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. 2021 Sep 20;13(9):1878.
doi: 10.3390/v13091878.

Neonatal Development in Prenatally Zika Virus-Exposed Infant Macaques with Dengue Immunity

Karla Ausderau  1   2 , Sabrina Kabakov  1 , Elaina Razo  3 , Ann M Mitzey  4 , Kathryn M Bach  1 , Chelsea M Crooks  5 , Natalie Dulaney  1 , Logan Keding  4 , Cristhian Salas-Quinchucua  5 , Lex G Medina-Magües  5 , Andrea M Weiler  6 , Mason Bliss  6 , Jens Eickhoff  7 , Heather A Simmons  6 , Andres Mejia  6 , Kathleen M Antony  8 , Terry Morgan  9 , Saverio Capuano 3rd  6 , Mary L Schneider  1 , Matthew T Aliota  10 , Thomas C Friedrich  5   6 , David H O'Connor  6   11 , Thaddeus G Golos  4   6   8 , Emma L Mohr  3
Affiliations

Neonatal Development in Prenatally Zika Virus-Exposed Infant Macaques with Dengue Immunity

Karla Ausderau et al. Viruses. .

Abstract

Infants exposed to Zika virus (ZIKV) prenatally may develop birth defects, developmental deficits, or remain asymptomatic. It is unclear why some infants are more affected than others, although enhancement of maternal ZIKV infection via immunity to an antigenically similar virus, dengue virus (DENV), may play a role. We hypothesized that DENV immunity may worsen prenatal ZIKV infection and developmental deficits in offspring. We utilized a translational macaque model to examine how maternal DENV immunity influences ZIKV-exposed infant macaque neurodevelopment in the first month of life. We inoculated eight macaques with prior DENV infection with ZIKV, five macaques with ZIKV, and four macaques with saline. DENV/ZIKV-exposed infants had significantly worse visual orientation skills than ZIKV-exposed infants whose mothers were DENV-naive, with no differences in motor, sensory or state control development. ZIKV infection characteristics and pregnancy outcomes did not individually differ between dams with and without DENV immunity, but when multiple factors were combined in a multivariate model, maternal DENV immunity combined with ZIKV infection characteristics and pregnancy parameters predicted select developmental outcomes. We demonstrate that maternal DENV immunity exacerbates visual orientation and tracking deficits in ZIKV-exposed infant macaques, suggesting that human studies should evaluate how maternal DENV immunity impacts long-term neurodevelopment.

Keywords: macaque model; maternal DENV infection; neurodevelopment; prenatal ZIKV exposure.

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Conflict of interest statement

D.H.O. is a paid consultant for Battelle, assisting in the design and interpretation of their nonhuman primate ZIKV studies. His relationship does not carry with it any restrictions on publication, and any associated intellectual property will be disclosed and processed according to UW-Madison policy. None of the animals used in this study are involved in any studies with Battelle. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript; or in the decision to publish the results.

Figures

Figure 1
Figure 1
Experimental timeline schema. Female macaques (n = 8) were inoculated with DENV 1–2 months prior to breeding. Around gestational day 45, dams were either inoculated with ZIKV or saline. Blood was drawn daily to measure ZIKV plasma viral loads (*) for 10 days, then twice weekly until viremia cleared, then weekly until delivery by Cesarean section (C-section). Infants had blood drawn for a ZIKV plasma viral load within the first week of life and participated in weekly neurodevelopmental exams (Schneider Neonatal Assessment Protocol; SNAP) weekly (^) for the first month of life. Precise gestational days at inoculation and C-section are noted in Table 1, and average infant ages at developmental testing are noted in Supplementary Table S4.
Figure 2
Figure 2
Neonatal neurodevelopment in the first month of life. Neurodevelopment was measured by the SNAP at 7, 14, 21, and 28 days of life. Scores in the (A) Orientation, (B) Motor Maturity and Activity, (C) Sensory Responsiveness, and (D) State control constructs are illustrated. * = p < 0.05, *** = p < 0.001.
Figure 3
Figure 3
Neonatal neurodevelopment in the orientation domain. Orientation construct was separated into a subgroup analysis of (A) Visual orientation, (B) Visual tracking, (C) Focus, and (D) Auditory orientation. * = p < 0.05, ** = p < 0.01, *** = p < 0.001.
Figure 4
Figure 4
Maternal ZIKV infection characteristics and neutralizing antibody responses. (A) Plasma viremia curves for individual animals, denoted by different lines for each animal. Dashed line is the limit of quantification. (B) Duration of viremia, from the day of inoculation until the last day of a positive plasma viral load (t-test, p-value = 0.4638). (C) Proportion of dams within each group with viremia duration greater or less than 21 days (t-test, p-value = 0.2657). (D) Peak viral plasma loads, defined as the highest plasma vRNA titer (t-test, p-value = 0.4208). (E) DENV PRNT90 on the day of ZIKV inoculation (ZIKV-only animals not tested). (F) ZIKV PRNT90 at 28 days post-ZIKV inoculation (control animals not tested). (G) ZIKV vRNA distribution within the maternal–fetal interface, displayed as the proportion of cotyledons with a positive viral load.
Figure 5
Figure 5
Fetal growth parameter trajectories for ZIKV-exposed, DENV/ZIKV-exposed and control fetuses. Fetal growth parameters throughout gestation were calculated as Z scores relative to age-matched fetal macaque parameters [21] and graphically represented as a linear trajectory. Fetal head circumference growth trajectory is represented in (A), biparietal diameter in (B), femur length in (C), and abdominal circumference in (D).
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