • Martinez-Cerdeno V.
      • et al.
      Microglia: An intrinsic component of the proliferative zones in the fetal rhesus monkey (Macaca mulatta) cerebral cortex.
      ,
      • Noctor S.C.
      • Penna E.
      • Shepherd H.
      • Chelson C.
      • Barger N.
      • Martinez-Cerdeno V.
      • et al.
      Periventricular microglial cells interact with dividing precursor cells in the nonhuman primate and rodent prenatal cerebral cortex.
      ). In particular, the population of microglia located close to the ventricle establish numerous contacts with NPCs, envelop mitotic NPCs in a cell cycle–dependent manner (
      • Barger N.
      • Keiter J.
      • Kreutz A.
      • Krishnamurthy A.
      • Weidenthaler C.
      • Martinez-Cerdeno V.
      • et al.
      Microglia: An intrinsic component of the proliferative zones in the fetal rhesus monkey (Macaca mulatta) cerebral cortex.
      ,
      • Noctor S.C.
      • Penna E.
      • Shepherd H.
      • Chelson C.
      • Barger N.
      • Martinez-Cerdeno V.
      • et al.
      Periventricular microglial cells interact with dividing precursor cells in the nonhuman primate and rodent prenatal cerebral cortex.
      ), and phagocytose NPCs, which slows production of cortical neurons and glia (
      • Cunningham C.L.
      • Martinez-Cerdeno V.
      • Noctor S.C.
      Microglia regulate the number of neural precursor cells in the developing cerebral cortex.
      ).
      Microglia colonize key structures, such as the telencephalon, in significantly larger numbers and at earlier stages of fetal development in nonhuman primates than in small animal species (
      • Barger N.
      • Keiter J.
      • Kreutz A.
      • Krishnamurthy A.
      • Weidenthaler C.
      • Martinez-Cerdeno V.
      • et al.
      Microglia: An intrinsic component of the proliferative zones in the fetal rhesus monkey (Macaca mulatta) cerebral cortex.
      ), and evidence indicates that microglia in the primate brain differ from those in rodents (
      • Wolf S.A.
      • Boddeke H.W.
      • Kettenmann H.
      Microglia in physiology and disease.
      ). Together, these findings highlight the importance of nonhuman primates in modeling the intersection between the developing CNS and immune system. Indeed, the comparatively early arrival of microglia in proliferative zones of the fetal primate telencephalon, particularly during the months-long period of cortical neuron production, provides an opportunity for microglia to play a more prominent role in cellular genesis and maturation in primates and supports the concept that microglial cells contribute to formation of the telencephalon from early stages of development. However, this potential developmental benefit may come with risks. Fetal microglia rapidly respond to changes in the local environment, injury, and extrinsic factors introduced through maternal exposure to viral pathogens (
      • Bilbo S.D.
      • Block C.L.
      • Bolton J.L.
      • Hanamsagar R.
      • Tran P.K.
      Beyond infection—maternal immune activation by environmental factors, microglial development, and relevance for autism spectrum disorders.
      ), which has been demonstrated in the baboon and rhesus monkey (
      • Gurung S.
      • Reuter N.
      • Preno A.
      • Dubaut J.
      • Nadeau H.
      • Hyatt K.
      • et al.
      Zika virus infection at mid-gestation results in fetal cerebral cortical injury and fetal death in the olive baboon.
      ,
      • Tarantal A.F.
      • Hartigan-O’Connor D.J.
      • Penna E.
      • Kreutz A.
      • Martinez M.L.
      • Noctor S.C.
      Fetal rhesus monkey first trimester Zika virus infection impacts cortical development in the second and third trimesters.
      ). For example, fetal exposure to Zika virus results in profound changes in key components of the fetal cerebral cortex. At 3 weeks after fetal Zika virus inoculation, microglial distribution in the fetal rhesus monkey was shown to be altered, with microglia collected in large heterotopic clusters throughout cortical proliferative zones (see below). The microglial clusters were associated with disturbed distribution of NPCs, enlarged blood vessels, and a thinner cortical plate that persisted 3 months after Zika virus exposure (
      • Tarantal A.F.
      • Hartigan-O’Connor D.J.
      • Penna E.
      • Kreutz A.
      • Martinez M.L.
      • Noctor S.C.
      Fetal rhesus monkey first trimester Zika virus infection impacts cortical development in the second and third trimesters.
      ).
      Further, we have found that microglia in the typically developing fetal brain exhibit multiple phenotypes that are revealed through differential expression of markers such as CD68. This includes analysis of morphological features such as an ameboid versus ramified cellular phenotype, and extension of phagocytic cups that contact precursor cells and differentiating cells in the germinal zones. These analyses have captured distinct states of microglial activation at the molecular and morphological levels and the relative proportion of these cellular phenotypes during development (
      • Cunningham C.L.
      • Martinez-Cerdeno V.
      • Noctor S.C.
      Microglia regulate the number of neural precursor cells in the developing cerebral cortex.
      ,
      • Barger N.
      • Keiter J.
      • Kreutz A.
      • Krishnamurthy A.
      • Weidenthaler C.
      • Martinez-Cerdeno V.
      • et al.
      Microglia: An intrinsic component of the proliferative zones in the fetal rhesus monkey (Macaca mulatta) cerebral cortex.
      ). Environmental stimuli that induce a maternal immune response are therefore capable of engaging immune cells in fetal tissues, including the brain, and potentially altering the normal developmental trajectory. These data support the concept that microglia may be one conduit between pathogen exposure and atypical outcomes in primate neurodevelopment. Further studies on intercellular communications in the prenatal proliferative zones will aid in defining the functional roles of microglial cells in the developing brain under typical developmental conditions and with respect to neurodevelopmental disorders. These data exemplify why rhesus monkeys are an essential model for understanding CNS development and the role of viral and other teratogens.

      Viral Teratogens

      As noted above, the rhesus monkey closely mirrors human development, including length of gestation, growth characteristics, and organ ontogeny. The importance of these features is clear in the historical accounting of the thalidomide tragedy (
      • Vargesson N.
      Thalidomide-induced teratogenesis: History and mechanisms.
      ) and, more recently, viral teratogens such as the TORCH (Toxoplasma gondii, other, rubella virus, cytomegalovirus [CMV], and herpes simplex virus) agents, Zika virus, and CMV (
      • Coyne C.B.
      • Lazear H.M.
      Zika virus—reigniting the TORCH.
      ,
      • de Vries L.S.
      Viral infections and the neonatal brain.
      ,
      • Parker E.L.
      • Silverstein R.B.
      • Vera S.
      • Mysorekar I.U.
      Viral-immune cell interactions at the maternal-fetal interface in human pregnancy.
      ). The maternal-placental-fetal interface provides close contact between the uterine mucosa, placenta, and fetal membranes. Despite this potential physical and immunologic barrier, microorganisms can sometimes bypass the host adaptive and innate immune system and lead to congenital infection.

      Microglia and Zika Virus

      Although Zika virus was discovered in 1952 in Uganda (
      • Dick G.W.
      • Kitchen S.F.
      • Haddow A.J.
      Zika virus. I. Isolations and serological specificity.
      ), it remained little studied until the South American outbreak in 2015 (
      • Rasmussen S.A.
      • Jamieson D.J.
      • Honein M.A.
      • Petersen L.R.
      Zika virus and birth defects—reviewing the evidence for causality.
      ). Studies in nonhuman primates soon followed, which demonstrated features consistent with typical human infections (
      • Dudley D.M.
      • Aliota M.T.
      • Mohr E.L.
      • Newman C.M.
      • Golos T.G.
      • Friedrich T.C.
      • et al.
      Using macaques to address critical questions in Zika virus research.
      ,
      • Newman C.
      • Friedrich T.C.
      • O’Connor D.H.
      Macaque monkeys in Zika virus research: 1947–present.
      ). Most often, infected adult macaques manifest only transient viremia and subclinical disease; the infection may be transmitted from dams to their fetuses and can cause adverse fetal outcomes. In humans, the congenital sequelae to in utero infection (congenital Zika syndrome) develop in approximately 1 in 7 infants born to infected mothers (
      • Rice M.E.
      • Galang R.R.
      • Roth N.M.
      • Ellington S.R.
      • Moore C.A.
      • Valencia-Prado M.
      • et al.
      Zika-associated birth defects and neurodevelopmental abnormalities possibly associated with congenital Zika virus infection—U.S. territories and freely associated states, 2018.
      ).
      Our studies have addressed the impact of Zika virus on fetal development more directly, by inoculating early-gestation fetal rhesus monkeys using an ultrasound-guided approach (intraperitoneal or intracranial) (
      • Tarantal A.F.
      • Hartigan-O’Connor D.J.
      • Penna E.
      • Kreutz A.
      • Martinez M.L.
      • Noctor S.C.
      Fetal rhesus monkey first trimester Zika virus infection impacts cortical development in the second and third trimesters.
      ). Transient maternal viremia was observed, and sustained maternal immune activation was detected by flow cytometry. Maternal T cell activation and maturation was assessed by following expression of CCR5, HLA-DR, and memory/effector subset markers. Maternal CCR5 expression by CD4+ T cells followed a pattern of early upregulation with a later decline, in a pattern similar to maternal viral load; maximum maternal viral load and CCR5 expression appeared to be associated. The increased expression of CCR5 followed the early spike in maternal viral load by 10 to 30 days. In some cases, maternal CCR5 expression was maintained despite resolution of viremia. As noted above, significant morphologic changes were observed in the fetal cerebral cortex at 3 weeks after Zika virus inoculation, including massive alterations in the distribution, density, number, and morphology of microglial cells in proliferative regions of the fetal cerebral cortex; an altered distribution of Tbr2+ NPCs; increased diameter and volume of blood vessels in the cortical proliferative zones; and a thinner cortical plate. At 3 months after inoculation, alterations in morphology, distribution, and microglial cell density were also observed with an increase in blood vessel volume and a thinner cortical plate.
      One question under study is whether adverse fetal outcomes require direct infection of fetal tissues or if placental infection and resulting dysfunction are important contributors. Studies in macaques are particularly important in resolving this question because of similarities in placental structure as noted above. Placental Zika virus infection in humans and rhesus monkeys has been shown to result in placental inflammation and vasculitis (
      • Chen Q.
      • Gouilly J.
      • Ferrat Y.J.
      • Espino A.
      • Glaziou Q.
      • Cartron G.
      • et al.
      Metabolic reprogramming by Zika virus provokes inflammation in human placenta.
      ,
      • Crooks C.M.
      • Weiler A.M.
      • Rybarczyk S.L.
      • Bliss M.
      • Jaeger A.S.
      • Murphy M.E.
      • et al.
      African-lineage Zika virus replication dynamics and maternal-fetal interface infection in pregnant rhesus macaques.
      ,
      • Parker E.L.
      • Silverstein R.B.
      • Vera S.
      • Mysorekar I.U.
      Viral-immune cell interactions at the maternal-fetal interface in human pregnancy.
      ,
      • Dudley D.M.
      • Aliota M.T.
      • Mohr E.L.
      • Newman C.M.
      • Golos T.G.
      • Friedrich T.C.
      • et al.
      Using macaques to address critical questions in Zika virus research.
      ,
      • Narang K.
      • Cheek E.H.
      • Enninga E.A.L.
      • Theiler R.N.
      Placental immune responses to viruses: Molecular and histo-pathologic perspectives.
      ,
      • Pereira L.
      Congenital viral infection: Traversing the uterine-placental interface.
      ), providing evidence to support that more studies are needed to understand the role of the placenta and the maternal-placental-fetal interface in the range of outcomes associated with infection.

      CMV and Fetal Immunity

      CMV is the most common congenital viral infection in the United States, with approximately 1% of newborns infected (
      • Pereira L.
      Congenital viral infection: Traversing the uterine-placental interface.
      ). A primary infection in the first trimester has a 40% risk of transmission with 25% resulting in birth defects. Fetal and/or postnatal CMV infections can have a profound, permanent impact on immune function and can result in postnatal hearing loss and neurodevelopmental delays. CMV infection influences nearly 60% of all immune phenotypes and functional responses, including a major impact on the memory T cell pool, with about 10% of the memory T cell repertoire (both CD4+ and CD8+) being CMV specific (
      • Sylwester A.W.
      • Mitchell B.L.
      • Edgar J.B.
      • Taormina C.
      • Pelte C.
      • Ruchti F.
      • et al.
      Broadly targeted human cytomegalovirus-specific CD4(+) and CD8(+) T cells dominate the memory compartments of exposed subjects.
      ). Human CMV infection is associated with expansion of and adaptive changes in subsets of NK cells, e.g., gNK cells, a class of cells with memory function that do not rely on germline-encoded, antigen-specific receptors (
      • Zhang T.
      • Scott J.M.
      • Hwang I.
      • Kim S.
      Antibody-dependent memory-like NK cells distinguished by FcRγ-deficiency.
      ). Some investigators have argued that gNK cells are essentially specific to CMV infection, as CMV-seronegative individuals with prevalent gNK cells are frequently shown to possess CMV-specific T cells. CMV infection is also associated with expansion of adaptive immune cells with innate features, e.g., NK-like cytotoxic T lymphocytes, which are CD8+ cytotoxic T lymphocytes with NK-like surface markers and functional activity. We recently demonstrated that these cells are equivalent to cells previously identified variously as innate memory cells, virtual memory cells, or antimicrobial cytotoxic T lymphocytes, and that their expansion is driven by host interleukin 15 production (
      • Méndez-Lagares G.
      • Chin N.
      • Chang W.L.W.
      • Lee J.
      • Rosás-Umbert M.
      • Kieu H.T.
      • et al.
      Cytomegalovirus mediates expansion of IL-15-responsive innate-memory cells with SIV killing function.
      ). Innate memory cells express HLA class I–specific inhibitory receptors most often associated with NK cells (e.g., NKG2A) and have the capacity to kill class Ia–deficient targets, such as HIV-infected cells and many tumor cells (
      • Mazzarino P.
      • Pietra G.
      • Vacca P.
      • Falco M.
      • Colau D.
      • Coulie P.
      • et al.
      Identification of effector-memory CMV-specific T lymphocytes that kill CMV-infected target cells in an HLA-E-restricted fashion.
      ).
      To assess the potential protective role that transplacentally transferred anti-rhesus CMV (RhCMV) immunoglobulin G (IgG) might play in limiting fetal disease, maternal and fetal antibodies to RhCMV were analyzed in rhesus monkeys by obtaining paired maternal/fetal blood samples during gestation, at birth, and postnatally (
      • Barry P.A.
      • Lockridge K.M.
      • Salamat S.
      • Tinling S.P.
      • Yue Y.
      • Tarantal A.F.
      Nonhuman primate models of intrauterine cytomegalovirus infection.
      ). In uninfected control fetuses, antiviral IgG titers were first detected in the fetal circulation in the early second trimester (approximately 1%–2% of maternal titers), which corresponded to transplacentally transferred IgG. Mean titers in the fetus increased to 12.5% of maternal titers by the late second trimester and increased further during gestation to approximately 50% of maternal titers in the third trimester and at birth. Because maternal RhCMV titers remained unchanged during gestation, relative increases in fetal IgG titers reflect increased transplacental transfer of maternal IgG. Analyses were then performed in fetuses that were directly inoculated intraperitoneally with RhCMV in the late first trimester or early second trimester. For fetuses inoculated in the first trimester, titers paralleled those from control fetuses during gestation. A distinct pattern was observed in fetuses inoculated in the early second trimester when compared to uninoculated: significantly higher RhCMV IgG responses were noted in the third trimester, at term, and at 1-month postnatal age. Since maternal RhCMV titers remained constant across gestation, the increased titers reflected IgG of fetal and neonatal origin. These results demonstrate that fetuses are immunologically competent for de novo IgG production and that the fetal primate develops some degree of effector function at an early stage, although the contribution of this effector function to protection against pathogens remains to be determined.

      Conclusions

      The developmental origins of health and disease hypothesis, previously known as the Barker hypothesis, proposes that organ systems are shaped prenatally in ways that set the stage for health or disease across the lifespan (
      • Penkler M.
      • Hanson M.
      • Biesma R.
      • Müller R.
      DOHaD in science and society: Emergent opportunities and novel responsibilities.
      ). The continued rise in allergic and autoimmune diseases highlights the susceptibility of developing immune pathways, with inflammation a common theme for many chronic illnesses (
      • Duan Y.
      • Zeng L.
      • Zheng C.
      • Song B.
      • Li F.
      • Kong X.
      • et al.
      Inflammatory links between high fat diets and diseases.
      ,
      • Hagberg H.
      • Gressens P.
      • Mallard C.
      Inflammation during fetal and neonatal life: Implications for neurologic and neuropsychiatric disease in children and adults.
      ,
      • Lockett G.A.
      • Human J.
      • Holloway J.W.
      Does allergy begin in utero?.
      ). The need for nonhuman primates in translational research, particularly related to pregnancy, fetal/neonatal development including the CNS, and the role of the immune system, continues to remain a high priority (
      • Dudley D.M.
      • Aliota M.T.
      • Mohr E.L.
      • Newman C.M.
      • Golos T.G.
      • Friedrich T.C.
      • et al.
      Using macaques to address critical questions in Zika virus research.
      ,
      • Betizeau M.
      • Cortay V.
      • Patti D.
      • Pfister S.
      • Gautier E.
      • Bellemin-Mènard A.
      • et al.
      Precursor diversity and complexity of lineage relationship in the outer subventricular zone of the primate.
      ,
      • Li M.
      • Brokaw A.
      • Furuta A.M.
      • Coler B.
      • Obregon-Perko V.
      • Chahroudi A.
      • et al.
      Non-human primate models to investigate mechanisms of infection-associated fetal and pediatric injury, teratogenesis, and stillbirth.
      ,
      • PrabhuDas M.
      • Bonney E.
      • Caron K.
      • Dey S.
      • Erlebacher A.
      • Fazleabas A.
      • et al.
      Immune mechanisms at the maternal-fetal interface: Perspectives and challenges.
      ,
      • Sartoretti J.
      • Eberhardt C.S.
      The potential role of nonhuman primate models to better comprehend early life immunity and maternal antibody transfer.
      ,
      • Semmes E.C.
      • Chen J.L.
      • Goswami R.
      • Burt T.D.
      • Permar S.R.
      • Fouda G.G.
      Understanding early-life adaptive immunity to guide interventions for pediatric health.
      ). Ongoing studies that explore the role of the maternal-placental-fetal interface are needed to address new approaches to protect against congenital disease and the potential for neurodevelopmental disorders (
      • Al-Haddad B.J.S.
      • Oler E.
      • Armistead B.
      • Elsayed N.A.
      • Weinberger D.R.
      • Bernier R.
      • et al.
      The fetal origins of mental illness.
      ,
      • Raper J.
      • Kovacs-Balint Z.
      • Mavigner M.
      • Gumber S.
      • Burke M.W.
      • Habib J.
      • et al.
      Long-term alterations in brain and behavior after postnatal Zika virus infection in infant macaques.
      ,
      • Venceslau E.M.
      • Guida J.P.
      • Amaral E.
      • Modena J.L.P.
      • Costa M.L.
      Characterization of placental infection by Zika virus in humans: A review of the literature.
      ).

      Acknowledgments and Disclosures

      This work was supported by the National Institutes of Health (Grant Nos. OD023716 [to AFT, SCN], NS103658 [to AFT, SCN, DJH-O], NS109379 [to SCN, AFT], NS111313 [to SCN, AFT], AI133548 [to AFT], AI084109 [to DJH-O, AFT], and AI090677 [to DJH-O]) and National Institutes of Health Primate Center base operating grant (Grant No. OD011107 ). In vivo imaging was performed with instrumentation funded by the National Institutes of Health S10 High-End Instrumentation Grant Program (Grant Nos. OD016261 and RR025063 [to AFT]).
      The authors report no biomedical financial interests or potential conflicts of interest.

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