Sustained Microglial Activation Promotes Synaptic Loss and Neuronal Dysfunction after Recovery from ZIKV Infection.

Zika virus (ZIKV), transmitted by Aedes mosquitoes, has been a global health concern since 2007. It primarily causes fetal microcephaly and neuronal defects through maternal transmission and induces neurological complications in adults. Recent studies report elevated proinflammatory cytokines and persistent neurological alterations post recovery, but the in vivo mechanisms remain unclear. In our study, viral RNA loads in the brains of mice infected with ZIKV peaked at 7 days post infection and returned to baseline by day 21, indicating recovery. RNA sequencing of the cerebral cortex at 7 and 21 days revealed upregulated genes related to neuroinflammation and microglial activation. Histological analyses indicated neuronal cell death and altered neurite morphology owing to severe neuroinflammation. Additionally, sustained microglial activation was associated with increased phospho-Tau levels, constituting a marker of neurodegeneration. These findings highlight how persistent microglial activation leads to neuronal dysfunction post ZIKV recovery, providing insights into the molecular pathogenesis of ZIKV-induced brain abnormalities.

Zika virus vertical transmission induces neuroinflammation and synapse impairment in brain cells derived from children born with Congenital Zika Syndrome.

Zika virus (ZIKV) infection was first reported in 2015 in Brazil as causing microcephaly and other developmental abnormalities in newborns, leading to the identification of Congenital Zika Syndrome (CZS). Viral infections have been considered an environmental risk factor for neurodevelopmental disorders outcome, such as Autism Spectrum Disorder (ASD). Moreover, not only the infection per se, but maternal immune system activation during pregnancy, has been linked to fetal neurodevelopmental disorders. To understand the impact of ZIKV vertical infection on brain development, we derived induced pluripotent stem cells (iPSC) from Brazilian children born with CZS, some of the patients also being diagnosed with ASD. Comparing iPSC-derived neurons from CZS with a control group, we found lower levels of pre- and postsynaptic proteins and reduced functional synapses by puncta co-localization. Furthermore, neurons and astrocytes derived from the CZS group showed decreased glutamate levels. Additionally, the CZS group exhibited elevated levels of cytokine production, one of which being IL-6, already associated with the ASD phenotype. These preliminary findings suggest that ZIKV vertical infection may cause long-lasting disruptions in brain development during fetal stages, even in the absence of the virus after birth. These disruptions could contribute to neurodevelopmental disorders manifestations such as ASD. Our study contributes with novel knowledge of the CZS outcomes and paves the way for clinical validation and the development of potential interventions to mitigate the impact of ZIKV vertical infection on neurodevelopment.

Integrative analysis of molecular pathways and morphological anomalies associated with congenital Zika syndrome.

Congenital Zika syndrome (CZS) comprises a set of clinical manifestations that can be presented by neonates born to mothers infected by the Zika virus (ZIKV). CZS-associated phenotypes include neurological, skeletal, and systemic alterations and long-term developmental sequelae. One of the most frequently reported clinical conditions is microcephaly characterized by a reduction in head circumference and cognitive complications. Nevertheless, the associations among the diverse signaling pathways underlying CZS phenotypes remain to be elucidated. To shed light on CZS, we have extensively reviewed the morphological anomalies resulting from ZIKV infection, as well as genes and proteins of interest obtained from the published literature. With this list of genes or proteins, we performed computational analyses to explore the cellular processes, molecular mechanisms, and molecular pathways related to ZIKV infection. Therefore, in this review, we comprehensively describe the morphological abnormalities caused by congenital ZIKV infection and, through the analysis noted above, propose common molecular pathways altered by ZIKV that could explain both central nervous system and craniofacial skeletal alterations.

Neurovirulence of Usutu virus in human fetal organotypic brain slice cultures partially resembles Zika and West Nile virus.

Usutu (USUV), West Nile (WNV), and Zika virus (ZIKV) are neurotropic arthropod-borne viruses (arboviruses) that cause severe neurological disease in humans. However, USUV-associated neurological disease is rare, suggesting a block in entry to or infection of the brain. We determined the replication, cell tropism and neurovirulence of these arboviruses in human brain tissue using a well-characterized human fetal organotypic brain slice culture model. Furthermore, we assessed the efficacy of interferon-ß and 2'C-methyl-cytidine, a synthetic nucleoside analogue, in restricting viral replication. All three arboviruses replicated within the brain slices, with WNV reaching the highest titers, and all primarily infected neuronal cells. USUV- and WNV-infected cells exhibited a shrunken morphology, not associated with detectable cell death. Pre-treatment with interferon-ß inhibited replication of all arboviruses, while 2'C-methyl-cytidine reduced only USUV and ZIKV titers. Collectively, USUV can infect human brain tissue, showing similarities in tropism and neurovirulence as WNV and ZIKV. These data suggest that a blockade to infection of the human brain may not be the explanation for the low clinical incidence of USUV-associated neurological disease. However, USUV replicated more slowly and to lower titers than WNV, which could help to explain the reduced severity of neurological disease resulting from USUV infection.

The inoculum dose of Zika virus can affect the viral replication dynamics, cytokine responses and survival rate in immunocompromised AG129 mice.

Zika virus, a mosquito-borne arbovirus, has repeatedly caused large pandemics with symptoms worsening from mild and self-limiting diseases to Guillain-Barré syndrome in adults and fetal microcephaly in newborns. In recent years, Zika virus diseases have posed a serious threat to human health. The shortage of susceptible small animal models makes it difficult to study pathogenic mechanisms and evaluate potential therapies for Zika virus infection. Therefore, we chose immunocompromised mice (AG129 mice) deficient in IFN-α/ß and IFN-γ receptors, which can abolish the innate immune system that prevents Zika virus infection early. AG129 mice were infected with the Zika virus, and this mouse model exhibited replication dynamics, tissue tropism, pathological lesion and immune activation of the Zika virus. Our results suggest that the inoculum dose of Zika virus can affect the viral replication dynamics, cytokine responses and survival rate in AG129 mice. By testing the potential antiviral drug favipiravir, several critical indicators, including replication dynamics and survival rates, were identified in AG129 mice after Zika virus infection. It is suggested that the model is reliable for drug evaluation. In brief, this model provides a potential platform for studies of the infectivity, virulence, and pathogenesis of the Zika virus. Moreover, the development of an accessible mouse model of Zika virus infection will expedite the research and deployment of therapeutics and vaccines.

[The viral protein NS1: a major player in the pathogenesis of orthoflaviviruses]. / La protéine virale NS1 : un acteur majeur de la pathogenèse des orthoflavivirus.

Orthoflaviviruses are enveloped positive-sense RNA viruses comprising numerous human pathogens transmitted by hematophagous arthropods. This includes viruses such as dengue virus, Zika virus, and yellow fever virus. The viral nonstructural protein NS1 plays a central role in the pathogenesis and cycle of these viruses by acting in two different forms: associated with the plasma membrane (NS1m) or secreted outside the cell (NS1s). The versatility of NS1 is evident in its ability to modulate various aspects of the infectious process, from immune evasion to pathogenesis. As an intracellular protein, it disrupts many processes, interfering with signaling pathways and facilitating viral replication in concert with other viral proteins. As a secreted protein, NS1 actively participates in immune evasion, interfering with the host immune system, inhibiting the complement system, facilitating viral dissemination, and disrupting the integrity of endothelial barriers. This review primarily aims to address the role of NS1 in viral pathogenesis associated with orthoflaviviruses.

Disruption of myelin structure and oligodendrocyte maturation in a macaque model of congenital Zika infection.

Zika virus (ZikV) infection during pregnancy can cause congenital Zika syndrome (CZS) and neurodevelopmental delay in infants, of which the pathogenesis remains poorly understood. We utilize an established female pigtail macaque maternal-to-fetal ZikV infection/exposure model to study fetal brain pathophysiology of CZS manifesting from ZikV exposure in utero. We find prenatal ZikV exposure leads to profound disruption of fetal myelin, with extensive downregulation in gene expression for key components of oligodendrocyte maturation and myelin production. Immunohistochemical analyses reveal marked decreases in myelin basic protein intensity and myelinated fiber density in ZikV-exposed animals. At the ultrastructural level, the myelin sheath in ZikV-exposed animals shows multi-focal decompaction, occurring concomitant with dysregulation of oligodendrocyte gene expression and maturation. These findings define fetal neuropathological profiles of ZikV-linked brain injury underlying CZS resulting from ZikV exposure in utero. Because myelin is critical for cortical development, ZikV-related perturbations in oligodendrocyte function may have long-term consequences on childhood neurodevelopment, even in the absence of overt microcephaly.

Exposure to Zika and chikungunya viruses impacts aspects of the vectorial capacity of Aedes aegypti and Culex quinquefasciatus.

Zika (ZIKV) and chikungunya (CHIKV) are arboviruses that cause infections in humans and can cause clinical complications, representing a worldwide public health problem. Aedes aegypti is the primary vector of these pathogens and Culex quinquefasciatus may be a potential ZIKV vector. This study aimed to evaluate fecundity, fertility, survival, longevity, and blood feeding activity in Ae. aegypti after exposure to ZIKV and CHIKV and, in Cx. quinquefasciatus exposed to ZIKV. Three colonies were evaluated: AeCamp (Ae. aegypti-field), RecL (Ae. aegypti-laboratory) and CqSLab (Cx. quinquefasciatus-laboratory). Seven to 10 days-old females from these colonies were exposed to artificial blood feeding with CHIKV or ZIKV. CHIKV caused reduction in fecundity and fertility in AeCamp and reduction in survival and fertility in RecL. ZIKV impacted survival in RecL, fertility in AeCamp and, fecundity and fertility in CqSLab. Both viruses had no effect on blood feeding activity. These results show that CHIKV produces a higher biological cost in Ae. aegypti, compared to ZIKV, and ZIKV differently alters the biological performance in colonies of Ae. aegypti and Cx. quinquefasciatus. These results provide a better understanding over the processes of virus-vector interaction and can shed light on the complexity of arbovirus transmission.

Gain without pain: adaptation and increased virulence of Zika virus in vertebrate host without fitness cost in mosquito vector.

IMPORTANCE: Previously, we modeled direct transmission chains of Zika virus (ZIKV) by serially passaging ZIKV in mice and mosquitoes and found that direct mouse transmission chains selected for viruses with increased virulence in mice and the acquisition of non-synonymous amino acid substitutions. Here, we show that these same mouse-passaged viruses also maintain fitness and transmission capacity in mosquitoes. We used infectious clone-derived viruses to demonstrate that the substitution in nonstructural protein 4A contributes to increased virulence in mice.

Transcriptomic reveals the ferroptosis features of host response in a mouse model of Zika virus infection.

Zika virus (ZIKV) is a neurotropic flavivirus. The outbreak of ZIKV in 2016 created a global health emergency. However, the underlying pathogenic mechanisms remain elusive. We investigated the host response features of in vivo replication in a mouse model of ZIKV infection, by performing a series of transcriptomic and bioinformatic analyses of ZIKV and mock-infected brain tissue. Tissue damage, inflammatory cells infiltration and high viral replication were observed in the brain tissue of ZIKV infected mice. RNA-Seq of the brain indicated the activation of ferroptosis pathways. Enrichment analysis of ferroptosis regulators revealed their involvement in pathways such as mineral absorption, fatty acid biosynthesis, fatty acid degradation, PPAR signaling pathway, peroxidase, and adipokinesine signalling pathway. We then identified 12 interacted hub ferroptosis regulators (CYBB, HMOX1, CP, SAT1, TF, SLC39A14, FTL, LPCAT3, FTH1, SLC3A2, TP53, and SLC40A1) that were related to the differential expression of CD8+ T cells, microglia and monocytes. CYBB, HMOX1, SALT, and SLAC40A1 were selected as potential biomarkers of ZIKV infection. Finally, we validated our results using RT-qPCR and outside available datasets. For the first time, we proposed a possible mechanism of ferroptosis in brain tissue infected by ZIKV in mice and identified the four key ferroptosis regulators.

Os sentidos produzidos por cuidadoras escolares de crianças com SCZV / Los sentidos producidos por cuidadores escolares de niños con SCZV / The senses produced by school caregivers of children with SCZV

RESUMO. Este estudo, fundamentado na perspectiva da psicologia cultural-histórica sobre a pessoa com deficiência, teve por objetivo apreender a dimensão subjetiva da realidade (ou as mediações) das crianças com a Síndrome Congênita do Zika Vírus (SCZV) no contexto escolar de desenvolvimento e aprendizagem a partir dos sentidos produzidos por cuidadoras escolares. Para tal, foram realizadas entrevistas semiestruturadas com três cuidadoras escolares que trabalham em três creches pertencentes ao sistema de educação de ensino de Campina Grande/PB. Para análise dos dados, foi realizado o procedimento dos Núcleos de Significação, que visa à apreensão das contradições que constituem as produções de significação discursiva dos sujeitos participantes. Os resultados indicaram que as cuidadoras escolares priorizam a mediação pedagógica na relação estabelecida com as crianças com SCZV, embora não desconsiderem a instância do cuidado em termos das necessidades especiais relacionadas à integridade psicomotora que essas crianças apresentam. Ademais, foi evidenciado que as participantes salientam as potencialidades das crianças em detrimento da falta ou lesão gerada pela deficiência.

RESUMEN. Este estudio, basado en la perspectiva de la psicología cultural-histórica sobre las personas con discapacidad, tenía como objetivo apreciar la dimensión subjetiva de la realidad de los niños con Síndrome Congénito del Virus del Zika (SCVZ). en el contexto escolar del desarrollo y el aprendizaje de los significados producidos por los cuidadores escolares. Para ello, se realizaron entrevistas semiestructuradas con tres cuidadores escolares de guarderías diferentes que pertenecen al sistema educativo de Campina Grande/PB. Para el análisis de datos, se realizó el procedimiento de los núcleos de significación, cuyo objetivo es aprehender las contradicciones que constituyen las producciones de significado discursiva de los participantes. Los resultados indicaron que los cuidadores de la escuela dan prioridad a la mediación pedagógica en la relación establecida con los niños con SCVZ, aunque no descuidan la instancia de cuidado en cuanto a las necesidades especiales relacionadas con la integridad psicomotora que tienen estos niños. Además, se destacó que los participantes ponen de relieve el potencial de los niños en detrimento de la falta o lesión generada por la discapacidad.

ABSTRACT This study is based by the perspective of the cultural-historical psychology on people with disabilities, aimed to apprehend the subjective dimension of the reality (or mediations) of children with Congenital Zika Virus Syndrome (CZVS) on the school context development and learning from the senses produced by school children caregivers. For this reason, semi-structured interviews were conducted with three caregivers working in three daycare centers belonging to the teaching system of education in Campina Grande/PB. For data analysis, was performed the meaning core, which aims to apprehend the contradictions that constitute the productions of discursive meaning in the participating subjects. The results indicated that school caregivers prioritize the mediation in the relationship established with children CZVS, though not disregard the instance of care in terms of the special needs related to psychomotor integrity that these children have. Furthermore, it was evidenced that the participants emphasize the children's potentialities to the detriment of the lack or injury generated by the disability.

Pathogenicity and Structural Basis of Zika Variants with Glycan Loop Deletions in the Envelope Protein.

The glycan loop of Zika virus (ZIKV) envelope protein (E) contains the glycosylation site and has been well documented to be important for viral pathogenesis and transmission. In the present study, we report that deletions in the E glycan loop, which were recorded in African ZIKV strains previously, have re-emerged in their contemporary Asian lineages. Here, we generated recombinant ZIKV containing specific deletions in the E glycan loop by reverse genetics. Extensive in vitro and in vivo characterization of these deletion mutants demonstrated an attenuated phenotype in an adult A129 mouse model and reduced oral infections in mosquitoes. Surprisingly, these glycan loop deletion mutants exhibited an enhanced neurovirulence phenotype, and resulted in a more severe microcephalic brain in neonatal mouse models. Crystal structures of the ZIKV E protein and a deletion mutant at 2.5 and 2.6 Å, respectively, revealed that deletion of the glycan loop induces encephalitic flavivirus-like conformational alterations, including the appearance of perforations on the surface and a clear change in the topology of the loops. Overall, our results demonstrate that the E glycan loop deletions represent neonatal mouse neurovirulence markers of ZIKV. IMPORTANCE Zika virus (ZIKV) has been identified as a cause of microcephaly and acquired evolutionary mutations since its discovery. Previously deletions in the E glycan loop were recorded in African ZIKV strains, which have re-emerged in the contemporary Asian lineages recently. The glycan loop deletion mutants are not glycosylated, which are attenuated in adult A129 mouse model and reduced oral infections in mosquitoes. More importantly, the glycan loop deletion mutants induce an encephalitic flavivirus-like conformational alteration in the E homodimer, resulting in a significant enhancement of neonatal mouse neurovirulence. This study underscores the critical role of glycan loop deletion mutants in ZIKV pathogenesis, highlighting a need for global virological surveillance for such ZIKV variants.

Zika virus causes placental pyroptosis and associated adverse fetal outcomes by activating GSDME.

Zika virus (ZIKV) can be transmitted from mother to fetus during pregnancy, causing adverse fetal outcomes. Several studies have indicated that ZIKV can damage the fetal brain directly; however, whether the ZIKV-induced maternal placental injury contributes to adverse fetal outcomes is sparsely defined. Here, we demonstrated that ZIKV causes the pyroptosis of placental cells by activating the executor gasdermin E (GSDME) in vitro and in vivo. Mechanistically, TNF-α release is induced upon the recognition of viral genomic RNA by RIG-I, followed by activation of caspase-8 and caspase-3 to ultimately escalate the GSDME cleavage. Further analyses revealed that the ablation of GSDME or treatment with TNF-α receptor antagonist in ZIKV-infected pregnant mice attenuates placental pyroptosis, which consequently confers protection against adverse fetal outcomes. In conclusion, our study unveils a novel mechanism of ZIKV-induced adverse fetal outcomes via causing placental cell pyroptosis, which provides new clues for developing therapies for ZIKV-associated diseases.

A Reverse Mutation E143K within the PrM Protein of Zika Virus Asian Lineage Natal RGN Strain Increases Infectivity and Cytopathicity.

Zika virus (ZIKV) is a positive-sense single-stranded RNA virus in the Flaviviridae, which is classified into two different lineages Asian and African. The outbreak of ZIKV Asian lineage isolates in 2015-2016 is associated with the increase in cases with prenatal microcephaly and Guillain-Barré syndrome, and has sparked attention throughout the world. Genome sequence alignment and the analysis of Asian and African lineage isolates indicate that amino acid changes, particular in positively charged amino acid substitutions in the pr region of prM protein might involve a phenotypic change that links with the global outbreak of ZIKV Asian-lineage. The study generated and characterized the virological properties of wild type and mutants of single-round infectious particles (SRIPs) and infectious clones (i.c.s) of ZIKV Asian-lineage Natal RGN strain, and then identified the function of amino acid substitutions at the positions 139 [Asn139→Ser139 (N139S)] and 143 [Glu143→Lys143 (E143K)] in ZIKV polyproteins (located within the pr region of prM protein) in the infectivity and cytopathogenicity. The E143K SRIP and i.c. of Natal RGN strain exhibited relatively higher levels of cytopathic effect, EGFP reporter, viral RNA and protein synthesis, and virus yield in three types of human cell lines, TE617, SF268 and HMC3, compared to wild type (WT), N139S SRIPs and i.c.s, which displayed more efficiency in replication kinetics. Additionally, E143K Natal RGN i.c. had greater activities of virus attachment and entry, yielded higher titers of intracellular and extracellular virions, and assembled the E proteins near to the plasma membrane in infected cells than the other i.c.s. The results indicate that the positively charged amino acid residue Lys143, a conserved residue in the pr region of prM of ZIKV African lineages, plays a crucial role in viral replication kinetics, including viral attachment, entry, assembly and egress. Thus, the negatively charged amino acid residue Glu143 within the pr region of prM leads to an alteration of the phenotypes, in particular, a lower replication efficiency of ZIKV Asian-lineage isolates with the attenuation of infectivity and cytopathicity.

Apoptosis during ZIKA Virus Infection: Too Soon or Too Late?

Cell death by apoptosis is a major cellular response in the control of tissue homeostasis and as a defense mechanism in the case of cellular aggression such as an infection. Cell self-destruction is part of antiviral responses, aimed at limiting the spread of a virus. Although it may contribute to the deleterious effects in infectious pathology, apoptosis remains a key mechanism for viral clearance and the resolution of infection. The control mechanisms of cell death processes by viruses have been extensively studied. Apoptosis can be triggered by different viral determinants through different pathways as a result of virally induced cell stresses and innate immune responses. Zika virus (ZIKV) induces Zika disease in humans, which has caused severe neurological forms, birth defects, and microcephaly in newborns during the last epidemics. ZIKV also surprised by revealing an ability to persist in the genital tract and in semen, thus being sexually transmitted. Mechanisms of diverting antiviral responses such as the interferon response, the role of cytopathic effects and apoptosis in the etiology of the disease have been widely studied and debated. In this review, we examined the interplay between ZIKV infection of different cell types and apoptosis and how the virus deals with this cellular response. We illustrate a duality in the effects of ZIKV-controlled apoptosis, depending on whether it occurs too early or too late, respectively, in neuropathogenesis, or in long-term viral persistence. We further discuss a prospective role for apoptosis in ZIKV-related therapies, and the use of ZIKV as an oncolytic agent.

Host cytoskeletal vimentin serves as a structural organizer and an RNA-binding protein regulator to facilitate Zika viral replication.

Emerging microbe infections, such as Zika virus (ZIKV), pose an increasing threat to human health. Investigations on ZIKV replication have revealed the construction of replication complexes (RCs), but the role of cytoskeleton in this process is largely unknown. Here, we investigated the function of cytoskeletal intermediate filament protein vimentin in the life cycle of ZIKV infection. Using advanced imaging techniques, we uncovered that vimentin filaments undergo drastic reorganization upon viral protein synthesis to form a perinuclear cage-like structure that embraces and concentrates RCs. Genetic removal of vimentin markedly disrupted the integrity of RCs and resulted in fragmented subcellular dispersion of viral proteins. This led to reduced viral genome replication, viral protein production, and release of infectious virions, without interrupting viral binding and entry. Furthermore, mass spectrometry and RNA-sequencing screens identified interactions and interplay between vimentin and hundreds of endoplasmic reticulum (ER)-resident RNA-binding proteins. Among them, the cytoplasmic-region of ribosome receptor binding protein 1, an ER transmembrane protein that directly binds viral RNA, interacted with and was regulated by vimentin, resulting in modulation of ZIKV replication. Together, the data in our work reveal a dual role for vimentin as a structural element for RC integrity and as an RNA-binding-regulating hub during ZIKV infection, thus unveiling a layer of interplay between Zika virus and host cell.

Novel Epidemic Metrics to Communicate Outbreak Risk at the Municipality Level: Dengue and Zika in the Dominican Republic.

Arboviruses remain a significant cause of morbidity, mortality and economic cost across the global human population. Epidemics of arboviral disease, such as Zika and dengue, also cause significant disruption to health services at local and national levels. This study examined 2014-2016 Zika and dengue epidemic data at the sub-national level to characterise transmission across the Dominican Republic. For each municipality, spatio-temporal mapping was used to characterise disease burden, while data were age and sex standardised to quantify burden distributions among the population. In separate analyses, time-ordered data were combined with the underlying disease migration interval distribution to produce a network of likely transmission chain events, displayed using transmission chain likelihood matrices. Finally, municipal-specific reproduction numbers (Rm) were established using a Wallinga-Teunis matrix. Dengue and Zika epidemics peaked during weeks 39-52 of 2015 and weeks 14-27 of 2016, respectively. At the provincial level, dengue attack rates were high in Hermanas Mirabal and San José de Ocoa (58.1 and 49.2 cases per 10,000 population, respectively), compared with the Zika burden, which was highest in Independencia and San José de Ocoa (21.2 and 13.4 cases per 10,000 population, respectively). Across municipalities, high disease burden was observed in Cotuí (622 dengue cases per 10,000 population) and Jimani (32 Zika cases per 10,000 population). Municipal infector-infectee transmission likelihood matrices identified seven 0% likelihood transmission events throughout the dengue epidemic and two 0% likelihood transmission events during the Zika epidemic. Municipality reproduction numbers (Rm) were consistently higher, and persisted for a greater duration, during the Zika epidemic (Rm = 1.0) than during the dengue epidemic (Rm < 1.0). This research highlights the importance of disease surveillance in land border municipalities as an early warning for infectious disease transmission. It also demonstrates that a high number of importation events are required to sustain transmission in endemic settings, and vice versa for newly emerged diseases. The inception of a novel epidemiological metric, Rm, reports transmission risk using standardised spatial units, and can be used to identify high transmission risk municipalities to better focus public health interventions for dengue, Zika and other infectious diseases.

Gain-of-function genetic screening identifies the antiviral function of TMEM120A via STING activation.

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.

Zika Virus Infection in the Ovary Induces a Continuously Elevated Progesterone Level and Compromises Conception in Interferon Alpha/Beta Receptor-Deficient Mice.

Zika virus (ZIKV) belongs to mosquito-borne flaviviruses. Unlike other members in the family, ZIKV can be sexually transmitted, and the female genital tracts are susceptible to ZIKV. However, the impact of ZIKV infection on nonpregnant female reproductive health is not understood. In this study, we investigated the effects of ZIKV infection on the ovary by using nonpregnant female interferon α/ß receptor-deficient (Ifnar1-/-) mice. The results showed that the ovary supported ZIKV replication, and the granulosa and theca cells of antral follicles were susceptible. ZIKV replication in situ significantly reduced the numbers of antral follicles, aggravated follicular atresia, and disrupted folliculogenesis. Notably, ZIKV replication in the ovary caused disordered ovarian steroidogenesis manifested by decreased expression of key enzymes linked to sex hormone synthesis, including the cytochrome P450 17A1 (CYP17A1) and aromatase (CYP19A1). Further, we observed that ZIKV infection disrupted the estrous cycle and thus prolonged the time to conceive. More importantly, although ZIKV RNA could not be detected at 3 months postinfection, damaged ovarian structure and dysfunction were also observed. Taken together, our study demonstrates that ZIKV infection in nonpregnant female mice cause ovarian damage and dysfunction, even long after ZIKV clearance. These data provide important information to understand the effects of ZIKV infection in female reproductive tissues and basic evidence for further studies. IMPORTANCE Zika virus (ZIKV), a flavivirus, is primarily transmitted by mosquito bites. But it can also be transmitted vertically and sexually. Although ZIKV-associated Guillain-Barré syndrome and microcephaly have drawn great attention, there have been few studies on the potential effects of ZIKV on the genital tract of nonpregnant females. This study investigated the effects of ZIKV on the ovaries in mice. We found that ZIKV replicated in the ovary and the granulosa and theca cells of antral follicles were susceptible. ZIKV replication in situ significantly damaged ovarian structure and function and disrupted folliculogenesis. Notably, ZIKV infection further disrupted the estrous cycle and prolonged the time to conceive in mice by causing disordered ovarian steroidogenesis. These effects were observed in both the acute phase and the recovery phase after viral elimination. Overall, the new findings provide important additions to make out the potential adverse impacts of ZIKV on reproductive health in females.