Fetal brain lesions after subcutaneous inoculation of Zika virus in a pregnant nonhuman primate

Waldorf, Kristina M. Adams; Stencel-Baerenwald, Jennifer E.; Kapur, Raj P.; Studholme, Colin; Boldenow, Erica; Vornhagen, Jay; Baldessari, Audrey; Dighe, Manjiri; Thiel, Jeff; Merillat, Sean; Armistead, Blair; Tisoncik-Go, Jennifer; Green, Richard; Davis, Michael A.; Dewey, Elyse C.; Fairgrieve, Marian R.; Gatenby, J. Christopher; Richards, Todd L.; Garden, Gwenn A.; Diamond, Michael S.; Juul, Sandra E.; Grant, Richard; Kuller, La Rene; Shaw, Dennis; Ogle, Jason; Gough, Gillian; Lee, Wonsok; English, Chris; Hevner, Robert F.; Dobyns, William B.; Gale, Michael; Rajagopal, Lakshmi

doi:10.1038/nm.4193

Cited by 252 publications

(301 citation statements)

References 35 publications

(16 reference statements)

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“…Previous human and animal studies have established a causal relationship between ZIKV and microcephaly (6,(15)(16)(17)(18)(19)(20)(21). In the brain, neural stem cells, astrocytes, oligodendrocyte precursor cells, and microglia were found to be preferentially infected by ZIKV, whereas neurons were less susceptible to infection (22).…”

mentioning

confidence: 97%

Suppression of Zika Virus Infection and Replication in Endothelial Cells and Astrocytes by PKA Inhibitor PKI 14-22

Cheng

Silva

Huang

et al. 2018

J Virol

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The recent outbreak of Zika virus (ZIKV), a reemerging flavivirus, and its associated neurological disorders, such as Guillain-Barré (GB) syndrome and microcephaly, have generated an urgent need to develop effective ZIKV vaccines and therapeutic agents. Here, we used human endothelial cells and astrocytes, both of which represent key cell types for ZIKV infection, to identify potential inhibitors of ZIKV replication. Because several pathways, including the AMP-activated protein kinase (AMPK), protein kinase A (PKA), and mitogen-activated protein kinase (MAPK) signaling pathways, have been reported to play important roles in flavivirus replication, we tested inhibitors and agonists of these pathways for their effects on ZIKV replication. We identified the PKA inhibitor PKI 14-22 (PKI) to be a potent inhibitor of ZIKV replication. PKI effectively suppressed the replication of ZIKV from both the African and Asian/American lineages with a high efficiency and minimal cytotoxicity. While ZIKV infection does not induce PKA activation, endogenous PKA activity is essential for supporting ZIKV replication. Interestingly, in addition to PKA, PKI also inhibited another unknown target(s) to block ZIKV replication. PKI inhibited ZIKV replication at the postentry stage by preferentially affecting negative-sense RNA synthesis as well as viral protein translation. Together, these results have identified a potential inhibitor of ZIKV replication which could be further explored for future therapeutic application.IMPORTANCE There is an urgent need to develop effective vaccines and therapeutic agents against Zika virus (ZIKV) infection, a reemerging flavivirus associated with neurological disorders, including Guillain-Barré (GB) syndrome and microcephaly. By screening for inhibitors of several cellular pathways, we have identified the PKA inhibitor PKI 14-22 (PKI) to be a potent inhibitor of ZIKV replication. We show that PKI effectively suppresses the replication of all ZIKV strains tested with minimal cytotoxicity to human endothelial cells and astrocytes, two key cell types for ZIKV infection. Furthermore, we show that PKI inhibits ZIKV negative-sense RNA synthesis and viral protein translation. This study has identified a potent inhibitor of ZIKV infection which could be further explored for future therapeutic application.

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mentioning

confidence: 97%

Suppression of Zika Virus Infection and Replication in Endothelial Cells and Astrocytes by PKA Inhibitor PKI 14-22

Cheng

Silva

Huang

et al. 2018

J Virol

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“…Other recent studies of ZIKV infection in nonhuman primates have relied on a variety of 52 doses and routes with varying outcomes. For example, five sc inoculations each containing 1 x 53 10 7 PFU (a 50-fold higher cumulative dose than any other published study) of a Cambodian 54 strain of ZIKV in a pregnant pigtail macaque (Macaca nemestrina) resulted in severe fetal 55 neurodevelopmental abnormalities not seen in other studies using a smaller dose of different 56 ZIKV strains 5 . In rhesus and cynomolgus macaques (Macaca mulatta and Macaca fascicularis, 57 respectively), ZIKV RNA persisted in saliva and seminal fluids for at least three weeks after 58 clearance of the virus from the peripheral blood following sc inoculation with 1 x 10 6 PFU of a 59…”

Section: Introduction 18mentioning

confidence: 88%

“…Zika virus (ZIKV; Flaviviridae, Flavivirus) is primarily transmitted by Aedes aegypti mosquitoes, 19 but animal models of ZIKV pathogenesis have relied on needle inoculation [1][2][3][4][5][6][7] . Needle 20 inoculation has been performed using a range of doses, delivered subcutaneously at a single 21 site or at multiple sites, as well as intravenously, intravaginally, intrarectally, and intra-22 amniotically in pregnant animals.…”

Section: Introduction 18mentioning

confidence: 99%

Infection via mosquito bite alters Zika virus replication kinetics in rhesus macaques

Lalli

et al. 2017

Preprint

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For more than three decades it has been recognized that small amounts of vector saliva can significantly alter the infectivity of vector-borne pathogens and subsequent in vivo dynamics. Mouse and nonhuman primate models now serve as useful platforms to study Zika virus (ZIKV) pathogenesis, candidate therapies, and vaccines, but they rely on needle inoculation of virus: the effects of mosquito-borne infection on disease outcome have not been explored in these models. To model vector-borne transmission of ZIKV in nonhuman primates, we infected Aedes aegypti mosquitoes with ZIKV and allowed them to feed on four ZIKV-naive rhesus macaques. We compared ZIKV replication kinetics and tissue distribution between animals that were subcutaneously inoculated with 104 plaque-forming units of ZIKV and those that were exposed via mosquito bite. Here, we show that infection via mosquito bite delays ZIKV replication to peak viral loads in rhesus macaques. Importantly, in mosquito-infected animals ZIKV tissue distribution was limited to hemolymphatic tissues, female reproductive tract tissues, kidney, and liver, potentially emulating key features of human ZIKV infections, most of which are characterized by mild or asymptomatic disease. This newly developed system will be valuable for studying ZIKV disease because it more closely mimics human infection by mosquito bite than needle-based inoculations.

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“…Fetal autopsy revealed the Zika virus in the brain, and significant cerebral white matter hypoplasia, periventricular white matter gliosis, and axonal and ependymal injury. 30 Based on these observations, there is likely an association between Zika virus infection during pregnancy and an increased risk of microcephaly in the fetus. 31 Mathematical analysis was carried out on the risk of microcephaly in the fetus in the case of their mother being infected with the Zika virus.…”

Section: Complicationsmentioning

confidence: 99%

Zika virus infection: Clinical overview with a summary of Japanese cases

Kutsuna

2017

Clinical & Exp Neuroim

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Zika virus infection is a mosquito-borne infection caused by the Zika virus, a member of the genus Flavivirus in the family Flaviviridae. The infection is transmitted to humans mainly by Aedes aegypti and Aedes albopictus mosquitoes. Sexual contact has also been reported to cause infection. It can be diagnosed based on the detection of the virus from blood or urine samples, detection of the viral genes by reverse transcription polymerase chain reaction, positive conversion of immunoglobulin M or neutralizing antibodies, or a significant increase in antibody titer in paired sera. No effective antiviral drugs or vaccines are currently available. On rare occasions, individuals infected with the Zika virus subsequently develop Guillain-Barr e syndrome. In addition, pregnant women infected with the Zika virus can have an increased risk of fetal microcephaly, which has been recognized as a social problem. Finally, I summarized Zika virus infection in Japan as of June 2017.

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Fetal brain lesions after subcutaneous inoculation of Zika virus in a pregnant nonhuman primate

Cited by 252 publications

References 35 publications

Suppression of Zika Virus Infection and Replication in Endothelial Cells and Astrocytes by PKA Inhibitor PKI 14-22

Suppression of Zika Virus Infection and Replication in Endothelial Cells and Astrocytes by PKA Inhibitor PKI 14-22

Infection via mosquito bite alters Zika virus replication kinetics in rhesus macaques

Zika virus infection: Clinical overview with a summary of Japanese cases

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