Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2024 Feb 15;13(2):177.
doi: 10.3390/pathogens13020177.

Zika Virus-A Reemerging Neurotropic Arbovirus Associated with Adverse Pregnancy Outcomes and Neuropathogenesis

Kenneth C Elliott  1   2 , Joseph J Mattapallil  2
Affiliations
Review

Zika Virus-A Reemerging Neurotropic Arbovirus Associated with Adverse Pregnancy Outcomes and Neuropathogenesis

Kenneth C Elliott et al. Pathogens. .

Abstract

Zika virus (ZIKV) is a reemerging flavivirus that is primarily spread through bites from infected mosquitos. It was first discovered in 1947 in sentinel monkeys in Uganda and has since been the cause of several outbreaks, primarily in tropical and subtropical areas. Unlike earlier outbreaks, the 2015-2016 epidemic in Brazil was characterized by the emergence of neurovirulent strains of ZIKV strains that could be sexually and perinatally transmitted, leading to the Congenital Zika Syndrome (CZS) in newborns, and Guillain-Barre Syndrome (GBS) along with encephalitis and meningitis in adults. The immune response elicited by ZIKV infection is highly effective and characterized by the induction of both ZIKV-specific neutralizing antibodies and robust effector CD8+ T cell responses. However, the structural similarities between ZIKV and Dengue virus (DENV) lead to the induction of cross-reactive immune responses that could potentially enhance subsequent DENV infection, which imposes a constraint on the development of a highly efficacious ZIKV vaccine. The isolation and characterization of antibodies capable of cross-neutralizing both ZIKV and DENV along with cross-reactive CD8+ T cell responses suggest that vaccine immunogens can be designed to overcome these constraints. Here we review the structural characteristics of ZIKV along with the evidence of neuropathogenesis associated with ZIKV infection and the complex nature of the immune response that is elicited by ZIKV infection.

Keywords: ADE; CZS; Dengue; Zika; cross-neutralization; neuropathology; pregnancy.

PubMed Disclaimer

Conflict of interest statement

The authors declare no conflicts of interest.

Figures

Figure 1
Figure 1
Cartoon structure of ZIKV and DENV particle and genome map. Zika virus and Dengue virus are members of the Flaviviridae family, containing a positive sense, single stranded ~10.5kb RNA genome. (a) ZIKV and DENV virions are enveloped and consist of three structural proteins, namely capsid (C), membrane (M), and envelope (E) proteins. Capsid proteins make up the icosahedral nucleocapsid that surrounds the genomic material. The M protein is only expressed on mature virions, it contains transmembrane regions, and is organized as a heterodimer underneath the E protein. The E protein contains the primary antigenic targets and is responsible for viral entry and assembly. (b) The genome encodes 3 structural genes (C, prM, E) and 7 nonstructural genes (NS1, NS2A, NS2B, NS3, NS4A, NS4B, NS5). NS2A assists with virion assembly through recruitment of the NS2BNS3 protease. NS2B dimerizes with NS3 to act as a protease and cleave the viral polypeptide.
Figure 2
Figure 2
Innate and adaptive immune response to ZIKV infection. (a) ZIKV infects target cells through receptor-mediated endocytosis and replicates in the cytoplasm. Replication intermediates such as single stranded and double stranded RNA are sensed by pathogen recognition receptors such as NLRP3, MDA5, TLR3, and RIG-I, which drives the activation and phosphorylation of IRF3 and IRF7, which translocate to the nucleus and drive the production of Type I IFNs. These Type I IFNs will be exported from the cell and interact with receptors on neighboring cells, leading to the phosphorylation and activation of the JAK/STAT pathway. Activation and phosphorylation of the JAK/STAT pathway leads to the recruitment of IRF9, which will translocate to the nucleus and bind to the Interferon Stimulated Response Element (ISRE), leading to the transcription of over 100 interferon stimulated genes (ISG) that induce an antiviral state. (b) Adaptive immune responses are characterized by the activation of ZIKV-specific CD8 cytotoxic T cells that recognize epitopes in the context of MHC Class I and eliminate infected cells through the release of the perforin and Granzyme B. ZIKV-specific CD8 T cell responses have been shown to recognize epitopes located within the prM, E, NS3, and NS5 proteins. ZIKV-specific adaptive B cell responses have been mapped to a number of proteins with neutralizing antibody responses primarily targeting the EDIII domain along with the E dimer epitope.
Figure 3
Figure 3
Sequence similarity between ZIKV and DENV E and NS1 proteins. (a) Phylogenetic tree and heat map showing the relatedness of ZIKV and DENV-1—4 E protein based on amino acid alignment. The NCBI Virus database [159] (https://www.ncbi.nlm.nih.gov/labs/virus/vssi/#/ accessed on 30 October 2023) was used to download the reference sequences for E proteins of ZIKV and DENV-1—4. The sequences were then aligned using the online Clustal Omega Multiple Sequence Alignment (MSA) Tool [160] (https://www.ebi.ac.uk/Tools/msa/clustalo/ accessed on 30 October 2023). The resulting output was then pasted into the online “Simple Phylogeny” tool [160] https://www.ebi.ac.uk/Tools/phylogeny/simple_phylogeny/ accessed on 30 October 2023). The phylogenic tree was then uploaded to iTOL [161] (https://itol.embl.de/ accessed on 30 October 2023) for visual enhancement and scaling. A heat map for amino acid identity was created from the Clustal Omega MSA. (b) Phylogenetic tree and heat map showing the relatedness of ZIKV and DENV-1–4 NS1 protein based on amino acid alignment. The NCBI Virus database [159] (https://www.ncbi.nlm.nih.gov/labs/virus/vssi/#/ accessed on 30 October 2023) was used to download the reference sequences for the NS1 proteins of ZIKV and DENV-2–4; no reference sequence was available for DENV-1 NS1. As such, the exact similarity between ZIKV NS1 and DENV1 is not available. The sequences were then aligned using the online Clustal Omega Multiple Sequence Alignment Tool [160] (https://www.ebi.ac.uk/Tools/msa/clustalo/ accessed on 30 October 2023). The resulting output was then pasted into the online “Simple Phylogeny” tool [160] (https://www.ebi.ac.uk/Tools/phylogeny/simple_phylogeny/ accessed on 30 October 2023). The phylogenetic tree was then uploaded to iTOL [161] (https://itol.embl.de/ accessed on 30 October 2023) for visual enhancement and scaling. The heat map for amino acid identity was created from the Clustal Omega MSA using Excel.
See this image and copyright information in PMC

Similar articles

See all similar articles

References

    1. Dick G.W., Kitchen S.F., Haddow A.J. Zika virus. I. Isolations and serological specificity. Trans. R. Soc. Trop. Med. Hyg. 1952;46:509–520. doi: 10.1016/0035-9203(52)90042-4. - DOI - PubMed
    1. Dick G.W. Epidemiological notes on some viruses isolated in Uganda; Yellow fever, Rift Valley fever, Bwamba fever, West Nile, Mengo, Semliki forest, Bunyamwera, Ntaya, Uganda S and Zika viruses. Trans. R. Soc. Trop. Med. Hyg. 1953;47:13–48. doi: 10.1016/0035-9203(53)90021-2. - DOI - PubMed
    1. Smithburn K.C., Kerr J.A., Gatne P.B. Neutralizing antibodies against certain viruses in the sera of residents of India. J. Immunol. 1954;72:248–257. doi: 10.4049/jimmunol.72.4.248. - DOI - PubMed
    1. Duffy M.R., Chen T.H., Hancock W.T., Powers A.M., Kool J.L., Lanciotti R.S., Pretrick M., Marfel M., Holzbauer S., Dubray C., et al. Zika virus outbreak on Yap Island, Federated States of Micronesia. N. Engl. J. Med. 2009;360:2536–2543. doi: 10.1056/NEJMoa0805715. - DOI - PubMed
    1. Buathong R., Hermann L., Thaisomboonsuk B., Rutvisuttinunt W., Klungthong C., Chinnawirotpisan P., Manasatienkij W., Nisalak A., Fernandez S., Yoon I.K., et al. Detection of Zika Virus Infection in Thailand, 2012–2014. Am. J. Trop. Med. Hyg. 2015;93:380–383. doi: 10.4269/ajtmh.15-0022. - DOI - PMC - PubMed

Grants and funding

This research had no external funding.
-