Research Article: Zika Virus Antagonizes Type I Interferon Responses during Infection of Human Dendritic Cells

Date Published: February 2, 2017

Publisher: Public Library of Science

Author(s): James R. Bowen, Kendra M. Quicke, Mohan S. Maddur, Justin T. O’Neal, Circe E. McDonald, Nadia B. Fedorova, Vinita Puri, Reed S. Shabman, Bali Pulendran, Mehul S. Suthar, Ted C. Pierson.

http://doi.org/10.1371/journal.ppat.1006164

Abstract

Zika virus (ZIKV) is an emerging mosquito-borne flavivirus that is causally linked to severe neonatal birth defects, including microcephaly, and is associated with Guillain-Barre syndrome in adults. Dendritic cells (DCs) are an important cell type during infection by multiple mosquito-borne flaviviruses, including dengue virus, West Nile virus, Japanese encephalitis virus, and yellow fever virus. Despite this, the interplay between ZIKV and DCs remains poorly defined. Here, we found human DCs supported productive infection by a contemporary Puerto Rican isolate with considerable variability in viral replication, but not viral binding, between DCs from different donors. Historic isolates from Africa and Asia also infected DCs with distinct viral replication kinetics between strains. African lineage viruses displayed more rapid replication kinetics and infection magnitude as compared to Asian lineage viruses, and uniquely induced cell death. Infection of DCs with both contemporary and historic ZIKV isolates led to minimal up-regulation of T cell co-stimulatory and MHC molecules, along with limited secretion of inflammatory cytokines. Inhibition of type I interferon (IFN) protein translation was observed during ZIKV infection, despite strong induction at the RNA transcript level and up-regulation of other host antiviral proteins. Treatment of human DCs with RIG-I agonist potently restricted ZIKV replication, while type I IFN had only modest effects. Mechanistically, we found all strains of ZIKV antagonized type I IFN-mediated phosphorylation of STAT1 and STAT2. Combined, our findings show that ZIKV subverts DC immunogenicity during infection, in part through evasion of type I IFN responses, but that the RLR signaling pathway is still capable of inducing an antiviral state, and therefore may serve as an antiviral therapeutic target.

Partial Text

Zika virus (ZIKV) is an emerging mosquito-borne flavivirus that is causally linked to severe neonatal birth defects upon congenital infection, including microcephaly and spontaneous abortion [1–5], and is associated with Guillain-Barre syndrome [6] and severe thrombocytopenia [7] in adults. ZIKV was first isolated in Uganda in 1947 from a Rhesus macaque [8] and later isolated from the mosquito Aedes africanus [9]. Phylogenetic analysis has identified three ZIKV lineages, the East African, West African and Asian genotypes, and suggests initial emergence from East Africa and subsequent spread to other regions [10]. Humoral immunity generated against one genotype of ZIKV provides cross-protection against heterologous strains, suggesting the existence of a single ZIKV serotype [11].

In our study, we show a contemporary Puerto Rican ZIKV strain, PR-2015, productively infects human DCs with notable donor variation in viral replication, despite no differences in viral binding. Ancestral ZIKV strains of the African (MR-1947 and Dak-1984) and Asian (P6-1966) lineages also infected human DCs. Each strain exhibited unique viral growth curves, with cell death only observed during infection with African lineage strains. We observed minimal up-regulation of co-stimulatory and MHC molecules, inflammatory cytokine secretion, as well as antagonism of type I IFN translation during ZIKV infection, despite notable transcriptional up-regulation of IFNB1. Despite this, ZIKV infection induced an antiviral state as noted by strong up-regulation of the RLRs (RIG-I, MDA5, and LGP2), STAT proteins (STAT1 and 2), and antiviral effectors (IFIT1, IFIT3, and viperin). Finally, RIG-I agonist treatment potently restricted ZIKV replication, while type I IFN was significantly less effective due to ZIKV antagonism of STAT1 and STAT2 phosphorylation.

 

Source:

http://doi.org/10.1371/journal.ppat.1006164

 

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