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1.
Proc Natl Acad Sci U S A ; 119(8)2022 02 22.
Artigo em Inglês | MEDLINE | ID: mdl-35193960

RESUMO

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.


Assuntos
Vimentina/metabolismo , Infecção por Zika virus/metabolismo , Animais , Linhagem Celular , China , Citoesqueleto/metabolismo , Retículo Endoplasmático/metabolismo , Interações entre Hospedeiro e Microrganismos/fisiologia , Humanos , Filamentos Intermediários/metabolismo , RNA Viral/metabolismo , Proteínas de Ligação a RNA/metabolismo , Vimentina/fisiologia , Proteínas Virais/metabolismo , Replicação Viral/fisiologia , Zika virus/metabolismo , Zika virus/patogenicidade , Zika virus/fisiologia , Infecção por Zika virus/virologia
2.
Int J Mol Sci ; 23(3)2022 Jan 24.
Artigo em Inglês | MEDLINE | ID: mdl-35163212

RESUMO

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.


Assuntos
Apoptose/fisiologia , Infecção por Zika virus/metabolismo , Zika virus/fisiologia , Animais , Antivirais/uso terapêutico , Morte Celular/fisiologia , Interações Hospedeiro-Patógeno/imunologia , Humanos , Imunidade Inata/imunologia , Interferons/uso terapêutico , Microcefalia/virologia , Fenômenos Fisiológicos Virais/imunologia , Replicação Viral/fisiologia , Zika virus/genética , Zika virus/patogenicidade , Infecção por Zika virus/virologia
3.
Nat Commun ; 13(1): 105, 2022 01 10.
Artigo em Inglês | MEDLINE | ID: mdl-35013224

RESUMO

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.


Assuntos
Interações Hospedeiro-Patógeno/genética , Canais Iônicos/genética , Proteínas de Membrana/genética , Infecção por Zika virus/genética , Zika virus/genética , Animais , Proteínas Reguladoras de Apoptose/genética , Proteínas Reguladoras de Apoptose/imunologia , Linhagem Celular Tumoral , Retículo Endoplasmático/genética , Retículo Endoplasmático/imunologia , Retículo Endoplasmático/virologia , Feminino , Regulação da Expressão Gênica , Complexo de Golgi/genética , Complexo de Golgi/imunologia , Complexo de Golgi/virologia , Hepatócitos/imunologia , Hepatócitos/virologia , Interações Hospedeiro-Patógeno/imunologia , Humanos , Fator Regulador 3 de Interferon/genética , Fator Regulador 3 de Interferon/imunologia , Interferon beta/genética , Interferon beta/imunologia , Interleucina-6/genética , Interleucina-6/imunologia , Canais Iônicos/deficiência , Canais Iônicos/imunologia , Proteínas de Membrana/imunologia , Camundongos , Camundongos Knockout , Fosforilação , Isoformas de Proteínas/genética , Isoformas de Proteínas/imunologia , /imunologia , Proteínas de Ligação a RNA/genética , Proteínas de Ligação a RNA/imunologia , Transdução de Sinais , Proteínas não Estruturais Virais/genética , Proteínas não Estruturais Virais/imunologia , Zika virus/crescimento & desenvolvimento , Zika virus/patogenicidade , Infecção por Zika virus/imunologia , Infecção por Zika virus/virologia
4.
Viruses ; 14(1)2022 01 17.
Artigo em Inglês | MEDLINE | ID: mdl-35062366

RESUMO

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.


Assuntos
Dengue/epidemiologia , Epidemias/estatística & dados numéricos , Saúde Pública/métodos , Infecção por Zika virus/epidemiologia , Cidades/estatística & dados numéricos , Conjuntos de Dados como Assunto , Dengue/prevenção & controle , Vírus da Dengue/patogenicidade , República Dominicana/epidemiologia , Epidemias/prevenção & controle , Humanos , Modelos Estatísticos , Zika virus/patogenicidade , Infecção por Zika virus/prevenção & controle
5.
J Virol ; 96(2): e0118921, 2022 01 26.
Artigo em Inglês | MEDLINE | ID: mdl-34730391

RESUMO

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.


Assuntos
Fertilização , Ovário/virologia , Progesterona/sangue , Zika virus/patogenicidade , Animais , Modelos Animais de Doenças , Ciclo Estral , Feminino , Atresia Folicular , Camundongos , Ovário/patologia , Ovário/fisiopatologia , Receptor de Interferon alfa e beta/deficiência , Especificidade da Espécie , Replicação Viral , Zika virus/fisiologia , Infecção por Zika virus/sangue , Infecção por Zika virus/virologia
6.
Biochim Biophys Acta Biomembr ; 1864(1): 183804, 2022 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-34656553

RESUMO

Protein-lipid interactions modulate a plethora of physiopathologic processes and have been the subject of countless studies. However, these kinds of interactions in the context of viral envelopes have remained relatively unexplored, partially because the intrinsically small dimensions of the molecular systems escape to the current resolution of experimental techniques. However, coarse-grained and multiscale simulations may fill that niche, providing nearly atomistic resolution at an affordable computational price. Here we use multiscale simulations to characterize the lipid-protein interactions in the envelope of the Zika Virus, a prominent member of the Flavivirus genus. Comparisons between the viral envelope and simpler molecular systems indicate that the viral membrane is under extreme pressures and asymmetric forces. Furthermore, the dense net of protein-protein contacts established by the envelope proteins creates poorly solvated regions that destabilize the external leaflet leading to a decoupled dynamics between both membrane layers. These findings lead to the idea that the Flaviviral membrane may store a significant amount of elastic energy, playing an active role in the membrane fusion process.


Assuntos
Fusão de Membrana/genética , Lipídeos de Membrana/genética , Fagocitose/genética , Zika virus/genética , Membrana Celular/genética , Membrana Celular/metabolismo , Humanos , Lipídeos de Membrana/metabolismo , Vírion/genética , Vírion/patogenicidade , Zika virus/patogenicidade , Infecção por Zika virus/genética , Infecção por Zika virus/virologia
7.
Biochim Biophys Acta Mol Basis Dis ; 1868(1): 166270, 2022 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-34582966

RESUMO

Zika virus (ZIKV) infection has caused severe unexpected clinical outcomes in neonates and adults during the recent outbreak in Latin America, particularly in Brazil. Congenital malformations associated with ZIKV have been frequently reported; nevertheless, the mechanism of vertical transmission and the involvement of placental cells remains unclear. In this study, we applied quantitative proteomics analysis in a floating explant model of chorionic villi of human placental tissues incubated with ZIKV and with ZIKV pre-adsorbed with anti-ZIKV envelope protein. Proteomic data are available via ProteomeXchange with identifier PXD025764. Altered levels of proteins were involved in cell proliferation, apoptosis, inflammatory processes, and the integrin-cytoskeleton complex. Antibody-opsonized ZIKV particles differentially modulated the pattern of protein expression in placental cells; this phenomenon may play a pivotal role in determining the course of infection and the role of mixed infections. The expression of specific proteins was also evaluated by immunoperoxidase assays. These data fill gaps in our understanding of early events after ZIKV placental exposure and help identify infection control targets.


Assuntos
Placenta/metabolismo , Proteínas do Envelope Viral/genética , Infecção por Zika virus/genética , Zika virus/genética , Adulto , Apoptose/genética , Brasil/epidemiologia , Anormalidades Congênitas/epidemiologia , Anormalidades Congênitas/genética , Anormalidades Congênitas/virologia , Feminino , Humanos , Recém-Nascido , Transmissão Vertical de Doenças Infecciosas/prevenção & controle , Placenta/patologia , Placenta/virologia , Gravidez , Proteômica , Zika virus/patogenicidade , Infecção por Zika virus/epidemiologia , Infecção por Zika virus/transmissão , Infecção por Zika virus/virologia
8.
Proc Natl Acad Sci U S A ; 118(49)2021 12 07.
Artigo em Inglês | MEDLINE | ID: mdl-34873063

RESUMO

Flaviviruses such as Zika virus and West Nile virus have the potential to cause severe neuropathology if they invade the central nervous system. The type I interferon response is well characterized as contributing to control of flavivirus-induced neuropathogenesis. However, the interferon-stimulated gene (ISG) effectors that confer these neuroprotective effects are less well studied. Here, we used an ISG expression screen to identify Shiftless (SHFL, C19orf66) as a potent inhibitor of diverse positive-stranded RNA viruses, including multiple members of the Flaviviridae (Zika, West Nile, dengue, yellow fever, and hepatitis C viruses). In cultured cells, SHFL functions as a viral RNA-binding protein that inhibits viral replication at a step after primary translation of the incoming genome. The murine ortholog, Shfl, is expressed constitutively in multiple tissues, including the central nervous system. In a mouse model of Zika virus infection, Shfl -/- knockout mice exhibit reduced survival, exacerbated neuropathological outcomes, and increased viral replication in the brain and spinal cord. These studies demonstrate that Shfl is an important antiviral effector that contributes to host protection from Zika virus infection and virus-induced neuropathological disease.


Assuntos
Proteínas de Ligação a RNA/metabolismo , Infecção por Zika virus/patologia , Zika virus/metabolismo , Animais , Linhagem Celular , Efeito Citopatogênico Viral , Modelos Animais de Doenças , Suscetibilidade a Doenças/metabolismo , Suscetibilidade a Doenças/virologia , Flavivirus/genética , Infecções por Flavivirus/genética , Infecções por Flavivirus/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fármacos Neuroprotetores/metabolismo , Proteínas de Ligação a RNA/genética , Replicação Viral/fisiologia , Zika virus/patogenicidade , Infecção por Zika virus/genética
9.
Viruses ; 13(12)2021 12 06.
Artigo em Inglês | MEDLINE | ID: mdl-34960717

RESUMO

The evasion of the Interferon response has important implications in Zika virus (ZIKV) disease. Mutations in ZIKV viral protein NS4B, associated with modulation of the interferon (IFN) system, have been linked to increased pathogenicity in animal models. In this study, we unravel ZIKV NS4B as antagonist of the IFN signaling cascade. Firstly, we reported the genomic characterization of NS4B isolated from a strain of the 2016 outbreak, ZIKV Brazil/2016/INMI1, and we predicted its membrane topology. Secondly, we analyzed its phylogenetic correlation with other flaviviruses, finding a high similarity with dengue virus 2 (DEN2) strains; in particular, the highest conservation was found when NS4B was aligned with the IFN inhibitory domain of DEN2 NS4B. Hence, we asked whether ZIKV NS4B was also able to inhibit the IFN signaling cascade, as reported for DEN2 NS4B. Our results showed that ZIKV NS4B was able to strongly inhibit the IFN stimulated response element and the IFN-γ-activated site transcription, blocking IFN-I/-II responses. mRNA expression levels of the IFN stimulated genes ISG15 and OAS1 were also strongly reduced in presence of NS4B. We found that the viral protein was acting by suppressing the STAT1 phosphorylation and consequently blocking the nuclear transport of both STAT1 and STAT2.


Assuntos
Interferon Tipo I/metabolismo , Interferon gama/metabolismo , Fator de Transcrição STAT1/metabolismo , Proteínas não Estruturais Virais/metabolismo , Infecção por Zika virus/virologia , Zika virus/metabolismo , 2',5'-Oligoadenilato Sintetase/genética , Transporte Ativo do Núcleo Celular , Sequência de Aminoácidos , Animais , Núcleo Celular/metabolismo , Chlorocebus aethiops , Citocinas/genética , Células HEK293 , Humanos , Interferon Tipo I/antagonistas & inibidores , Interferon Tipo I/imunologia , Interferon beta/biossíntese , Interferon gama/antagonistas & inibidores , Interferon gama/imunologia , Fosforilação , Filogenia , Conformação Proteica , Elementos de Resposta , Transdução de Sinais , Ubiquitinas/genética , Células Vero , Proteínas não Estruturais Virais/química , Proteínas não Estruturais Virais/genética , Zika virus/química , Zika virus/isolamento & purificação , Zika virus/patogenicidade
10.
Cells ; 10(11)2021 11 09.
Artigo em Inglês | MEDLINE | ID: mdl-34831310

RESUMO

Zika virus (ZIKV) infection during pregnancy can cause devastating fetal neuropathological abnormalities, including microcephaly. Most studies of ZIKV infection in pregnancy have focused on post-implantation stage embryos. Currently, we have limited knowledge about how a pre-implantation stage embryo deals with a viral infection. This study investigates ZIKV infection on mouse trophoblast stem cells (TSCs) and their in vitro differentiated TSCs (DTSCs), which resemble the cellular components of the trophectoderm layer of the blastocyst that later develops into the placenta. We demonstrate that TSCs and DTSCs are permissive to ZIKV infection; however, ZIKV propagated in TSCs and DTSCs exhibit substantially lower infectivity, as shown in vitro and in a mouse model compared to ZIKV that was generated in Vero cells or mouse embryonic fibroblasts (MEFs). We further show that the low infectivity of ZIKV propagated in TSCs and DTSCs is associated with a reduced level of glycosylation on the viral envelope (E) proteins, which are essential for ZIKV to establish initial attachment by binding to cell surface glycosaminoglycans (GAGs). The decreased level of glycosylation on ZIKV E is, at least, partially due to the low-level expression of a glycosylation-related gene, Hexa, in TSCs and DTSCs. Furthermore, this finding is not limited to ZIKV since similar observations have been made as to the chikungunya virus (CHIKV) and West Nile virus (WNV) propagated in TSCs and DTSCs. In conclusion, our results reveal a novel phenomenon suggesting that murine TSCs and their differentiated cells may have adapted a cellular glycosylation system that can limit viral infectivity by altering the glycosylation of viral envelope proteins, therefore serving as a unique, innate anti-viral mechanism in the pre-implantation stage embryo.


Assuntos
Diferenciação Celular , Células-Tronco/citologia , Trofoblastos/citologia , Proteínas do Envelope Viral/metabolismo , Zika virus/fisiologia , Animais , Vírus Chikungunya/fisiologia , Chlorocebus aethiops , Embrião de Mamíferos/citologia , Fibroblastos/metabolismo , Fibroblastos/virologia , Glicosilação , Camundongos Endogâmicos C57BL , Modelos Biológicos , Receptor de Interferon alfa e beta/deficiência , Receptor de Interferon alfa e beta/metabolismo , Células-Tronco/metabolismo , Células-Tronco/virologia , Trofoblastos/virologia , Células Vero , Vírus do Nilo Ocidental/fisiologia , Zika virus/patogenicidade
11.
Int J Mol Sci ; 22(21)2021 Oct 27.
Artigo em Inglês | MEDLINE | ID: mdl-34769038

RESUMO

Tetraspanins are transmembrane glycoproteins that have been shown increasing interest as host factors in infectious diseases. In particular, they were implicated in the pathogenesis of both non-enveloped (human papillomavirus (HPV)) and enveloped (human immunodeficiency virus (HIV), Zika, influenza A virus, (IAV), and coronavirus) viruses through multiple stages of infection, from the initial cell membrane attachment to the syncytium formation and viral particle release. However, the mechanisms by which different tetraspanins mediate their effects vary. This review aimed to compare and contrast the role of tetraspanins in the life cycles of HPV, HIV, Zika, IAV, and coronavirus viruses, which cause the most significant health and economic burdens to society. In doing so, a better understanding of the relative contribution of tetraspanins in virus infection will allow for a more targeted approach in the treatment of these diseases.


Assuntos
Interações Hospedeiro-Patógeno/fisiologia , Tetraspaninas/fisiologia , Viroses/metabolismo , Regulação Viral da Expressão Gênica , HIV-1/patogenicidade , Humanos , Vírus da Influenza A/patogenicidade , Papillomaviridae/patogenicidade , SARS-CoV-2/patogenicidade , Viroses/genética , Viroses/virologia , Internalização do Vírus , Zika virus/patogenicidade
12.
Viruses ; 13(10)2021 10 04.
Artigo em Inglês | MEDLINE | ID: mdl-34696422

RESUMO

Over the years, viral infections have caused severe illness in humans. Zika Virus (ZIKV) is a flavivirus transmitted by mosquito vectors that leads to notable neurological impairment, whose most dramatic impact is the Congenital ZIKV Syndrome (CZS). ZIKV targets neuronal precursor cells leading to apoptosis and further impairment of neuronal development, causing microcephaly, lissencephaly, ventriculomegaly, and calcifications. Several regulators of biological processes are involved in CZS development, and in this context, microRNAs (miRNAs) seem to have a fundamental role. miRNAs are important regulators of protein translation, as they form the RISC silencing complex and interact with complementary mRNA target sequences to further post-transcriptional repression. In this context, little is known about their participation in the pathogenesis of viral infections. In this review, we discuss how miRNAs could relate to ZIKV and other flavivirus infections.


Assuntos
MicroRNAs/genética , Infecção por Zika virus/genética , Infecção por Zika virus/patologia , Animais , Redes Reguladoras de Genes/genética , Humanos , Imunidade/genética , Imunidade/imunologia , MicroRNAs/metabolismo , Replicação Viral/genética , Zika virus/genética , Zika virus/patogenicidade , Zika virus/fisiologia , Infecção por Zika virus/virologia
13.
Viruses ; 13(10)2021 10 06.
Artigo em Inglês | MEDLINE | ID: mdl-34696437

RESUMO

The 2016 Zika virus (ZIKV) epidemic illustrates the impact of flaviviruses as emerging human pathogens. For unknown reasons, ZIKV replicates more efficiently in neural progenitor cells (NPCs) than in postmitotic neurons. Here, we identified host factors used by ZIKV using the NCI-60 library of cell lines and COMPARE analysis, and cross-analyzed this library with two other libraries of host factors with importance for ZIKV infection. We identified BAF45b, a subunit of the BAF (Brg1/Brm-associated factors) protein complexes that regulate differentiation of NPCs to post-mitotic neurons. ZIKV (and other flaviviruses) infected HAP1 cells deficient in expression of BAF45b and other BAF subunits less efficiently than wildtype (WT) HAP1 cells. We concluded that subunits of the BAF complex are important for infection of ZIKV and other flavivirus. Given their function in cell and tissue differentiation, such regulators may be important determinants of tropism and pathogenesis of arthropod-borne flaviviruses.


Assuntos
Proteínas de Ligação a DNA/metabolismo , Fatores de Transcrição/metabolismo , Infecção por Zika virus/metabolismo , Zika virus/metabolismo , Aedes/virologia , Animais , Linhagem Celular , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/fisiologia , Flavivirus , Haploidia , Interações entre Hospedeiro e Microrganismos/genética , Humanos , Fatores de Transcrição/genética , Fatores de Transcrição/fisiologia , Replicação Viral/fisiologia , Zika virus/patogenicidade , Infecção por Zika virus/virologia
14.
Viruses ; 13(10)2021 10 16.
Artigo em Inglês | MEDLINE | ID: mdl-34696518

RESUMO

Since the explosive outbreak of Zika virus in Brazil and South/Central America in 2015-2016, the frequency of infections has subsided, but Zika virus remains present in this region as well as other tropical and sub-tropical areas of the globe. The most alarming aspect of Zika virus infection is its association with severe birth defects when infection occurs in pregnant women. Understanding the mechanism of Zika virus pathogenesis, which comprises features unique to Zika virus as well as shared with other teratogenic pathogens, is key to future prophylactic or therapeutic interventions. Nonhuman primate-based research has played a significant role in advancing our knowledge of Zika virus pathogenesis, especially with regard to fetal infection. This review summarizes what we have learned from these models and potential future research directions.


Assuntos
Macaca/virologia , Infecção por Zika virus/metabolismo , Infecção por Zika virus/patologia , Animais , Brasil/epidemiologia , América Central/epidemiologia , Modelos Animais de Doenças , Surtos de Doenças , Feminino , Gravidez , Complicações Infecciosas na Gravidez/virologia , Zika virus/patogenicidade , Infecção por Zika virus/virologia
15.
Sci Rep ; 11(1): 19635, 2021 10 04.
Artigo em Inglês | MEDLINE | ID: mdl-34608212

RESUMO

Zika virus (ZIKV) is a mosquito-borne flavivirus that causes febrile illness. The recent spread of ZIKV from Asia to the Americas via the Pacific region has revealed unprecedented features of ZIKV, including transplacental congenital infection causing microcephaly. Amino acid changes have been hypothesized to underlie the spread and novel features of American ZIKV strains; however, the relationship between genetic changes and the epidemic remains controversial. A comparison of the characteristics of a Southeast Asian strain (NIID123) and an American strain (PRVABC59) revealed that the latter had a higher replication ability in cultured cells and higher virulence in mice. In this study, we aimed to identify the genetic region of ZIKV responsible for these different characteristics using reverse genetics. A chimeric NIID123 strain in which the E protein was replaced with that of PRVABC59 showed a lower growth ability than the recombinant wild-type strain. Adaptation of the chimeric NIID123 to Vero cells induced a Phe-to-Leu amino acid substitution at position 146 of the prM protein; PRVABC59 also has Leu at this position. Leu at this position was found to be responsible for the viral replication ability and partially, for the pathogenicity in mouse testes.


Assuntos
Substituição de Aminoácidos , Interações Hospedeiro-Patógeno , Mutação , Proteínas do Envelope Viral/genética , Infecção por Zika virus/virologia , Zika virus/genética , Animais , Chlorocebus aethiops , Modelos Animais de Doenças , Genoma Viral , Genômica/métodos , Camundongos , Células Vero , Virulência , Replicação Viral , Zika virus/patogenicidade , Infecção por Zika virus/patologia
16.
Viruses ; 13(9)2021 09 11.
Artigo em Inglês | MEDLINE | ID: mdl-34578389

RESUMO

Zika virus (ZIKV) infection during pregnancy causes a wide spectrum of congenital abnormalities and postnatal developmental sequelae such as fetal loss, intrauterine growth restriction (IUGR), microcephaly, or motor and neurodevelopmental disorders. Here, we investigated whether a mouse pregnancy model recapitulated a wide range of symptoms after congenital ZIKV infection, and whether the embryonic age of congenital infection changed the fetal or postnatal outcomes. Infection with ZIKV strain PRVABC59 from embryonic day 6.5 (E6.5) to E8.5, corresponding to the mid-first trimester in humans, caused fetal death, fetal resorption, or severe IUGR, whereas infection from E9.5 to E14.5, corresponding to the late-first to second trimester in humans, caused stillbirth, neonatal death, microcephaly, and postnatal growth deficiency. Furthermore, 4-week-old offspring born to dams infected at E12.5 showed abnormalities in neuropsychiatric state, motor behavior, autonomic function, or reflex and sensory function. Thus, our model recapitulated the multiple symptoms seen in human cases, and the embryonic age of congenital infection was one of the determinant factors of offspring outcomes in mice. Furthermore, maternal neutralizing antibodies protected the offspring from neonatal death after congenital infection at E9.5, suggesting that neonatal death in our model could serve as criteria for screening of vaccine candidates.


Assuntos
Feto/virologia , Microcefalia/virologia , Malformações do Sistema Nervoso/virologia , Infecção por Zika virus/congênito , Zika virus/patogenicidade , Animais , Modelos Animais de Doenças , Embrião de Mamíferos/virologia , Feminino , Camundongos , Camundongos Endogâmicos C57BL , Gravidez
17.
Parasit Vectors ; 14(1): 504, 2021 Sep 27.
Artigo em Inglês | MEDLINE | ID: mdl-34579782

RESUMO

BACKGROUND: Zika virus (ZIKV) is transmitted to humans primarily by Aedes aegypti. Previous studies on Ae. aegypti from Jiegao (JG) and Mengding (MD) in Yunnan province, China have shown that these mosquitoes are able to transmit ZIKV to their offspring through vertical transmission, indicating that these two Ae. aegypti strains pose a potential risk for ZIKV transmission. However, the vector competence of these two Ae. aegypti strains to ZIKV has not been evaluated and the molecular mechanisms influencing vector competence are still unclear. METHODS: Aedes aegypti mosquitoes from JG and MD were orally infected with ZIKV, and the infection rate (IR), dissemination rate (DR), transmission rate (TR) and transmission efficiency (TE) of these two mosquito strains were explored to evaluate their vector competence to ZIKV. On 2, 4 and 6 days post-infection (dpi), the small RNA profiles between ZIKV-infected and non-infected Ae. aegypti midgut and salivary gland tissues were compared to gain insights into the molecular interactions between ZIKV and Ae. aegypti. RESULTS: There were no significant differences in the IR, DR, TR and TE between the two Ae. aegypti strains (P > 0.05). However, ZIKV RNA appeared 2 days earlier in saliva of the JG strain, which indicated a higher competence of the JG strain to transmit ZIKV. Significant differences in the microRNA (miRNA) expression profiles between ZIKV-infected and non-infected Ae. aegypti were found in the 2-dpi libraries of both the midgut and salivary gland tissues from the two strains. In addition, 27 and 74 miRNAs (|log2 fold change| > 2) were selected from the miRNA expression profiles of ZIKV-infected and non-infected midgut and salivary gland tissues from the JG and MD strains, respectively. CONCLUSIONS: Our results provide novel insights into the ZIKV-mosquito interactions and build a foundation for future research on how miRNAs regulate the vector competence of mosquitoes to this arbovirus.


Assuntos
Aedes/genética , Aedes/virologia , Interações entre Hospedeiro e Microrganismos/genética , MicroRNAs/genética , Mosquitos Vetores/genética , Mosquitos Vetores/virologia , Infecção por Zika virus/transmissão , Zika virus/genética , Aedes/classificação , Animais , Vetores de Doenças , Feminino , Mosquitos Vetores/classificação , Glândulas Salivares/virologia , Carga Viral , Zika virus/patogenicidade , Infecção por Zika virus/virologia
18.
Biochim Biophys Acta Mol Basis Dis ; 1867(12): 166264, 2021 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-34481867

RESUMO

The molecular evolution of life on earth along with changing environmental, conditions has rendered mankind susceptible to endemic and pandemic emerging infectious diseases. The effects of certain systemic viral and bacterial infections on morbidity and mortality are considered as examples of recent emerging infections. Here we will focus on three examples of infections that are important in pregnancy and early childhood: SARS-CoV-2 virus, Zika virus, and Mycoplasma species. The basic structural characteristics of these infectious agents will be examined, along with their general pathogenic mechanisms. Coronavirus infections, such as caused by the SARS-CoV-2 virus, likely evolved from zoonotic bat viruses to infect humans and cause a pandemic that has been the biggest challenge for humanity since the Spanish Flu pandemic of the early 20th century. In contrast, Zika Virus infections represent an expanding infectious threat in the context of global climate change. The relationship of these infections to pregnancy, the vertical transmission and neurological sequels make these viruses highly relevant to the topics of this special issue. Finally, mycoplasmal infections have been present before mankind evolved, but they were rarely identified as human pathogens until recently, and they are now recognized as important coinfections that are able to modify the course and prognosis of various infectious diseases and other chronic illnesses. The infectious processes caused by these intracellular microorganisms are examined as well as some general aspects of their pathogeneses, clinical presentations, and diagnoses. We will finally consider examples of treatments that have been used to reduce morbidity and mortality of these infections and discuss briefly the current status of vaccines, in particular, against the SARS-CoV-2 virus. It is important to understand some of the basic features of these emerging infectious diseases and the pathogens involved in order to better appreciate the contributions of this special issue on how infectious diseases can affect human pregnancy, fetuses and neonates.


Assuntos
Infecções Bacterianas/prevenção & controle , Doenças Transmissíveis/transmissão , Viroses/prevenção & controle , Infecções Bacterianas/história , Infecções Bacterianas/transmissão , COVID-19/metabolismo , COVID-19/prevenção & controle , Doenças Transmissíveis/virologia , Feminino , História do Século XIX , História do Século XX , História do Século XXI , Humanos , Recém-Nascido , Transmissão Vertical de Doenças Infecciosas/história , Mycoplasma/patogenicidade , Infecções por Mycoplasma/metabolismo , Infecções por Mycoplasma/prevenção & controle , Gravidez , Gestantes , SARS-CoV-2/patogenicidade , Viroses/história , Viroses/transmissão , Zika virus/patogenicidade , Infecção por Zika virus/metabolismo , Infecção por Zika virus/prevenção & controle
19.
J Virol ; 95(22): e0097721, 2021 10 27.
Artigo em Inglês | MEDLINE | ID: mdl-34468175

RESUMO

Here, we examine in silico the infection dynamics and interactions of two Zika virus (ZIKV) genomes: one is the full-length ZIKV genome (wild type [WT]), and the other is one of the naturally occurring defective viral genomes (DVGs), which can replicate in the presence of the WT genome, appears under high-MOI (multiplicity of infection) passaging conditions, and carries a deletion encompassing part of the structural and NS1 protein-coding region. Ordinary differential equations (ODEs) were used to simulate the infection of cells by virus particles and the intracellular replication of the WT and DVG genomes that produce these particles. For each virus passage in Vero and C6/36 cell cultures, the rates of the simulated processes were fitted to two types of observations: virus titer data and the assembled haplotypes of the replicate passage samples. We studied the consistency of the model with the experimental data across all passages of infection in each cell type separately as well as the sensitivity of the model's parameters. We also determined which simulated processes of virus evolution are the most important for the adaptation of the WT and DVG interplay in these two disparate cell culture environments. Our results demonstrate that in the majority of passages, the rates of DVG production are higher inC6/36 cells than in Vero cells, which might result in tolerance and therefore drive the persistence of the mosquito vector in the context of ZIKV infection. Additionally, the model simulations showed a slower accumulation of infected cells under higher activation of the DVG-associated processes, which indicates a potential role of DVGs in virus attenuation. IMPORTANCE One of the ideas for lessening Zika pathogenicity is the addition of its natural or engineered defective virus genomes (DVGs) (have no pathogenicity) to the infection pool: a DVG is redirecting the wild-type (WT)-associated virus development resources toward its own maturation. The mathematical model presented here, attuned to the data from interplays between WT Zika viruses and their natural DVGs in mammalian and mosquito cells, provides evidence that the loss of uninfected cells is attenuated by the DVG development processes. This model enabled us to estimate the rates of virus development processes in the WT/DVG interplay, determine the key processes, and show that the key processes are faster in mosquito cells than in mammalian ones. In general, the presented model and its detailed study suggest in what important virus development processes the therapeutically efficient DVG might compete with the WT; this may help in assembling engineered DVGs for ZIKV and other flaviviruses.


Assuntos
Vírus Defeituosos , Interações entre Hospedeiro e Microrganismos , Infecção por Zika virus/virologia , Zika virus , Aedes , Animais , Chlorocebus aethiops , Vírus Defeituosos/crescimento & desenvolvimento , Vírus Defeituosos/patogenicidade , Células Vero , Replicação Viral , Zika virus/crescimento & desenvolvimento , Zika virus/patogenicidade
20.
PLoS One ; 16(9): e0256444, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34525107

RESUMO

OBJECTIVE: To describe the neurological and neurodevelopmental outcomes of children with Congenital Zika Syndrome (CZS) associated microcephaly beyond 2 years of age. METHOD: We followed children with CZS-associated microcephaly in an outpatient clinic in Salvador, Brazil. Neurological and neurodevelopmental assessments were performed using the Hammersmith Infant Neurological Examination (HINE) and Bayley Scales of Infant and Toddler Neurodevelopment (Bayley-III) respectively. RESULTS: Of the 42 children included, 19 were male (45.2%); median (interquartile range) age at neurological evaluation was 28 (25-32) months, and 36 (85.7%) had severe microcephaly. HINE and Bayley-III results were completed for 35/42 (83.3%) and 33/42 (78.5%) children respectively. Bayley-III identified a severe developmental delay in 32/33 (97.0%) children while 1/33 (3.0%) had only a mild delay. In the multivariable analysis, we found that Bayley-III and HINE scores were correlated. Better HINE scores were associated with higher Bayley-III cognitive raw scores (ß = 0.29; CI 95% = 0.02-0.57) and motor raw scores (ß = 0.43; CI 95% = 0.04-0.82) after adjusting for head circumference, prematurity, and age at neurodevelopmental evaluation. Furthermore, we found that greater head circumference at follow up was associated with higher cognitive (ß = 1.27; CI 95% = 0.01-2.53) and motor raw scores (ß = 2.03; CI 95% = 0.25-3.81). CONCLUSION: Children with CZS-associated microcephaly demonstrate severe neurodevelopmental delays and slower growth rates than their peers over time. Still, they have remarkably heterogeneous neurodevelopmental profiles according to neurological exam scores which correlate with their long-term outcomes. We found that HINE scores effectively captured the heterogeneity of neurological capabilities among these children and could be predictive of cognitive and motor development progress.


Assuntos
Deficiências do Desenvolvimento/diagnóstico , Microcefalia/diagnóstico , Microcefalia/epidemiologia , Infecção por Zika virus/diagnóstico , Brasil/epidemiologia , Cefalometria , Pré-Escolar , Deficiências do Desenvolvimento/fisiopatologia , Deficiências do Desenvolvimento/virologia , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Microcefalia/etiologia , Microcefalia/virologia , Exame Neurológico , Gravidez , Complicações Infecciosas na Gravidez/diagnóstico , Complicações Infecciosas na Gravidez/epidemiologia , Complicações Infecciosas na Gravidez/fisiopatologia , Complicações Infecciosas na Gravidez/virologia , Zika virus/patogenicidade , Infecção por Zika virus/complicações , Infecção por Zika virus/virologia
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