Elaina Park

Background: Zika Virus (ZIKV) is a positive enveloped single-stranded RNA flavivirus transmitted via mosquito vector or bodily fluids.^1,2 Vertical transmission is particularly concerning, as ZIKV has been detected in amniotic fluid, fetal brain tissue, and neonatal serum.¹  Infection during pregnancy can cause Congenital Zika Syndrome (CZS), characterized by microcephaly, neurodevelopmental disorders, urinary tract disorders, reduced brain tissue, fetal loss, and preterm birth.^3,4 Since 2007, outbreaks have spread across Pacific islands, Brazil, and Cape Verde, with 87 countries reporting mosquito-vector transmission by 2019 and warnings of potential resurgence.¹ While clinical outcomes of CZS are well-documented, the precise mechanisms by which ZIKV crosses blood barriers remain unknown, limiting therapeutic development. No FDA-approved treatments or vaccines currently exist, and symptoms are managed with acetaminophen and fluids, with NSAIDs contraindicated due to hemorrhagic syndrome risk associated with arboviral infections.¹ Mechanistic research has identified potential pathways for blood barrier crossing, presenting potential therapeutic and early detection developmental opportunities.⁵

Objective: This literature review explores the mechanisms by which ZIKV crosses the blood barriers and causes fetal infection, as well as how those mechanisms could inform potential detection and treatment strategies.

Search Methods: An online search of the PubMed database was conducted using the following search terms: “Zika virus”, “Congenital Zika virus”, and “Zika virus treatment”. Results were refined using filters, selecting for “Full Text”, “Exclude preprints”, and a timeframe of 2019-2026.

Results: ZIKV crosses the placental barrier by degrading tight junction proteins ZO-1 and occludin, while crossing the blood-brain barrier via transcytosis without barrier disruption.⁵ In vitro studies demonstrated that ZIKV-induced trophoblast ER stress downregulates HLA-C and HLA-G, disrupting immune tolerance and triggering decidual NK (dNK) cell-mediated killing.⁶ This response limits vertical transmission but contributes to placental damage and poor fetal outcomes.⁶ NK and CD8 T cells demonstrated protective effects against fetal infection and blocking IL-1 signaling improved placental function and reduced fetal mortality in mice.⁶ In cell culture, first-trimester macaque trophoblast stem cells displayed varying permissiveness to ZIKV infection with strong innate immune responses but minimal cytopathic effects.⁷ Extracellular vesicles from infected cells contained viral proteins and altered cargo, suggesting roles in immune modulation and infection propagation.⁷ Regarding developmental consequences, ZIKV impairs neurogenesis, axon outgrowth, and guidance, causing callosal dysgenesis during congenital infection and development.⁸ As a therapeutic candidate, peptide-porphyrin conjugates (PPCs) successfully crossed both barriers, interfered with ZIKV replication without disrupting barrier integrity, and demonstrated protease resistance.⁴

Conclusion: ZIKV has multiple paths to cross blood barriers, with the innate immune response both limiting vertical transmission and contributing to placental pathology. Congenital infection causes neuroanatomical and neurodevelopmental deficits beyond microcephaly. Understanding the basic mechanisms behind these processes may inform prenatal screening protocols and guide targeted interventions for high-risk pregnancies. Emerging therapeutic targets include: 1) maintaining tight junction integrity by targeting proteasomal degradation; 2) blocking or targeting ER stress; and 3) developing barrier-crossing antivirals like PPCs. Future research should investigate whether PPCs demonstrate similar efficacy in human placental models and determine optimal timing for therapeutic intervention during pregnancy.

Limitations: Referenced mechanistic and therapeutic studies only involved in vitro models and animal studies. Direct translational applicability to humans requires further investigation.

Works Cited:

1. Pielnaa P, Al-Saadawe M, Saro A, et al. Zika virus-spread, epidemiology, genome, transmission cycle, clinical manifestation, associated challenges, vaccine and antiviral drug development. Virology. 2020;543:34-42. doi:10.1016/j.virol.2020.01.015
2. Bhardwaj U, Pandey N, Rastogi M, Singh SK. Gist of Zika Virus pathogenesis. Virology. 2021;560:86-95. doi:10.1016/j.virol.2021.04.008
3. Antoniou E, Orovou E, Andronikidi PE, et al. Congenital Zika Infection and the Risk of Neurodevelopmental, Neurological, and Urinary Track Disorders in Early Childhood. A Systematic Review. Viruses. 2021;13(8):1671. Published 2021 Aug 23. doi:10.3390/v13081671
4. Todorovski T, Mendonça DA, Fernandes-Siqueira LO, et al. Targeting Zika Virus with New Brain- and Placenta-Crossing Peptide-Porphyrin Conjugates. Pharmaceutics. 2022;14(4):738. Published 2022 Mar 29. doi:10.3390/pharmaceutics14040738
5. Chiu CF, Chu LW, Liao IC, et al. The Mechanism of the Zika Virus Crossing the Placental Barrier and the Blood-Brain Barrier. Front Microbiol. 2020;11:214. Published 2020 Feb 20. doi:10.3389/fmicb.2020.00214
6. Sen Santara S, Crespo ÂC, Mulik S, et al. Decidual NK cells kill Zika virus-infected trophoblasts. Proc Natl Acad Sci U S A. 2021;118(47):e2115410118. doi:10.1073/pnas.2115410118
7. Block LN, Schmidt JK, Keuler NS, et al. Zika virus impacts extracellular vesicle composition and cellular gene expression in macaque early gestation trophoblasts. Sci Rep. 2022;12(1):7348. Published 2022 May 5. doi:10.1038/s41598-022-11275-9
8. Christoff RR, Quintanilha JH, Ferreira RO, et al. Congenital Zika Virus Infection Impairs Corpus Callosum Development. Viruses. 2023;15(12):2336. Published 2023 Nov 28. doi:10.3390/v15122336