Explore the vast range of titles available.

tRNA modifications are crucial for efficient protein synthesis, impacting codon recognition, tRNA stability, and translation rates. RNA viruses hijack the host’s translational machinery, including the pool of modified tRNA, to translate their own genomes. However, the mismatch between viral and host codon usage can lead to a limited availability of specific tRNA leading to ribosome stalling, posing a significant challenge for efficient protein translation. While some viruses address this challenge through codon optimization, we show here that SARS-CoV-2 (Coronavirus) and the Zika virus (ZIKV; Flavivirus) adopt a different approach, manipulating the host tRNA epitranscriptome. Analysis of codon bias indices confirmed a substantial divergence between viral and host codon usage, revealing a strong preference in viral genes for codons decoded by tRNAs requiring U34 wobble modification. Monitoring tRNA modification dynamics in infected cells showed that both SARS-CoV2 and ZIKV enhance U34 tRNA modifications during infection. Strikingly, impairing U34 tRNAs profoundly impacted viral replication, underscoring the strict reliance of SARS-CoV-2 and ZIKV on manipulating the host tRNA epitranscriptome to support the efficient translation of their genome.

The global emergence of Zika virus (ZIKV) revealed the unprecedented ability for a mosquito-borne virus to cause congenital birth defects. A puzzling aspect of ZIKV emergence is that all human outbreaks and birth defects to date have been exclusively associated with the Asian ZIKV lineage, despite a growing body of laboratory evidence pointing towards higher transmissibility and pathogenicity of the African ZIKV lineage. Whether this apparent paradox reflects the use of relatively old African ZIKV strains in most laboratory studies is unclear. Here, we experimentally compare seven low-passage ZIKV strains representing the recently circulating viral genetic diversity. We find that recent African ZIKV strains display higher transmissibility in mosquitoes and higher lethality in both adult and fetal mice than their Asian counterparts. We emphasize the high epidemic potential of African ZIKV strains and suggest that they could more easily go unnoticed by public health surveillance systems than Asian strains due to their propensity to cause fetal loss rather than birth defects. Here, the authors compare seven low passage Zika virus (ZIKV) strains representing the recently circulating viral genetic diversity of African and Asian strains and find that African ZIKV strains have higher transmissibility in mosquitoes and higher lethality in both adult and fetal mice.

Virus–host interactions determine an infection outcome. The Asian lineage of Zika virus (ZIKV), responsible for the recent epidemics, has fixed a mutation in the NS1 gene after 2012 that enhances mosquito infection. Here we report that the same mutation confers NS1 to inhibit interferon-β induction. This mutation enables NS1 binding to TBK1 and reduces TBK1 phosphorylation. Engineering the mutation into a pre-epidemic ZIKV strain debilitates the virus for interferon-β induction; reversing the mutation in an epidemic ZIKV strain invigorates the virus for interferon-β induction; these mutational effects are lost in IRF3-knockout cells. Additionally, ZIKV NS2A, NS2B, NS4A, NS4B, and NS5 can also suppress interferon-β production through targeting distinct components of the RIG-I pathway; however, for these proteins, no antagonistic difference is observed among various ZIKV strains. Our results support the mechanism that ZIKV has accumulated mutation(s) that increases the ability to evade immune response and potentiates infection and epidemics. The Asian lineage of Zika virus (ZIKV) has acquired a mutation in NS1 that enhances mosquito infection. Here, Xia et al. show that the same mutation interferes with interferon production through interaction with TBK1 and affects ZIKV replication in mice.

The 2015–2016 Zika virus (ZIKV) outbreak in the Americas revealed the ability of ZIKV from the Asian lineage to cause birth defects, generically called congenital Zika syndrome (CZS). Notwithstanding the long circulation history of Asian ZIKV, no ZIKV-associated CZS cases were reported prior to the outbreaks in French Polynesia (2013) and Brazil (2015). Whether the sudden emergence of CZS resulted from an evolutionary event of Asian ZIKV has remained unclear. We performed a comparative analysis of the pathogenicity of pre-epidemic and epidemic Asian ZIKV strains in mouse embryonic brains using a female immunocompetent intraplacental infection mouse model. All studied Asian ZIKV strains are neurovirulent, but pre-epidemic strains are consistently more pathogenic in the embryos than their epidemic equivalents. Pathogenicity is not directly linked to viral replication. By contrast, an influx of macrophages/microglial cells is noted in infected fetal brains for both pre-epidemic and epidemic ZIKV strains. Moreover, all tested ZIKV strains trigger an immunological response, whereby the intensity of the response differs between strains, and with epidemic ZIKV strains generally mounting a more attenuated immunostimulatory response. Our study reveals that Asian ZIKV strains evolved towards pathogenic attenuation, potentially resulting in CZS emergence in neonates rather than premature death in utero. During the 2015–2016 outbreak, Zika virus infection was linked to birth defects. Here, the authors show that epidemic strains cause less severe disease in mouse embryos than pre-epidemic strains and conclude that less severe disease leads to higher fetal survival rates but results in noticeable birth defects.

Recent Zika virus (ZIKV) outbreaks have highlighted the necessity for development of novel vector control strategies to combat arboviral transmission, including genetic versions of the sterile insect technique, artificial infection with Wolbachia to reduce population size and/or vectoring competency, and gene drive-based methods. Here, we describe the development of mosquitoes synthetically engineered to impede vector competence to ZIKV. We demonstrate that a polycistronic cluster of engineered synthetic small RNAs targeting ZIKV is expressed and fully processed in Aedes aegypti, ensuring the formation of mature synthetic small RNAs in the midgut where ZIKV resides in the early stages of infection. Critically, we demonstrate that engineered Ae. aegypti mosquitoes harboring the anti-ZIKV transgene have significantly reduced viral infection, dissemination, and transmission rates of ZIKV. Taken together, these compelling results provide a promising path forward for development of effective genetic-based ZIKV control strategies, which could potentially be extended to curtail other arboviruses.

Zika virus infection of pregnant nonhuman primates results in the loss of fetal neuronal progenitor cells, even in the absence of overt microcephaly. Zika virus (ZIKV) is a flavivirus with teratogenic effects on fetal brain, but the spectrum of ZIKV-induced brain injury is unknown, particularly when ultrasound imaging is normal. In a pregnant pigtail macaque ( Macaca nemestrina ) model of ZIKV infection, we demonstrate that ZIKV-induced injury to fetal brain is substantial, even in the absence of microcephaly, and may be challenging to detect in a clinical setting. A common and subtle injury pattern was identified, including (i) periventricular T2-hyperintense foci and loss of fetal noncortical brain volume, (ii) injury to the ependymal epithelium with underlying gliosis and (iii) loss of late fetal neuronal progenitor cells in the subventricular zone (temporal cortex) and subgranular zone (dentate gyrus, hippocampus) with dysmorphic granule neuron patterning. Attenuation of fetal neurogenic output demonstrates potentially considerable teratogenic effects of congenital ZIKV infection even without microcephaly. Our findings suggest that all children exposed to ZIKV in utero should receive long-term monitoring for neurocognitive deficits, regardless of head size at birth.

Flaviviruses, including Zika virus (ZIKV), utilise host mRNA degradation machinery to produce subgenomic flaviviral RNA (sfRNA). In mammalian hosts, this noncoding RNA facilitates replication and pathogenesis of flaviviruses by inhibiting IFN-signalling, whereas the function of sfRNA in mosquitoes remains largely elusive. Herein, we conduct a series of in vitro and in vivo experiments to define the role of ZIKV sfRNA in infected Aedes aegypti employing viruses deficient in production of sfRNA. We show that sfRNA-deficient viruses have reduced ability to disseminate and reach saliva, thus implicating the role for sfRNA in productive infection and transmission. We also demonstrate that production of sfRNA alters the expression of mosquito genes related to cell death pathways, and prevents apoptosis in mosquito tissues. Inhibition of apoptosis restored replication and transmission of sfRNA-deficient mutants. Hence, we propose anti-apoptotic activity of sfRNA as the mechanism defining its role in ZIKV transmission. The function on subgenomic flaviviral RNA (sfRNA) in the mosquito vector is not well understood. Here, Slonchak et al. show that sfRNA affects virus-induced apoptosis and dissemination of ZIKV in Aedes aegypti mosquitoes, suggesting a role of sfRNA in Zika virus replication and transmission.

Zika virus (ZIKV) infection can be associated with neurological pathologies, such as microcephaly in newborns and Guillain-Barre syndrome in adults. Effective therapeutics are currently not available. As such, a comprehensive understanding of virus-host interactions may guide the development of medications for ZIKV. Here we report a human genome-wide overexpression screen to identify host factors that regulate ZIKV infection and find TMEM120A as a ZIKV restriction factor. TMEM120A overexpression significantly inhibits ZIKV replication, while TMEM120A knockdown increases ZIKV infection in cell lines. Moreover, Tmem120a knockout in mice facilitates ZIKV infection in primary mouse embryonic fibroblasts (MEF) cells. Mechanistically, the antiviral activity of TMEM120A is dependent on STING, as TMEM120A interacts with STING, promotes the translocation of STING from the endoplasmic reticulum (ER) to ER-Golgi intermediate compartment (ERGIC) and enhances the phosphorylation of downstream TBK1 and IRF3, resulting in the expression of multiple antiviral cytokines and interferon-stimulated genes. In summary, our gain-of-function screening identifies TMEM120A as a key activator of the antiviral signaling of STING. Understanding the interplay between host and viral factors during infection is essential for the interactome of infection. Here the authors perform a gain-of-function screen to identify factors involved during Zika virus infection and identify TMEM120A as a key factor in the STING mediated immune responses.

In December, 2015, the first imported case of Zika virus (ZIKV) infection was diagnosed in French Guiana in a group of 136 travellers returning from Suriname. No autochthonous cases had been detected in French Guiana at that time. To prevent secondary cases, we systematically screened co-travellers 1, 10, and 30 days after their return (clinical examination, urine samples, and blood samples).

Viral cerebritis can disrupt cerebral embryogenesis and result in microcephaly and other neurological abnormalities.2 Zika virus has been isolated from the brains and cerebrospinal fluid of neonates born with congenital microcephaly and identified in the placental tissue of mothers who had had clinical symptoms consistent with Zika virus infection during their pregnancies.3-5 The spatiotemporal association of cases of microcephaly with the Zika virus outbreak and the evidence emerging from case reports and epidemiologic studies, has led to a strong scientific consensus that Zika virus is implicated in congenital abnormalities.6,7 Existing evidence and unpublished data shared with WHO highlight the wider range of congenital abnormalities probably associated with the acquisition of Zika virus infection in utero. With such spread, it is possible that many thousands of infants will incur moderate to severe neurological disabilities. [...]routine surveillance systems and research protocols need to include a larger population than simply children with microcephaly.