A rhesus macaque model of Asian-lineage Zika virus infection

Dudley, Dawn M.; Aliota, Matthew T.; Mohr, Emma L.; Weiler, Andrea M.; Lehrer-Brey, Gabrielle; Weisgrau, Kim L.; Mohns, Mariel S.; Breitbach, Meghan E.; Rasheed, Mustafa N; Newman, Christina M.; Gellerup, Dane D.; Moncla, Louise H.; Post, Jennifer; Schultz-Darken, Nancy; Schotzko, Michele L; Hayes, Jennifer; Eudailey, Josh; Moody, M. Anthony; Permar, Sallie R.; O’Connor, Shelby L.; Rakasz, Eva G.; Simmons, Heather A.; Capuano, Saverio; Golos, Thaddeus G.; Osorio, Jorge E.; Friedrich, Thomas C.; O’Connor, David H.

doi:10.1038/ncomms12204

Cited by 359 publications

(567 citation statements)

References 25 publications

(26 reference statements)

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“…To assess differences in ZIKV replication between virus delivery by needle 73 versus mosquito vector, we infected rhesus macaques with the Puerto Rican ZIKV isolate 74 PRVABC59 by either sc inoculation (n=3) or by exposure to infected mosquitoes (n=4). All three 75 sc-inoculated macaques were productively infected, with viral load dynamics similar to what we 76 have reported previously 1,2 . All four animals exposed to Ae.…”

Section: Introduction 18supporting

confidence: 74%

“…Our studies using the same route and doses ranging from 1 x 10 4 to 1 x 10 6 60 PFU of a French Polynesian isolate showed no persistence in body fluids after the resolution of 61 acute plasma viremia in non-pregnant macaques 2 . In yet another study in rhesus macaques, 62 intravenous administration of 1 x 10 5 PFU of a Brazilian ZIKV isolate resulted in a short-lived 63 plasma viremia and vRNA distribution in a variety of tissues two weeks post-infection 7 .…”

Section: Introduction 18mentioning

confidence: 98%

“…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%

“…46 The amount of ZIKV inoculated by mosquitoes into a host is not known. In the majority of our 47 previous studies we used an inoculum dose of 1 x 10 4 PFU injected subcutaneously (sc) 1,2,24 , 48 which we chose as a dose likely to be delivered by a ZIKV-infected mosquito. This was based 49 on previous studies, which found that mosquitoes delivered ~1 x 10 4 -1 x 10 6 PFU of West Nile 50 virus (WNV) 12 and as much as 1 x 10 4 50% mosquito infectious doses of dengue virus (DENV) 51 25 .…”

Section: Introduction 18mentioning

confidence: 99%

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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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Section: Introduction 18supporting

confidence: 74%

Section: Introduction 18mentioning

confidence: 98%

Section: Introduction 18mentioning

confidence: 99%

Section: Introduction 18mentioning

confidence: 99%

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

Lalli

et al. 2017

Preprint

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“…[34][35][36][37] Li et al 38 observed that experimental infection of infected embryonic mouse brains with ZIKV resulted in smaller brain size with enlarged lateral ventricles and thinner cortical plates when compared with uninfected controls. In this model, the neural progenitor cells and intermediate or basal progenitor cells were the primary cells affected.…”

Section: Experimental Infection Neurotropism Andmentioning

confidence: 99%

Zika Virus Infection in Pregnancy, Microcephaly, and Maternal and Fetal Health: What We Think, What We Know, and What We Think We Know

M¹,

Schwartz

2016

Archives of Pathology &Amp; Laboratory Medicine

117

113

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Context.-The global epidemic of Zika virus (ZIKV) infection has emerged as an important public health problem affecting pregnant women and their infants.Objectives.-To review the causal association between ZIKV infection during pregnancy and intrauterine fetal infection, microcephaly, brain damage, congenital malformation syndrome, and experimental laboratory models of fetal infection. Many questions remain regarding the risk factors, pathophysiology, epidemiology, and timing of maternal-fetal transmission and disease. These include mechanisms of fetal brain damage and microcephaly; the role of covariables, such as viral burden, duration of viremia, and host genetics, on vertical transmission; and the clinical and pathologic spectrum of congenital Zika syndrome. Additional questions include defining the potential long-term physical and neurobehavioral outcomes for infected infants, whether maternal or fetal host genetics influence the clinical outcome, and whether ZIKV infection can cause maternal morbidity. Finally, are experimental laboratory and animal models of ZIKV infection helpful in addressing maternal-fetal viral transmission and the development of congenital microcephaly? This communication provides current information and attempts to address some of these important questions.Data Sources.-Comprehensive review of published scientific literature.Conclusions.-Recent advances in epidemiology, clinical medicine, pathology, and experimental studies have provided a great amount of new information regarding vertical ZIKV transmission and the mechanisms of congenital microcephaly, brain damage, and congenital Zika syndrome in a relatively short time. However, much work still needs to be performed to more completely understand the maternal and fetal aspects of this new and emerging viral disease.

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Association of Severe Hydrocephalus With Congenital Zika Syndrome

Linden¹,

Petribu²,

Pessoa

et al. 2019

JAMA Neurol

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IMPORTANCE Hydrocephalus is a treatable but potentially fatal complication that has not been previously described in congenital Zika syndrome (CZS).OBJECTIVE To describe the clinical features and imaging findings in 24 patients with congenital Zika syndrome (CZS) who developed hydrocephalus. DESIGN, SETTING, AND PARTICIPANTSThis case series included patients with hydrocephalus who were born in October and November 2015 and followed up until mid-2017 in the 2 largest national referral centers for CZS in Brazil. The participants included consecutively enrolled children with a clinical and laboratorial diagnosis of CZS who developed clinical and/or image findings suggestive of hydrocephalus and who were confirmed to experience increased intracranial hypertension during ventriculoperitoneal shunt procedures. MAIN OUTCOMES AND MEASURESTo retrospectively describe clinical and image findings in these 24 patients. RESULTS This multicenter cohort included 308 patients with CZS; 24 consecutive children were enrolled in this study. These children were aged between 3 to 18 months, and 13 of 24 (54%) were female. All patients presented with at least 1 positive test result for anti-Zika antibodies in cerebrospinal fluid or serum and had classic signs of CZS. At the time of hydrocephalus diagnosis, only 14 of 24 patients (58%) had symptoms and signs suggestive of hydrocephalus (mainly worsening seizures, vomiting, irritability, and/or sudden increase of head circumference percentile). Two of 24 patients (8%) had no symptoms suggestive of hydrocephalus but were found to have reduced brain volume on repeated imaging. Cerebellar or brainstem hypoplasia on baseline imaging were found in 18 of 23 patients (78%). At the second computed tomographic scan, all patients showed a marked increase of ventricular volume, compatible with communicating hydrocephalus, and reduction of brain tissue that was visibly worse than on baseline imaging for the 23 patients with repeated scans. CONCLUSIONS AND RELEVANCEWe present evidence that hydrocephalus is a complication of CZS in at least a proportion of patients. The clinical spectrum of this condition continues to evolve, but given that presenting signs and symptoms of hydrocephalus can be challenging to recognize in CZS, we provisionally recommend that high suspicion and appropriate monitoring for hydrocephalus should be part of the standard care of patients with CZS.

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A rhesus macaque model of Asian-lineage Zika virus infection

Cited by 359 publications

References 25 publications

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

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

Zika Virus Infection in Pregnancy, Microcephaly, and Maternal and Fetal Health: What We Think, What We Know, and What We Think We Know

Association of Severe Hydrocephalus With Congenital Zika Syndrome

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