Zika virus infection at mid-gestation results in fetal cerebral cortical injury and fetal death in the olive baboon

Abstract

Zika virus (ZIKV) infection during pregnancy in humans is associated with an increased incidence of congenital anomalies including microcephaly as well as fetal death and miscarriage and collectively has been referred to as Congenital Zika Syndrome (CZS). Animal models for ZIKV infection in pregnancy have been developed including mice and non-human primates (NHPs). In macaques, fetal CZS outcomes from maternal ZIKV infection range from none to significant. In the present study we develop the olive baboon (Papio anubis), as a model for vertical transfer of ZIKV during pregnancy. Four mid-gestation, timed-pregnant baboons were inoculated with the French Polynesian ZIKV isolate (104 ffu). This study specifically focused on the acute phase of vertical transfer. Dams were terminated at 7 days post infection (dpi; n = 1), 14 dpi (n = 2) and 21 dpi (n = 1). All dams exhibited mild to moderate rash and conjunctivitis. Viremia peaked at 5–7 dpi with only one of three dams remaining mildly viremic at 14 dpi. An anti-ZIKV IgM response was observed by 14 dpi in all three dams studied to this stage, and two dams developed a neutralizing IgG response by either 14 dpi or 21 dpi, the latter included transfer of the IgG to the fetus (cord blood). A systemic inflammatory response (increased IL2, IL6, IL7, IL15, IL16) was observed in three of four dams. Vertical transfer of ZIKV to the placenta was observed in three pregnancies (n = 2 at 14 dpi and n = 1 at 21 dpi) and ZIKV was detected in fetal tissues in two pregnancies: one associated with fetal death at ~14 dpi, and the other in a viable fetus at 21 dpi. ZIKV RNA was detected in the fetal cerebral cortex and other tissues of both of these fetuses. In the fetus studied at 21 dpi with vertical transfer of virus to the CNS, the frontal cerebral cortex exhibited notable defects in radial glia, radial glial fibers, disorganized migration of immature neurons to the cortical layers, and signs of pathology in immature oligodendrocytes. In addition, indices of pronounced neuroinflammation were observed including astrogliosis, increased microglia and IL6 expression. Of interest, in one fetus examined at 14 dpi without detection of ZIKV RNA in brain and other fetal tissues, increased neuroinflammation (IL6 and microglia) was observed in the cortex. Although the placenta of the 14 dpi dam with fetal death showed considerable pathology, only minor pathology was noted in the other three placentas. ZIKV was detected immunohistochemically in two placentas (14 dpi) and one placenta at 21 dpi but not at 7 dpi. This is the first study to examine the early events of vertical transfer of ZIKV in a NHP infected at mid-gestation. The baboon thus represents an additional NHP as a model for ZIKV induced brain pathologies to contrast and compare to humans as well as other NHPs.

Montelukast, an Anti-asthmatic Drug, Inhibits Zika Virus Infection by Disrupting Viral Integrity

“…ZIKV is one of the mosquito-borne flaviviruses discovered about 70 years ago and has spread all over the world in recent years, which causes Guillain-Barré syndrome, congenital Zika syndrome, and damage to testicular tissue (Brasil et al, 2016;Baud et al, 2017;Gurung et al, 2019;Peixoto et al, 2019). Currently, there are no vaccines or drugs approved for prevention and treatment of ZIKV infection, leading to the necessity and urgency of the development of anti-ZIKV therapy.…”

“…Since the first isolation in 1947 from the rhesus macaque in Zika forest, Uganda, and publication of the first human case of infection in 1952, Zika virus (ZIKV), a mosquito-borne enveloped RNA virus, has become a member of Flavivirus genus in the Flaviviridae family for more than 70 years together with dengue virus (DENV), yellow fever virus (YFV), Japanese encephalitis virus (JEV), and West Nile virus (WNV). The infection of ZIKV has aroused global awareness only in recent years because of some severe neurological complications such as Guillain-Barré syndrome (Brasil et al, 2016;Peixoto et al, 2019) and congenital Zika syndrome (Baud et al, 2017;Gurung et al, 2019), which consists of many clinical manifestations including intracranial calcification (ICC) and cerebellar hypoplasia (de Fatima Vasco Aragao et al, 2016;Oliveira Melo et al, 2016;Cui et al, 2017), and is remarkably typified by microcephaly found both in humans and in animal models (Cui et al, 2017), although symptoms of majority of infection with ZIKV are mild or asymptomatic. In addition, infection with ZIKV leads to impaired human spermatozoa production demonstrated by decreased sperm count in the early stage of ZIKV infection (Joguet et al, 2017).…”

Experimental Infection of Mid-Gestation Pregnant Female and Intact Male Sheep with Zika Virus

“…Established animal models of ZIKV infection during pregnancy that result in vertical transmission include non-human primates (NHP) and type-1 interferon/interferon receptor deficient mice. In NHP models, first trimester infection most frequently results in fetal demise and reduced fetal development even in asymptomatic mothers, while second trimester infections tend to produce fetuses with higher viral loads but greater fetal viability [8][9][10]. In all NHP models, fetal pathology ranges from mild to severe manifestations, consistent with Congenital Zika Syndrome (CZS) seen in humans [11][12][13][14][15][16].…”

Animal Models of Zika Virus Sexual Transmission

“…Olive baboons were also used to model ZIKV infection during pregnancy. Infection of 4 log 10 of ZIKV H/PF/2013 resulted in vertical transmission in 3 out of 4 pregnant NHPs [94]. Unlike the non-pregnant animals, all dams presented rash and conjunctivitis [94].…”

“…Infection of 4 log 10 of ZIKV H/PF/2013 resulted in vertical transmission in 3 out of 4 pregnant NHPs [94]. Unlike the non-pregnant animals, all dams presented rash and conjunctivitis [94]. Fetal death and defects in the frontal cortex of the fetus were observed [94].…”