African-Lineage Zika Virus Replication Dynamics and Maternal-Fetal Interface Infection in Pregnant Rhesus Macaques

Crooks, Chelsea M.; Weiler, Andrea M.; Rybarczyk, Sierra; Bliss, Mason I.; Jaeger, Anna S.; Murphy, Megan E.; Simmons, Heather A.; Mejía, Andrés; Fritsch, Michael K.; Hayes, Jennifer; Eickhoff, Jens; Mitzey, Ann M.; Razo, Elaina; Braun, Katarina M.; Brown, Elizabeth; Yamamoto, Keisuke; Shepherd, Phoenix M.; Possell, Amber; Weaver, Kara; Antony, Kathleen M.; Morgan, Terry K.; Zeng, Xiankun; Dudley, Dawn M.; Peterson, Eric J.; Schultz-Darken, Nancy; O’Connor, David H.; Mohr, Emma L.; Golos, Thaddeus G.; Aliota, Matthew T.; Friedrich, Thomas C.

doi:10.1128/jvi.02220-20

Cited by 29 publications

(64 citation statements)

References 37 publications

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“…The rhesus macaque has become an increasingly valuable animal model for studying viral pathogens such as CMV and Zika virus that are frequently transmitted to the developing fetus during pregnancy ( 67 – 70 ). Hence, the molecular interactions between macaque NK cell receptors and their MHC class I ligands that occur at the maternal-fetal interface may be especially important for understanding viral transmission and pathogenesis in this context.…”

Section: Discussionmentioning

confidence: 99%

KIR3DL05 and KIR3DS02 Recognition of a Nonclassical MHC Class I Molecule in the Rhesus Macaque Implicated in Pregnancy Success

et al. 2022

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Knowledge of the MHC class I ligands of rhesus macaque killer-cell Ig-like receptors (KIRs) is fundamental to understanding the role of natural killer (NK) cells in this species as a nonhuman primate model for infectious diseases, transplantation and reproductive biology. We previously identified Mamu-AG as a ligand for KIR3DL05. Mamu-AG is a nonclassical MHC class I molecule that is expressed at the maternal-fetal interface of the placenta in rhesus macaques similar to HLA-G in humans. Although Mamu-AG and HLA-G share similar molecular features, including limited polymorphism and a short cytoplasmic tail, Mamu-AG is considerably more polymorphic. To determine which allotypes of Mamu-AG serve as ligands for KIR3DL05, we tested reporter cell lines expressing five different alleles of KIR3DL05 (KIR3DL05*001, KIR3DL05*004, KIR3DL05*005, KIR3DL05*008 and KIR3DL05*X) for responses to target cells expressing eight different alleles of Mamu-AG. All five allotypes of KIR3DL05 responded to Mamu-AG2*01:01, two exhibited dominant responses to Mamu-AG1*05:01, and three had low but detectable responses to Mamu-AG3*03:01, -AG3*03:02, -AG3*03:03 and -AG3*03:04. Since KIR3DL05*X is the product of recombination between KIR3DL05 and KIR3DS02, we also tested an allotype of KIR3DS02 (KIR3DS02*004) and found that this activating KIR also recognizes Mamu-AG2*01:01. Additional analysis of Mamu-AG variants with single amino acid substitutions identified residues in the α1-domain essential for recognition by KIR3DL05. These results reveal variation in KIR3DL05 and KIR3DS02 responses to Mamu-AG and define Mamu-AG polymorphisms that differentially affect KIR recognition.

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Section: Discussionmentioning

confidence: 99%

KIR3DL05 and KIR3DS02 Recognition of a Nonclassical MHC Class I Molecule in the Rhesus Macaque Implicated in Pregnancy Success

et al. 2022

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“…Eight ZIKV-naive rhesus macaque dams (046-101, 046-102, 046-103, 046-104, 046-105, 046-106, 046-107, 046-108) were inoculated subcutaneously (SQ) with a high dose, 1×10 8 PFU/ml, of Zika virus/A.africanus-tc/Senegal/1984/DAKAR 41524 (ZIKV-DAK; GenBank: KX601166) at approximately GD 45 (range = GD 41-48) (Fig 1A and S1 Table). Data from these animals were compared to historical data collected from four dams infected with a low dose (1×10 4 PFU/ml) of ZIKV-DAK and five dams mock-inoculated with sterile phosphate-buffered saline (PBS) (24). Physical exams of infected dams showed no ZIKV infection-associated symptoms such as rash or fever (S2A Fig).…”

Section: Resultsmentioning

confidence: 99%

“…Overall plasma vRNA loads were calculated for dams receiving a high dose of ZIKV-DAK (1×10 8 PFU/ml) and historical controls that received a lower dose (1×10 4 PFU/ml) (24) using the trapezoidal method to calculate the area under the curve (AUC) in R Studio v. 1.4.1717. AUC values were then compared between groups (high-dose versus low-dose) using a t-test.…”

Section: Methodsmentioning

confidence: 99%

“…Saliva swabs were collected from dams on days zero to four and seven to 10 post-challenge, and then at all blood collection time points thereafter. Data collected from these eight dams were compared to data from dams previously infected with a low dose (1x10 4 PFU) of ZIKV-DAK, as well as dams mock-inoculated with 1X phosphate-buffered saline (1X PBS) comparably sampled as controls (24).…”

Section: Methodsmentioning

confidence: 99%

“…To determine if the high rate of early fetal loss associated with ZIKV-DAK in mice translates to primates, Crooks et al inoculated four animals subcutaneously (SQ) with a low dose (1x10 4 PFU) of ZIKV-DAK during the first trimester (gestational day 45). Given that first trimester ZIKV infections are more frequently associated with adverse fetal outcomes and ZIKV was detected in the MFI of the four low-dose ZIKV-DAK animals, it is surprising that all four animals had pregnancies proceed normally to study endpoint (20). Two other n=1 studies using Asian-lineage ZIKV (ZIKV-PR, ZIKV-CAM) have reported more frequent adverse pregnancy outcomes when macaques are infected SQ with approximately 10,000 times more virus than typically transmitted by mosquito bite (21)(22)(23).…”

Section: Introductionmentioning

confidence: 99%

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Fetal loss in pregnant rhesus macaques infected with high-dose African-lineage Zika virus

Raasch

Yamamoto

Newman

et al. 2022

Preprint

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Countermeasures against Zika virus (ZIKV), including vaccines, are frequently tested in nonhuman primates (NHP). Macaque models are important for understanding how ZIKV infections impact human pregnancy due to similarities in placental development. The lack of consistent adverse pregnancy outcomes in ZIKV-affected pregnancies poses a challenge in macaque studies where group sizes are often small (4-8 animals). Studies in small animal models suggest that African-lineage Zika viruses can cause more frequent and severe fetal outcomes. No adverse outcomes were observed in macaques inoculated with a low dose of African-lineage ZIKV at gestational day (GD) 45. Here, we inoculate eight pregnant rhesus macaques with a higher dose of African-lineage ZIKV at GD 45 to test the hypothesis that adverse pregnancy outcomes are dose-dependent. Three of eight pregnancies ended prematurely with fetal death. ZIKV was detected in both fetal and placental tissues from all cases of early fetal loss. Further refinements of this challenge system (e.g., varying the dose and timing of infection) could lead to an even more consistent, unambiguous fetal loss phenotype for assessing ZIKV countermeasures in pregnancy. These data demonstrate that high-dose inoculation with African-lineage ZIKV causes pregnancy loss in macaques and also suggest that ZIKV-induced first trimester pregnancy could be strain-specific.

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Zika virus as a cause of birth defects: Were the teratogenic effects of Zika virus missed for decades?

Gilbert

Petersen

Honein

et al. 2022

Birth Defects Research

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Zika virus (ZIKV) was identified as a teratogen in 2016 when an increase in severe microcephaly and other brain defects was observed in fetuses and newborns following outbreaks in French Polynesia (2013–2014) and Brazil (2015–2016) and among travelers to other countries experiencing outbreaks. Some have questioned why ZIKV was not recognized as a teratogen before these outbreaks: whether novel genetic changes in ZIKV had increased its teratogenicity or whether its association with birth defects had previously been undetected. Here we examine the evidence for these two possibilities. We describe evidence for specific mutations that arose before the French Polynesia outbreak that might have increased ZIKV teratogenicity. We also present information on children born with findings consistent with congenital Zika syndrome (CZS) as early as 2009 and epidemiological evidence that suggests increases in CZS‐type birth defects before 2013. We also explore reasons why a link between ZIKV and birth defects might have been missed, including issues with surveillance of ZIKV infections and of birth defects, challenges to ZIKV diagnostic testing, and the susceptibility of different populations to ZIKV infection at the time of pregnancy. Although it is not possible to prove definitively that ZIKV had teratogenic properties before 2013, several pieces of evidence support the hypothesis that its teratogenicity had been missed in the past. These findings emphasize the need for further investments in global surveillance for emerging infections and for birth defects so that infectious teratogens can be identified more expeditiously in the future.

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African-Lineage Zika Virus Replication Dynamics and Maternal-Fetal Interface Infection in Pregnant Rhesus Macaques

Cited by 29 publications

References 37 publications

KIR3DL05 and KIR3DS02 Recognition of a Nonclassical MHC Class I Molecule in the Rhesus Macaque Implicated in Pregnancy Success

KIR3DL05 and KIR3DS02 Recognition of a Nonclassical MHC Class I Molecule in the Rhesus Macaque Implicated in Pregnancy Success

Fetal loss in pregnant rhesus macaques infected with high-dose African-lineage Zika virus

Zika virus as a cause of birth defects: Were the teratogenic effects of Zika virus missed for decades?

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