Zika viral dynamics and shedding in rhesus and cynomolgus macaques

Osuna, Christa E.; Lim, So-Yon; Deléage, Claire; Griffin, Bryan D.; Stein, Derek; Schroeder, Lukas T.; Omange, Robert W; Best, Katharine; Luo, Ma; Hraber, Peter; Andersen, Hanne; Cardozo-Ojeda, E Fabian; Huang, Scott; Vanlandingham, Dana L.; Higgs, Stephen; Perelson, Alan S.; Estes, Jacob D.; Safronetz, David; Lewis, Mark G.; Whitney, James B.

doi:10.1038/nm.4206

Cited by 276 publications

(382 citation statements)

References 52 publications

Supporting

Mentioning

335

Contrasting

Unclassified

Order By: Relevance

“…Inoculation of rhesus macaques with an Asian lineage ZIKV strain (H/FP/2013) resulted in mild weight loss, development of a mild rash around the injection site, and elevated serum creatine kinase and alanine aminotransferase in some animals (87). Although weight loss and rash were not observed across all studies, elevated liver enzymes at early times postinfection were a consistent feature of ZIKV infection of rhesus macaques (38,87,88). In some experiments, ZIKV infection also resulted in elevated body temperature for up to 10 days postinfection (38,88).…”

mentioning

confidence: 90%

See 1 more Smart Citation

Animal Models of Zika Virus Infection, Pathogenesis, and Immunity

Morrison

Diamond

2017

J Virol

232

View full text Add to dashboard Cite

Zika virus (ZIKV) is an emerging mosquito-transmitted flavivirus that now causes epidemics affecting millions of people on multiple continents. The virus has received global attention because of some of its unusual epidemiological and clinical features, including persistent infection in the male reproductive tract and sexual transmission, an ability to cross the placenta during pregnancy and infect the developing fetus to cause congenital malformations, and its association with Guillain-Barré syndrome in adults. This past year has witnessed an intensive effort by the global scientific community to understand the biology of ZIKV and to develop pathogenesis models for the rapid testing of possible countermeasures. Here, we review the recent advances in and utility and limitations of newly developed mouse and nonhuman primate models of ZIKV infection and pathogenesis.

show abstract

mentioning

confidence: 90%

“…(i) Pathogenesis in immunocompetent adult macaques. Nonhuman primates (NHPs) also are being used to evaluate aspects of ZIKV biology and pathogenesis (38,(87)(88)(89)(90). Several groups have characterized ZIKV infection in pregnant and nonpregnant rhesus, cynomolgus, and pigtail macaques.…”

mentioning

confidence: 99%

Animal Models of Zika Virus Infection, Pathogenesis, and Immunity

Morrison

Diamond

2017

J Virol

232

View full text Add to dashboard Cite

show abstract

“…Immunocompetent mice do not develop disease symptoms, but persistent testicular infection for up to 45 days in IFNAR1-deficient mice has been associated with proinflammatory responses, infiltration of leukocytes into the testes, and damaged architecture of the seminiferous epithelium (11,12). Similarly, nonhuman primate studies have also reported the presence of ZIKV RNA in the testes 7 to 8 days after infection (13). In humans, some, but not all, ZIKV-infected men present with hematospermia; however, the presence of the virus in semen even after the clearance of viremia suggests that sexual transmission is not the result of hematospermiainduced blood-borne transmission and that ZIKV has the ability to establish persistent testicular infection.…”

mentioning

confidence: 99%

Zika Virus Infects Human Sertoli Cells and Modulates the Integrity of the In Vitro Blood-Testis Barrier Model

Siemann

Strange

Maharaj

et al. 2017

J Virol

112

View full text Add to dashboard Cite

Confirmed reports of Zika virus (ZIKV) in human seminal fluid for months after the clearance of viremia suggest the ability of ZIKV to establish persistent infection in the seminiferous tubules, an immune-privileged site in the testis protected by the blood-testis barrier, also called the Sertoli cell (SC) barrier (SCB). However, cellular targets of ZIKV in human testis and mechanisms by which the virus enters seminiferous tubules remain unclear. We demonstrate that primary human SCs were highly susceptible to ZIKV compared to the closely related dengue virus and induced the expression of alpha interferon (IFN-␣), key cytokines, and cell adhesion molecules (vascular cell adhesion molecule 1 [VCAM-1] and intracellular adhesion molecule 1 [ICAM-1]). Furthermore, using an in vitro SCB model, we show that ZIKV was released on the adluminal side of the SCB model with a higher efficiency than in the blood-brain barrier model. ZIKV-infected SCs exhibited enhanced adhesion of leukocytes that correlated with decreases in SCB integrity. ZIKV infection did not affect the expression of tight and adherens junction proteins such as ZO-1, claudin, and JAM-A; however, exposure of SCs to inflammatory mediators derived from ZIKV-infected macrophages led to the degradation of the ZO-1 protein, which correlated with increased SCB permeability. Taken together, our data suggest that infection of SCs may be one of the crucial steps by which ZIKV gains access to the site of spermatozoon development and identify SCs as a therapeutic target to clear testicular infections. The SCB model opens up opportunities to assess interactions of SCs with other testicular cells and to test the ability of anti-ZIKV drugs to cross the barrier.IMPORTANCE Recent outbreaks of ZIKV, a neglected mosquito-borne flavivirus, have identified sexual transmission as a new route of disease spread, which has not been reported for other flaviviruses. To be able to sexually transmit for months after the clearance of viremia, ZIKV must establish infection in the seminiferous tubules, the site of spermatozoon development. However, little is known about the cell types that support ZIKV infection in the human testis. Currently, there are no models to study mechanisms of virus persistence in the seminiferous tubules. We provide evidence that ZIKV infection of human Sertoli cells, which are an important component of the seminiferous tubules, is robust and induces a strong antiviral response. The use of an in vitro Sertoli cell barrier to describe how ZIKV or inflammatory mediators derived from ZIKV-infected macrophages compromise barrier integrity will enable studies to explore the interactions of other testicular cells with Sertoli cells and to test novel antivirals for clearing testicular ZIKV infection.

show abstract

“…Needle inoculation remains an important option when it is 242 necessary to control the exact dose delivered, but the dose and number of sc inoculations could 243 alter virus distribution and replication kinetics. For example, several recent studies using needle 244 inoculation detected a broad ZIKV RNA tissue distribution, including in reproductive organs, the 245 CNS, and brain 7,26,36,37 . Likewise, we also found evidence of ZIKV infection of the brain and eye 246 in our needle inoculated animals.…”

Section: Cc-by-nc-nd 40 International License Peer-reviewed) Is Thementioning

confidence: 99%

“…Thai ZIKV isolate 26 . 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 .…”

Section: Introduction 18mentioning

confidence: 99%

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

Lalli

et al. 2017

Preprint

View full text Add to dashboard Cite

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.

show abstract

Zika viral dynamics and shedding in rhesus and cynomolgus macaques

Cited by 276 publications

References 52 publications

Animal Models of Zika Virus Infection, Pathogenesis, and Immunity

Animal Models of Zika Virus Infection, Pathogenesis, and Immunity

Zika Virus Infects Human Sertoli Cells and Modulates the Integrity of the In Vitro Blood-Testis Barrier Model

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

Contact Info

Product

Resources

About